Oxford Handbook of Practical Drug Therapy (2 edn)
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Antibacterial drugs
Penicillins BNF 5.1.1 374
Carbapenems BNF 5.1.2 378
Cephalosporins and cephamycins BNF 5.1.2 380
Glycopeptide antibiotics BNF 5.1.7 384
Tetracyclines BNF 5.1.3 and 13.6.2 388
Aminoglycoside antibiotics BNF 5.1.4 394
Macrolide antibiotics BNF 5.1.5 398
Sulfonamides and trimethoprim (including co-trimoxazole) BNF 5.1.8 and 13.10.1.1 404
Metronidazole and tinidazole BNF 5.1.11 410
Quinolone antibiotics BNF 5.1.12 414
Antituberculosis drugs
Antituberculosis drugs BNF 5.1.9 418
Antimalarial drugs
Antimalarial drugs BNF 5.4.1 444
Antibacterial drugs: Penicillins BNF 5.1.1
Beta-lactam antibiotics
Penicillinase (β-lactamase)-sensitive penicillins
Benzylpenicillin (penicillin G, parenteral)
Penicillin V (phenoxymethyl penicillin, oral)
Penicillinase-resistant penicillins
Flucloxacillin
Broad-spectrum penicillins
Ampicillin
Amoxicillin
Co-amoxiclav (amoxicillin plus clavulanic acid; Augmentin®)
Antipseudomonal penicillins
Piperacillin (with tazobactam; Tazocin®)
Ticarcillin (plus clavulanic acid)
These are inhibitors of β-lactamase. Compound formulations with a penicillin can overcome β-lactamase-mediated resistance.
However, not all resistance is β-lactam-mediated. For example, penicillin-resistant pneumococci and gonococci have other resistance mechanisms.
Potential uses
Widely-used antibiotics with good penetration of body tissues and fluids.
Relatively poor penetration of the CSF, unless the meninges are inflamed (e.g. meningococcal meningitis).
Flucloxacillin is given for infections due to staphylococci, as most produce beta-lactamase.
Commonly used for the treatment of endocarditis and cellulitis.
The broad-spectrum penicillins cover Gram-positive bacteria (e.g. enterococci) and some Gram-negative bacteria, but are susceptible to beta-lactamase.
Commonly used for respiratory tract and urinary tract infections.
Resistance to these drugs is common amongst staphylococci and Escherichia coli.
Co-amoxiclav has better coverage of these resistant bacteria.
The antipseudomonal penicillins (carboxypenicillins) should be reserved for the treatment of infections due to Pseudomonas aeruginosa.
They may be used in combination with an aminoglycoside antibiotic, as they have synergistic actions.
Commonly used for the treatment of neutropenic sepsis and endocarditis.
Contraindications and cautions
Allergy to penicillin is common (around 3% of patients).
Always ask about a history of allergy when prescribing an antibiotic; take a complete history if the patient says that they are allergic—sometimes they are not allergic when they think they are.
Those with a history of true allergy to penicillin should not be given any beta-lactam antibiotic, including cephalosporins, carbapenems, and co-amoxiclav.
A non-confluent rash affecting only a small area or occurring >72 hours after starting the penicillin does not usually represent an allergic reaction; cephalosporins and carbapenems are not subsequently contraindicated.
The ampicillin rash is not evidence of allergy but can be hard to distinguish from true allergy; it is a maculopapular rash on the legs and can spread to the buttocks, trunk, and arms, occurring 10–14 days after the start of therapy; type III allergy to penicillins can cause a similar rash after 7–10 days.
Penicillins accumulate in renal insufficiency. High dosages can cause cerebral irritation.
Antibiotic solutions for intravenous injection contain large amounts of electrolytes (Na+ and K+); these will also accumulate in renal insufficiency.
Avoid intrathecal injection of penicillins.
Penicillins are not known to be harmful in pregnancy, but avoid clavulanic acid, unless it is essential.
How to use
Always consider the likely causative organisms when treating infection empirically.
Avoid using a broad-spectrum drug when one with a narrow spectrum will cover the causative organism.
Using a broad-spectrum antibiotic increases the risk of antibiotic-associated diarrhoea (see 
Cephalosporins, p. 383 ).
MRSA commonly causes hospital-acquired infection and is increasingly common in the community as well.
It is resistant to all beta-lactams, including flucloxacillin.
Consider MRSA as a causative organism if a patient becomes unwell in hospital or does not respond to conventional treatment.
To avoid infection of other patients, discuss appropriate eradication and treatment regimens and precautions with your microbiology and infection control teams.
Most common and most serious adverse effects
Hypersensitivity is relatively common. An urticarial rash occurs in about 3% of patients. Anaphylactic reactions are much less common (0.05% or less).
A significant number of patients develop a rash that is not directly due to the penicillin. This may be due to the disease or a viral infection (e.g. Epstein–Barr virus).
Penicillins can cause cerebral irritation and convulsions. The use of high dosages in patients with renal insufficiency increases the risk.
Eradication of the patient’s normal flora can cause:
Superinfection by Candida in the oropharynx; this is most common in the elderly and debilitated.
Antibiotic-associated diarrhoea; avoid broad-spectrum drugs unless essential.
Penicillins commonly cause diarrhoea by different mechanisms (see Cephalosporins, p. 383 ).
Penicillins can cause cholestatic jaundice. The risk is greatest with flucloxacillin and formulations containing clavulanic acid.
Elderly patients and those treated for >2 weeks are at greatest risk.
The jaundice can appear several weeks after the drug has been stopped.
Rare adverse effects include:
Coombs’-positive haemolytic anaemia and thrombocytopenia.
interstitial nephritis.
hypernatraemia and hyperkalaemia in patients with renal insufficiency (see earlier notes).
IgE antibody-mediated reactions Reactive degradation products of the penicillin molecule combine with a protein carrier and act as haptens. The clinical spectrum that results ranges from a mild local reaction to anaphylactic shock.
Non-IgE antibody-mediated reactions Modification of erythrocyte surface components due to binding of beta-lactams or their metabolic products can cause the formation of antierythrocyte antibodies, resulting in a Coombs’-positive haemolytic anaemia.
Immediate hypersensitivity reactions to penicillins can be life threatening and will recur on subsequent exposure. All patients should be asked about a history of drug hypersensitivity and every drug chart should state clearly all known drug hypersensitivities (commonly referred to as ‘drug allergy’). If there are none then the chart should state ‘no known medicine allergy’. The UK’s National Patient Safety Agency (
www.npsa.nhs.uk) recommends that you ‘do not prescribe, dispense or administer medicines to patients if you do not know their medicine or allergy history and it has not been documented’.
Major drug-drug interactions
Diarrhoea due to a penicillin may reduce the effectiveness of the oral contraceptive owing to reduced absorption; warn the patient.
Penicillins reduce the excretion of some NSAIDs by reducing their tubular secretion.
Monitoring
Safety and efficacy
Measures of clinical improvement are the most important, but inflammatory markers, such as the ESR and CRP, are often helpful; remember that very occasionally penicillins cause fever.
Whenever possible, take cultures before staring antibiotic treatment. Check the sensitivities of the causative organism. Discuss any unusual results with a microbiologist.
Measure the patient’s renal function and liver function tests, especially if long-term treatment is required (>7 days).
Patient information
Warn the patient of the risk of a rash and other hypersensitivity phenomena.
Warn female patients that if they develop diarrhoea the oral contraceptive may be ineffective.
Prescribing information: Penicillins
There are many formulations of these drugs. The following are given as examples. Dosages and duration of treatment will depend on the indication. Check your local antibiotics policy.
Benzylpenicillin
By intramuscular injection or slow intravenous injection/infusion, usual dosage range 2.4–4.8 g daily in 4 divided doses.
Flucloxacillin
By mouth, 250–500 mg every 6 hours. Give at least 30 minutes before food.
By intramuscular injection, 250–500 mg every 6 hours.
By slow intravenous injection/infusion, 0.25–2.0 g every 6 hours.
Ampicillin
By mouth, 0.25–1.0 g every 6 hours. Give at least 30 minutes before food.
By intramuscular injection, 500 mg every 4–6 hours.
By slow intravenous injection/infusion, 500 mg every 4–6 hours.
Amoxicillin
By mouth, 250–500 mg every 8 hours.
By intramuscular injection, 500 mg every 8 hours.
By slow intravenous injection/infusion, 0.5–1.0 g every 8 hours.
Co-amoxiclav (Augmentin®)
By mouth, 250 mg amoxicillin and 125 mg clavulanic acid in a single tablet; 1 tablet 3 times daily.
Double the dose of amoxicillin (but not clavulanic acid) in severe infections.
Piperacillin (with tazobactam)
By slow intravenous injection/infusion, usually 4.5 g every 6–8 hours.
Antibacterial drugs: Carbapenems BNF 5.1.2
Beta-lactam antibiotics
Imipenem
Use in combination with cilastatin, which blocks the renal metabolism of imipenem, increasing its duration of action
Meropenem
Ertapenem
Doripenem
Aztreonam (a monobactam). Specialist use only. Gram-negative but not Gram-positive cover.
Potential uses
These drugs have a very broad spectrum of activity.
Aerobic and anaerobic, Gram-positive and Gram-negative organisms
The spectrum includes Pseudomonas spp.
They do not cover meticillin-resistant Staphylococcus aureus (MRSA).
Meropenem has slightly better Gram-negative activity.
Contraindications and cautions
Those with a history of allergy to penicillin should not be given any beta-lactam antibiotic, including cephalosporins, carbapenems, and co-amoxiclav. The incidence of cross-reaction is about 50% in those who have had a type I reaction, such as anaphylactic shock or urticaria.
A non-confluent rash affecting only a small area or occurring >72 hours after starting the penicillin does not usually represent an allergic reaction.
These drugs accumulate in renal insufficiency.
The dose of imipenem or meropenem should be reduced as follows:
mild insufficiency, reduce the frequency from every 8 hours to every 12 hours.
moderate insufficiency, halve the usual dose and give every 12 hours.
severe insufficiency, halve the usual dose and give every 24 hours.
Antibiotic solutions for intravenous injection contain a large amount of electrolytes (Na+ and K+); these will also accumulate in renal insufficiency
Avoid these drugs if the patient has epilepsy; the risk of fits is greater with imipenem.
These drugs are not known to be safe in pregnancy. There is some evidence of toxicity from imipenem in animals.
How to use
Always consider the likely causative organisms when treating infections empirically.
Avoid using a broad-spectrum drug when one with a narrow spectrum will cover the causative organism.
These drugs have a very broad spectrum, but they are not appropriate in most settings when the likely causative organisms are known.
Most hospitals restrict their use to places where infection by a wide range of resistant organisms is possible (e.g. on the ICU).
Do not forget that these drugs do not cover MRSA.
Discuss the case with a specialist in infections before using these drugs.
Most common and most serious adverse effects
Hypersensitivity is relatively common. This is usually characterized by a rash, which can be severe.
Carbapenems lower the seizure threshold. The risk is greater with imipenem, which is not recommended for the treatment of meningitis.
They can also cause confusion.
Carbapenems can cause antibiotic-associated diarrhoea (see Cephalosporins, p. 383 ).
Carbapenems can cause abnormalities of liver function tests.
Carbapenems can cause a positive Coombs’ test; haemolytic anaemia is rare.
Major drug-drug interactions
The risk of seizures is increased if imipenem is given with ganciclovir; avoid this combination.
Safety and efficacy
Measures of clinical improvement are the most important, but inflammatory markers, such as the ESR and CRP, are often helpful.
Whenever possible, take cultures before starting antibiotic treatment. Check the sensitivities of the causative organism. Discuss any unusual results with a microbiologist.
Measure the patient’s renal function and liver function. Reduce the dose as outlined earlier in renal insufficiency.
Patient information
Check that the patient is not allergic to penicillins before giving these drugs.
Prescribing information: Carbapenems
Dosages and duration of treatment will depend on the indication. Check your local antibiotics policy.
Imipenem (with cilastatin)
By intravenous infusion, usual dose 500 mg (of imipenem) tds or qds.
See earlier notes for dosage adjustments in renal insufficiency.
Higher doses may be required; seek microbiological advice.
Meropenem
By intravenous infusion, 500 mg tds.
See earlier notes for dosage adjustments in renal insufficiency.
Higher doses may be required; seek microbiological advice.
Antibacterial drugs: Cephalosporins and cephamycins BNF 5.1.2
Beta-lactam antibiotics
First-generation
Principally Gram-positive cover (but not Enterococcus spp.)
cefradine, cefazolin, cefalexin, cefadroxil
Second-generation
Improved Gram-negative cover but at the expense of Gram-positive cover
cefuroxime, cefaclor, cefamandole, cefprozil
Third-generation
Greater Gram-negative cover, but less Gram-positive cover, especially Staphylococcus aureus
cefotaxime and ceftriaxone
ceftazidime (covers Pseudomonas but has minimal Gram-positive cover)
Other cephalosporins
cefpirome
cefixime
cefpodoxime, covers respiratory tract pathogens
Cephamycin
cefoxitin (has some anaerobic activity)
Potential uses
Widely-used antibiotics with good penetration of body tissues and fluids.
Relatively poor penetration to CSF, unless the meninges are inflamed.
See box and Penicillins, p. 374 .
Cefotaxime is commonly used as a first-line drug for the treatment of meningitis (a notifiable disease—see Antituberculosis drugs, p. 421 for more information).
Commonly used for surgical prophylaxis (see p. 411 ).
Contraindications and cautions
Those with a history of allergy to penicillin should not be given any beta-lactam antibiotic, including cephalosporins, carbapenems, and co-amoxiclav.
A non-confluent rash affecting only a small area or occurring more than 72 hours after starting the penicillin does not usually represent an allergic reaction.
These drugs can accumulate in renal insufficiency.
Antibiotic solutions for intravenous injection contain a large amount of electrolytes (Na+ and K+); these will also accumulate in renal insufficiency.
As a rule of thumb, give the usual initial dose but reduce subsequent doses by half in renal insufficiency.
These drugs are not known to be harmful in pregnancy, but avoid them unless they are essential.
Avoid these drugs if the patient has porphyria.
How to use
The term ‘kef’ is commonly used to describe these drugs. Do not do this. Be specific about the cephalosporin to which you are referring. These antibiotics do not all have the same spectrum of activity and mistakes have been made.
Always consider the likely causative organisms when treating infection empirically.
Avoid using a broad-spectrum drug when one with a narrow spectrum will cover the causative organism.
Cephalosporins are probably some of the most inappropriately used antibiotics.
Using a broad-spectrum antibiotic increases the risk of antibiotic-associated diarrhoea (see below).
Cephalosporins are now the most common cause of antibiotic-associated diarrhoea.
See notes below; limit intravenous treatment to the shortest possible time.
Most common and most serious adverse effects
Hypersensitivity is relatively common. An urticarial rash occurs in 5% of patients. Anaphylactic reactions are much less common.
Eradication of the patient’s normal flora can cause:
Superinfection by Candida in the oropharynx; this is most common in elderly and debilitated people.
Antibiotic-associated diarrhoea; avoid broad-spectrum drugs unless essential; cephalosporins commonly cause diarrhoea by different mechanisms (see teaching point box, p. 383 ).
Cephalosporins can cause abnormalities of liver function tests, and frank hepatitis.
Rare adverse effects include:
Coombs’-positive haemolytic anaemia.
Bone marrow suppression (thrombocytopenia).
Interference with the action of clotting factors, causing haemorrhage.
Hypernatraemia and hyperkalaemia in patients with renal insufficiency (see earlier notes).
Major drug-drug interactions
The risk of drug interactions is small.
Cephalosporins can potentiate the effect of warfarin, but the effect is inconsistent. Some can cause bleeding disorders.
Antacids may reduce the absorption of these drugs given by mouth.
Monitoring
Safety and efficacy
Measures of clinical improvement are the most important, but inflammatory markers, such as the ESR and CRP, are often helpful.
Whenever possible, take cultures before starting antibiotic treatment. Check the sensitivities of the causative organism. Discuss any unusual results with a microbiologist.
Measure the patient’s renal function and liver function tests, especially if long-term treatment is required (>7 days).
Cephalosporins can give a false-positive urine glucose test and Coombs’ test.
Patient information
Warn the patient of the risk of a rash and other hypersensitivity phenomena.
Warn female patients that if they develop diarrhoea the oral contraceptive pill may be ineffective.
Prescribing information: Cephalosporins and cephamycins
There are many drugs and formulations. Their uses and spectra of activity are not equivalent. The following are given as examples. Dosages and duration of treatment will depend on the indication. Check your local antibiotics policy.
Cefalexin for urinary tract, respiratory tract, sinus, skin, and soft tissue infections by sensitive organisms.
By mouth, 250 mg qds or 500 mg bd.
Cefuroxime, second-generation drug, commonly used for surgical prophylaxis.
By slow intravenous injection/infusion, 1.5 g at induction (surgical prophylaxis) or 750 mg tds for other indications.
Dose can be doubled in severe infections.
Ceftriaxone, third-generation drug, commonly used for treatment of meningitis.
By slow intravenous injection/infusion, 2 g bd for meningitis, otherwise once daily.
Lower doses may be appropriate.
Ceftazidime, a third-generation drug with activity against Pseudomonas.
By slow intravenous injection/infusion, 1 g tds.
Dose may be doubled in severe infections.
Cefotaxime, a third-generation drug with a broad spectrum.
By slow intravenous injection/infusion, 1 g bd.
Can be increased up to 12 g daily (in divided doses in severe infection).
Antibiotics can cause diarrhoea in several ways:
They alter bowel flora, which can cause diarrhoea.
Alteration of the bowel’s normal flora can allow overgrowth of other organisms, such as Clostridium difficile; this overgrowth can cause a diarrhoeal illness ranging in severity up to pseudomembranous colitis.
Some antibiotics (penicillins) can cause diarrhoea due to a hypersensitivity reaction; this is rare.
The increasing use of broad-spectrum antibiotics has made this condition very common in hospitals. Clindamycin was the first antibiotic to be associated with pseudomembranous colitis, but cephalosporins are now the most common cause of diarrhoea due to Clostridium difficile. Consider carefully whether a narrow-spectrum antibiotic would suffice, before you prescribe a broad-spectrum antibiotic.
Elderly and debilitated people are at greatest risk; the risk increases with prolonged courses of antibiotics, but it can appear after only a single dose.
The most severe form of antibiotic-associated diarrhoea, pseudomembranous colitis, is not a trivial disease; it can be fatal, especially in those who are already frail; furthermore, it prolongs hospital stays by up to 10 days, increasing the risk of other hospital-acquired infection and placing a considerable burden on resources.
Clostridium difficile is diagnosed by identification of its toxin in the stool; the toxin can be present after the diarrhoea has subsided, and presence of the toxin alone is not grounds for treatment; however, infection control procedures should be followed.
Review the current antibiotic regimen.
Avoid broad-spectrum drugs, unless they are essential.
Limit intravenous antibiotic treatment to the shortest possible time.
Follow universal precautions when attending to and examining patients.
Take care to avoid cross-contamination from those known to be infected.
Supportive measures are essential. Ensure that the patient has an adequate fluid intake.
Follow infection control procedures carefully.
Oral metronidazole is the first-line treatment.
By mouth, 400 mg tds for 7 days.
If this is ineffective, consider treatment with oral vancomycin (even in those in whom intravenous vancomycin has been the cause).
By mouth, 125 mg every 6 hours, for 10–14 days.
In a small number of severe cases this will not be sufficient. Seek expert advice. Options include re-establishment of the normal gut flora with lactobacillus (although trial evidence of efficacy is poor).
Antibacterial drugs: Glycopeptide antibiotics BNF 5.1.7
Antibiotics
Vancomycin
Teicoplanin
See teaching point, p. 387 .
Potential uses
Treatment of infection by Gram-positive cocci, especially multiresistant staphylococci (e.g. MRSA).
These drugs have no activity against Gram-negative bacteria.
Given into the peritoneal cavity for the treatment of peritonitis in patients receiving peritoneal dialysis (CAPD) (unlicensed indication).
Treatment of antibiotic-associated diarrhoea (vancomycin, given by mouth).
Contraindications and cautions
Glycopeptides are not absorbed in significant amounts when given by mouth. They must be given by intravenous infusion if systemic exposure is required.
Systemic administration is not suitable for the treatment of antibiotic-associated diarrhoea; in that case give by mouth
Glycopeptides are excreted by the kidney. They are given to patients with renal insufficiency, but close serum concentration monitoring is required.
Glycopeptides are not known to be safe in pregnancy; avoid using them parenterally unless essential.
How to use
Always consider the likely causative organisms when treating infections empirically.
Reserve glycopeptides for treatment of infections either known to be, or suspected to be, due to multiresistant organisms (see teaching point box, p. 387 ).
The standard vancomycin dose of 1 g twice daily is often excessive in elderly patients; reduce to 750 mg twice daily and measure the serum concentration early (see later notes).
Rapid intravenous injection can cause the ‘red man syndrome’ due to histamine release, characterized by fever, chills, rash, and hypotension. Give glycopeptides by intravenous infusion over 60–90 minutes.
Antibiotic-associated diarrhoea
Vancomycin is a second-line treatment, usually reserved for those patients who have failed to respond to a course of treatment with metronidazole. See Cephalosporins, p. 383 for guidance on the treatment of antibiotic-associated diarrhoea.
Most common and most serious adverse effects
Glycopeptides are excreted by the kidney and can be nephrotoxic. Take particular care and monitor the serum concentration closely in patients with renal insufficiency.
Glycopeptides can also be ototoxic.
Excessively rapid infusion can cause the ‘red man syndrome’ (see p. 384 ). Give these drugs by slow infusion.
Hypersensitivity is relatively common. This is most commonly characterized by a rash, which can be severe.
Occasionally glycopeptides can cause neutropenia, agranulocytosis, or thrombocytopenia.
Major drug-drug interactions
The risk of nephrotoxicity and ototoxicity is increased if these drugs are given with aminoglycosides, loop diuretics (e.g. furosemide), or ciclosporin.
Colestyramine antagonizes the action of vancomycin when it is given by mouth.
Monitoring
Safety and efficacy
Measures of clinical improvement are the most important, but inflammatory markers, such as the ESR and CRP are often helpful.
Whenever possible, take cultures before starting antibiotic treatment. Check the sensitivities of the causative organism. Discuss any unusual results with a microbiologist.
Measure the patient’s renal function before and during treatment. Measure a full blood count especially if long-term treatment is required (>7 days).
Serum concentration measurement
The information given relates to vancomycin serum concentrations. Teicoplanin concentrations are not routinely measured, but they can be used in some cases to optimize treatment.
Trough concentrations are most helpful; aim for a trough concentration of 5–10 mg/L.
If renal function is normal, take the sample after the third dose.
Plan when you will be taking serum samples for measurement and liaise with your laboratory to ensure that they will be able to process the samples at the times you request. This is especially important at weekends.
If the patient’s renal function is normal give the dose after taking the sample for measurement. Use the result to adjust the size of the next dose.
If the patient’s renal function is not normal, wait for the result before giving the next dose of vancomycin.
If you are unsure, take advice about dosage adjustment. Vancomycin acts by time-dependent killing, so it is usually better to reduce the dose than to increase the dosage interval.
Patient information
Warn the patient of the risk of rash and other hypersensitivity phenomena.
The mechanisms of action of antibiotics vary considerably. The ways in which they act may depend on the peak concentration of antibiotic (concentration-dependent killing) or on the length of time over which the bacteria are exposed to the drug (time-dependent killing).
The aminoglycosides are examples of the former, the glycopeptides of the latter.
This is why the dosage regimens and associated monitoring are very different for these two classes of antibiotics. See the monitoring sections for further information.
Prescribing information: Glycopeptide antibiotics
The following are given as examples. Dosages will depend on the indication and renal function. Check your local antibiotics policy.
Vancomycin
By intravenous infusion over 60–90 minutes; usual dose 1 g every 12 hours.
Take note of advice above and adjust according to serum trough concentration.
By mouth, for antibiotic-associated diarrhoea, 125 mg every 6 hours for 10–14 days.
Teicoplanin
By slow intravenous infusion, 400 mg every 12 hours.
Take note of advice above and adjust according to serum trough concentration.
Dose may be reduced to 200 mg every 12 hours after 3 doses.
The emergence of multiresistant organisms is a major public health challenge. They are most common in hospitals, where broad-spectrum antibiotics are widely used (e.g. in intensive care units), but there is an increasing incidence of multiresistant organisms in the community.
Some of these organisms are resistant to all classes of antibiotics.
The ability to treat multiresistant organisms can give the impression that antibiotics such as vancomycin are better and more powerful than conventional drugs, such as the penicillins. This impression is false; these antibiotics have a limited spectrum of activity and are relatively difficult to use. If your patient has a penicillin-sensitive organism, a penicillin is a much better and safer choice. Selection of resistant organisms is driven by the use of broad-spectrum antibiotics. Use a narrow-spectrum antibiotic if you know the causative organism. Reserve drugs such as vancomycin for those patients at risk from multiresistant organisms; inappropriate use will drive the selection of more and more resistant organisms. For example, vancomycin-resistant enterococci (VRE) and staphylococci (VRSA) are emerging.
Infection control procedures (isolation, hand washing, etc.) are as important as the appropriate antibiotic selection in the fight against multiresistant organisms.
Always discuss the case with a microbiologist before using these drugs.
An oxazolidinone antibiotic.
Has activity against MRSA and VRE.
This drug is a reversible MAOI; see MAOIs, p. 332 for further information.
Linezolid can cause myelosuppresion; monitor the full blood count closely.
Antibacterial drugs: Tetracyclines BNF 5.1.3 and 13.6.2
Antibiotics
Tetracycline
Oxytetracycline
Doxycycline
Minocycline
Demeclocycline
Chlortetracycline
Lymecycline
Doxycycline at sub-antimicrobial doses is an inhibitor of collagenase activity.
This effect is used therapeutically in the treatment of adult periodontitis. This is a specialized use and is an adjunct to supragingival and subgingival scaling and root planning. It should be given with oral hygiene instruction and carried out by a dental practitioner or hygienist, as appropriate.
The usual dose is 20 mg twice daily.
Collagenase is one of a large family of matrix metalloproteinases.
Tetracyclines inhibit other metalloproteinases, but the therapeutic potential of these other actions has not been established.
Because of these actions, chemically modified tetracyclines, with greatly reduced antimicrobial activity but increased inhibitory effects on matrix metalloproteases have been developed for use in conditions such as diabetic proteinuria, periodontitis, and tendinopathy.
Potential uses
These drugs have a broad spectrum, but their clinical usefulness is now limited by widespread resistance. However, they are still the drugs of choice for infection by intracellular organisms:
Chlamydiae (non-specific urethritis, psittacosis, trachoma).
Rickettsiae (e.g. Q fever).
Brucellae (with streptomycin or rifampicin).
Spirochaetes (Borrelia burgdorferi—Lyme disease).
Tetracyclines are also used to treat acne.
Demeclocycline is used to treat the syndrome of inappropriate ADH (SIADH); see also Lithium, p. 348 .
Doxycycline is used in prophylaxis against malaria (see Antimalarial drugs, p. 444 ).
Contraindications and cautions
Avoid tetracyclines in patients with myasthenia gravis or systemic lupus erythematosus; they can worsen muscle weakness.
Avoid tetracyclines if the patient has diabetes insipidus; they can exacerbate it.
Tetracyclines can worsen hepatic and renal function; avoid them in patients with renal or hepatic insufficiency.
Do not give tetracyclines to children; they are deposited in teeth and can cause dental yellowing and hypoplasia.
For the same reason, do not give these drugs to women who are pregnant or who are breastfeeding.
Tetracyclines can be deposited in the bones and teeth of women and children.
How to use
The absorption of tetracyclines is markedly inhibited by divalent and trivalent cations, with which they form chelates. The following should be avoided:
Milk and milk products.
Zinc, iron, magnesium, and aluminium (for example in antacids or supplements).
Take tetracyclines with plenty of water 30 minutes or more before food.
Diagnosis of the listed infections may require specialized investigations; seek advice from a microbiologist or infectious diseases specialist.
Demeclocycline reduces the sensitivity of the collecting ducts to ADH; this induces diabetes insipidus. This effect is sometimes used to treat SIADH. See Lithium, p. 348 for diagnostic criteria.
Treatment of acne (see teaching point box, p. 392 )
Tetracyclines can be given by mouth or by topical application for this indication.
Topical application has lower systemic exposure and so a lower risk of effects on bones and teeth.
Bacterial resistance is increasing, so limit the use of tetracyclines to patients with moderate acne with an inflammatory component.
Use a non-antibiotic antimicrobial (e.g. benzoyl peroxide) when possible
Do not use different oral and topical antibiotics at the same time.
Tetracyclines improve acne but take time to act and do not abolish it.
Some improvement may be seen within 4–6 weeks, but it can take 8–12 weeks before full improvement is seen.
Most common and most serious adverse effects
Adverse effects are more common with systemic than with topical administration.
Nausea and vomiting are common. Tetracyclines can cause oesophageal irritation; they should be taken with plenty of water (not milk).
Tetracyclines are excreted by the kidneys and can cause nephrotoxicity. Avoid them if the patient has renal insufficiency. Nephrotoxicity is more likely if the patient is dehydrated from vomiting or diuretics. Ensure that the patient remains well hydrated.
Doxycycline does not cause nephrotoxicity.
Demeclocycline can cause nephrogenic diabetes insipidus (see earlier notes).
Some of the breakdown products of tetracyclines are nephrotoxic; do not use out-of-date drugs.
Tetracyclines can cause a rise in the blood urea concentration without a rise in creatinine; take care; this can falsely suggest that the patient has renal insufficiency.
Hypersensitivity to tetracyclines is relatively common. Demeclocycline commonly causes a photosensitive rash.
Tetracyclines can cause irreversible pigmentation of the skin; this is seen especially with minocycline and is more common with prolonged use.
Tetracyclines are deposited in developing teeth, causing yellowing. They can also cause dental hypoplasia.
Tetracyclines can cause ‘benign’ intracranial hypertension (‘pseudotumor cerebri’). This is rare but potentially serious; the term ‘benign’ is misleading.
Ask the patient about headache and visual disturbance and withdraw the drug if these occur.
Tetracyclines can cause blood disorders (anaemia, thrombocytopenia), but these are rare.
Minocycline can cause a systemic lupus erythematosus-like syndrome; this is rare.
Major drug-drug interactions
Avoid milk and minerals that chelate tetracyclines (see earlier notes for a list).
Drugs that induce cytochome P450 enzymes increase the metabolism of tetracyclines, reducing their action. See Carbamazepine, p. 285 for more information.
Tetracyclines increase the effect of warfarin; measure the INR and reduce the warfarin dose if appropriate.
Doxycycline increases blood ciclosporin concentrations.
Do not give tetracyclines with retinoids (also used for acne); the risk of intracranial hypertension is increased.
Monitoring
Safety and efficacy
Measures of clinical improvement are the most important, but inflammatory markers such as the CRP and ESR are often helpful if these drugs are used to treat infection.
Whenever possible, take cultures before starting antibiotic treatment. Some of the organisms that tetracycline are used to treat require special culture conditions; discuss this with a microbiologist. Check the sensitivities of the causative organism.
Measure the patient’s renal function (urea and creatinine), taking note of the factors discussed earlier.
If treatment is to extend beyond 6 months, measurement of liver function tests is recommended. Examine the patient, looking for irreversible skin pigmentation.
Patient information
Warn the patient that topical tetracyclines can stain clothing.
Warn the patient to avoid milk, mineral supplements, and some other drugs (see earlier list) while taking tetracyclines.
Advise the patient to report promptly any persistent headaches or visual disturbances.
Prescribing information: Tetracyclines
There are many formulations of these drugs. The following are given as examples. Dosages and duration of treatment will depend on the indication. Check your local antibiotics policy.
Tetracycline for infection
By mouth, 250 mg every 6 hours.
May be increased to 500 mg every 6 hours.
Demeclocycline for treatment of SIADH
By mouth, initially 0.9–1.2 g daily, in divided doses.
Usual maintenance dose 600–900 mg.
Minocycline for acne
By mouth, 100 mg daily (dose may be divided).
Acne occurs when excess oil (sebum) production combined with dead skin cells clogs pores. Bacterial growth in the pores causes red inflamed pimples, pus-filled whiteheads, or blackheads.
Acne is more common:
In adolescents.
In men.
In greasy skin.
In unwashed skin.
During menstruation.
If anabolic steroids are used.
If pores are blocked by cosmetics.
Simple measures, such as regular washing (antibacterial soaps do not increase efficacy) and exposure to natural sunlight, may be all that is required for mild acne.
Acne can be scarring; severe acne should be treated early to prevent severe scarring.
All treatments take time to act.
Topical treatment is usually sufficient. A non-antibiotic antimicrobial agent, such as benzoyl peroxide or azelaic acid, is usually preferred, owing to increasing emergence of antibiotic resistance.
Consider treatment with a topical antibiotic if there has been no response after 2 months of treatment
Topical antibiotics (erythromycin, clindamycin, or tetracycline) should be reserved for patients with an inflammatory component
Adverse effects from these topical formulations are uncommon
If these treatments are ineffective, consider treatment with a topical retinoid
These take several months to act and are likely to cause redness of the skin and peeling.
Do not apply these drugs to large areas of the skin.
Avoid exposure to UV light; use a sunscreen if exposure to the sun is unavoidable.
These drugs are contraindicated during pregnancy; see Retinoids, p. 692 for more information.
A proportion of patients do not respond to topical treatments.
Consider systemic treatment in these cases.
First-line choices are oral antibacterial drugs, such as tetracyclines (see earlier notes) or erythromycin. Erythromycin can be used in younger patients, but bacterial resistance is widespread. Topical anticomedonal treatment (e.g. benzoyl peroxide) can be continued, but do not use different topical and systemic antibiotics at the same time (increases resistance)
Trimethoprim is a second-line option for resistant acne; treatment should be supervised by a specialist.
Co-cyprindiol (an antiandrogen plus an oestrogen) is a second-line option for women with acne. It is contraindicated in pregnancy and increases the risk of thromboembolism; the antiandrogen action may ameliorate hirsutism
Oral retinoids are reserved for treatment of the most severe acne. They can only be prescribed by consultant dermatologists. See Retinoids, p. 692 for more information.
Antibacterial drugs: Aminoglycoside antibiotics BNF 5.1.4
Antibiotics
Potential uses
These drugs are most commonly given for serious Gram-negative infections.
They have some action against some Gram-positive bacteria. For example, they act synergistically with penicillins in the treatment of staphylococcal endocarditis. The penicillin breaks the cell wall, allowing the aminoglycoside to enter.
Gentamicin is the usual drug of choice.
Amikacin is usually reserved for gentamicin-resistant Gram-negative bacteria.
Tobramycin is given by nebulizer for treatment of Pseudomonas aeruginosa in patients with cystic fibrosis.
Neomycin is too toxic for parenteral administration; it is given orally for gut clearance (sterilization) (e.g. as part of the treatment of hepatic encephalopathy).
These drugs penetrate the chest and abscesses poorly.
Contraindications and cautions
Aminoglycosides can interfere with neuromuscular transmission; avoid them in patients with myasthenia gravis.
Aminoglycosides are excreted by the kidney. They are given to patients with renal insufficiency, but close serum concentration monitoring is required if repeated doses are used.
Avoid aminoglycosides during pregnancy whenever possible; there is a risk of damage to the baby’s vestibular and auditory nerves.
How to use
Aminoglycosides are not absorbed from the gut; they must be given parenterally.
Tobramycin can be given by nebulized solution.
Aminoglycosides are given in two ways:
As a single large dose, usually once daily according to the regimen outlined in later notes.
For their synergistic action with another antibiotic (see earlier notes) (e.g. in the treatment of endocarditis). In this case, the drug is given as a smaller dose 2 or 3 times daily.
Most common and most serious adverse effects
Hypersensitivity is relatively common. A rash occurs in 5% of patients.
Streptomycin can cause contact dermatitis; wear gloves when handling it.
Aminoglycosides can be ototoxic and nephrotoxic. The risk is related to the trough concentration rather than the peak concentration. Make sure the serum concentration has fallen below 2 mg/L before giving another dose.
Aminoglycosides can have a neuromuscular blocking action, especially when given in large doses.
Neomycin can cause superinfection of the pharynx and gut with yeasts and fungi.
Aminoglycosides can cause antibiotic-associated diarrhoea, but this is uncommon.
Tobramycin can cause bronchospasm and haemoptysis when given by nebulizer (pretreatment inhaled bronchodilators can be given).
Major drug-drug interactions
The risk of nephrotoxicity is increased if aminoglycosides are given with loop diuretics (e.g. furosemide), antifungal drugs (e.g. amphotericin), cytotoxic drugs, and ciclosporin.
Neomycin reduces vitamin K absorption, potentiating the effect of warfarin. Neomycin also reduces the absorption of digoxin.
Aminoglycosides potentiate the effects of neuromuscular blocking drugs.
Monitoring
Safety and efficacy
Measures of clinical improvement are the most important, but inflammatory markers, such as the ESR and CRP, are often helpful.
Whenever possible, take cultures before starting antibiotic treatment. Check the sensitivities of the causative organism. Discuss any unusual results with a microbiologist.
Measure the patient’s renal function (even when giving tobramycin by nebulizer).
Gentamicin
Plan when you will be taking serum samples for measurement, and liaise with your laboratory to ensure that they will be able to process the samples at the times you request. This is especially important at weekends.
Measure the serum concentration and adjust the dose and dosage interval as appropriate. For twice or three times daily dosing:
Measure the serum concentration after 3 doses if renal function is normal. If renal function is abnormal, measure the concentration earlier. The peak concentration should be taken 1 hour after the dose has finished being given, and should be in the range 5–10 mg/L.
The trough concentration should be taken just before the next dose and should be <2 mg/L.
A nomogram for once-daily dosing is given on p. 397 .
Seek advice for target ranges of other aminoglycosides.
The rationale for pulse dosing of aminoglycosides is based on the following observations:
Aminoglycosides exhibit a significant post-antibiotic effect. An antibacterial effect is detectable beyond the time that the drug is detectable in the serum.
The bactericidal action of aminoglycosides is concentration dependent. The higher the ratio between the peak aminoglycoside concentration and minimum inhibitory concentration (MIC), the higher the kill rate. The multiple daily dosing regimen usually results in relatively low peak/MIC ratios (<5). When the same total daily dose is given as a single bolus (infused over 30–60 minutes), much higher ratios are obtained (>10).
Aminoglycoside uptake into renal tubule cells and the inner ear appears to be saturated at relatively low serum concentrations, suggesting that higher peaks do not necessarily result in a greater risk of toxicity.
Exclusion criteria for once-daily aminoglycoside dosing
Pregnancy
Severe liver disease (e.g. ascites)
Neutropenia
Extensive burns (>20% of body surface area)
Patients with Gram-positive infection (when the aminoglycoside is used for synergy)
Severe renal disease (creatinine clearance < 30 mL/min)
Patients with enterococcal endocarditis
Dosage
The single dose for gentamicin is 7 mg per kg body weight, unless the patient is more than 20% heavier than the ideal body weight. For obese patients, calculate a dosing weight:
The calculated dose is diluted in 100 mL of isotonic saline and infused over 1 hour.
Measure the serum concentration at 7–12 hours after the dose (take a careful note of the actual time).
Use the nomogram (see diagram) to calculate the frequency of dosing.
Patient information
Warn the patient of the risk of a rash and other hypersensitivity phenomena.
Prescribing information: Aminoglycoside antibiotics
There are many formulations of these drugs. The following are given as examples. Dosages will depend on the indication and renal function. Check your local antibiotics policy. See Azathioprine, p. 587 for more information on giving drug dosages by body weight.
Gentamicin
Once daily regimen, see ‘Once-daily gentamicin’ box, p. 397 .
Twice or three times daily regimen. By intramuscular injection or slow intravenous injection/infusion, usual dosage range 60–80 mg twice daily.
Amikacin
By intramuscular injection or slow intravenous injection/infusion, 15 mg/kg daily in 2 divided doses.
Can be increased to 22.5 mg/kg daily in 3 divided doses in severe infections.
Tobramycin
By intramuscular injection or slow intravenous injection/infusion, 3 mg/kg daily in 3 divided doses.
By nebulizer, 300 mg twice daily, usual treatment course is 28 days.
A 60-year-old man with infective endocarditis was given a combination of penicillin and gentamicin for 4 weeks. Frequent serum gentamicin peak and trough concentrations throughout the 4 weeks were satisfactory and he made a good recovery. However, he became unsteady on his feet and formal testing confirmed impaired auditory and vestibular function.
Administration of aminoglycoside antibiotics for more than a week, despite careful monitoring, is potentially hazardous, since the drug continues to accumulate in the tissues despite steady serum concentrations. Cumulative ototoxic damage can therefore occur in the absence of overtly toxic serum concentrations.
Antibacterial drugs: Macrolide antibiotics BNF 5.1.1
Antibiotics
Clindamycin. Commonly causes antibiotic-associated diarrhoea. Specialist use for bone infection. Used in combination with other antibiotics.
Potential uses
These drugs have an antibacterial spectrum that is similar to that of simple penicillins (e.g. benzylpenicillin).
They are commonly used if the patient is allergic to penicillins.
They do not penetrate the CNS, so cannot be used for meningitis.
They are also active against the bacteria that cause atypical pneumonias (e.g. Mycoplasma, Chlamydia, Legionella).
Azithromycin has a slightly different spectrum from erythromycin:
It covers Haemophilus influenzae.
It can be given as single dose for treatment of chlamydial and non-gonococcal urethritis.
Clarithromycin is commonly used as part of Helicobacter pylori eradication regimens (see Proton pump inhibitors, p. 36 ).
Erythromycin is used topically for the treatment of acne.
Erythromycin stimulates motilin receptors in the gut; this increases gut motility and is used therapeutically on the ICU and in patients with diabetic autonomic neuropathy.
Contraindications and cautions
Avoid macrolides in hepatic insufficiency; the risk of hepatotoxicity is increased.
They can also cause idiosyncratic heptatotoxicity.
Avoid macrolides if the patient has porphyria.
Reduce the dose if the patient has renal insufficiency.
Halve the dose of clarithromycin in mild renal insufficiency.
Limit the total daily dose to 1.5 g of erythromycin in mild renal insufficiency.
Macrolides are not known to be harmful in pregnancy, but the manufacturers advise that they should be avoided unless essential.
Macrolides can prolong the QT interval; avoid them in patients with known cardiac conduction abnormalities or in those taking other drugs that can prolong the QT interval.
How to use
Always consider the likely causative organisms when treating infections empirically.
Avoid using a broad-spectrum drug when one with a narrow spectrum will cover the causative organism.
Using a broad-spectrum antibiotic increases the risk of antibiotic-associated diarrhoea (see Cephalosporins, p. 383 ).
Erythromycin commonly causes nausea and vomiting; this can be reduced by giving a lower dose (e.g. 250 mg qds).
The higher dose is required if Legionella pneumophila could be the causative organism.
Clarithromycin and azithromycin cause less vomiting but are more expensive.
Intravenous erythromycin can cause thrombophlebitis; only give it into a large vein via a free-flowing cannula.
Erythromycin is used for the treatment of acne (see Tetracyclines, p. 392 for more information).
Bacterial resistance is increasing, so limit its use to patients with moderate acne with an inflammatory component.
Use a non-antibiotic antimicrobial (e.g. benzoyl peroxide) when possible.
Erythromycin can be given systemically for moderate to severe acne, but resistance is widespread. More commonly it is given topically for moderate acne.
Do not use different oral and topical antibiotics at the same time.
Most common and most serious adverse effects
Nausea and vomiting are the most common adverse effects of these drugs; see earlier notes for advice on how to mitigate this.
Macrolides can cause a rash, which may be severe.
Macrolides can prolong the QT interval; take care in patients who are cardiovascularly unstable.
Macrolides can cause cholestatic jaundice.
Eradication of the patient’s normal flora can cause antibiotic-associated diarrhoea; see Cephalosporins, p. 383 for guidance.
Major drug-drug interactions
Erythromycin and clarithromycin inhibit cytochrome P450 enzymes in the liver. This will reduce the metabolism of other drugs, increasing their effect. See teaching point box, p. 401 .
Clarithromycin reduces the absorption of zidovudine.
Monitoring
Safety and efficacy
Measures of clinical improvement are the most important, but inflammatory markers such as the CRP and ESR are often helpful.
Whenever possible, take cultures before staring antibiotic treatment. Check the sensitivities of the causative organism. Discuss any unusual results with a microbiologist.
Measure liver function tests, especially if long-term treatment is required (>7 days).
Measure the QT interval on an ECG, especially if the patient is cardiovascularly unstable.
Patient information
Warn the patient of the risk of nausea and vomiting.
Warn women that if they develop diarrhoea the oral contraceptive pill may be ineffective.
A 15-year-old boy with epilepsy had good seizure control with carbamazepine 400 mg bd. In the past he had developed a rash after taking amoxicillin, so when he went to his GP with a productive cough he was given erythromycin for 5 days. At the end of the course he had become drowsy and was slurring his words. Carbamazepine toxicity was confirmed, with a plasma concentration of 78 micromol/L (usual target range 13–42).
Erythromycin inhibits the drug metabolizing enzyme CYP3A4 and is implicated in a number of important drug-drug interactions.
Prescribing information: Macrolide antibiotics
There are many formulations of these drugs. The following are given as examples. Dosages and duration of treatment will depend on the indication. Check your local antibiotics policy.
Erythromycin
Several salts of erythromycin are available; the estolate is best absorbed when given by mouth and causes less nausea, vomiting, and anorexia; however, because systemic exposure is greater it is more likely to cause jaundice.
By mouth, 250–500 mg every 6 hours, or 0.5–1 g every 12 hours.
By intravenous infusion, 50 mg/kg by continuous infusion, or in divided doses every 6 hours.
Azithromycin
By mouth, 500 mg daily for 3 days.
Uncomplicated chlamydial infections and non-gonococcal urethritis, 1 g single dose
Clarithromycin
Eradication of H. pylori; see Proton pump inhibitors, p. 36 .
By mouth, 250 mg bd.
By intravenous infusion, 500 mg bd.
Telithromycin
By mouth, 800 mg daily.
Cytochrome P450 (CYP) isoforms (previously called mixed function oxidases) are critical enzymes responsible for the metabolism of many drugs. Of these CYP3A4 is the most abundant and most important. The liver is the most familiar location for drug metabolism, but other sites are also important. CYP3A4 is expressed in abundance in the gut wall and is responsible for the pre-systemic metabolism of several drugs. Pre-systemic metabolism limits the proportion of a drug dose that reaches the systemic circulation (bioavailability).
Components within grapefruit juice (which have not been conclusively identified) cause a post-translational reduction in CYP3A4 and CYP3A5 expression; other isoforms do not seem to be affected. The effect of this is a substantial increase in the proportions of certain drugs that reach the systemic circulation. The effect is most marked with drugs that undergo substantial presystemic metabolism and hence have low bioavailability. The effects can be clinically significant.
Other mechanisms that involve inhibition of organic anion transporting polypeptides have also been postulated, but these seem to be less important.
This effect is best described for grapefruit juice, and clinically important interactions have been observed following a normal (200–250 mL) intake of juice. Other juices including tangerine and star fruit have been implicated, although to a lesser extent.
Advise patients taking the drugs listed in the table to avoid grapefruit juice.
The list is not exhaustive and new drugs are frequently added; check the BNF regularly.
| Drug> | Potential risks associated with increased drug exposure |
|---|---|
Ciclosporin, sirolimus, tacrolimus | Increased risk of renal toxicity |
Some statins (atorvastatin, simvastatin, lovastatin) | Increased risk of myopathy |
Dihydropyridines (e.g. felodipine, lacidipine, nicardipine, nifedipine, nitrendipine) | Enhanced hypotensive action |
Phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil) | Priapism |
Some antiviral drugs (efavirenz, saquinavir) | Increased risk of toxicity; see prescribing information for individual drugs |
Amiodarone | Increased risk of cardiac arrhythmias |
| Drug> | Potential risks associated with increased drug exposure |
|---|---|
Ciclosporin, sirolimus, tacrolimus | Increased risk of renal toxicity |
Some statins (atorvastatin, simvastatin, lovastatin) | Increased risk of myopathy |
Dihydropyridines (e.g. felodipine, lacidipine, nicardipine, nifedipine, nitrendipine) | Enhanced hypotensive action |
Phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil) | Priapism |
Some antiviral drugs (efavirenz, saquinavir) | Increased risk of toxicity; see prescribing information for individual drugs |
Amiodarone | Increased risk of cardiac arrhythmias |
Drugs are metabolized in the liver by cytochrome P450 enzymes (CYPs). The isoform called CYP3A4 is responsible for the metabolism of many drugs. Erythromycin and clarithromycin (but not azithromycin) are inhibitors of CYP3A4. They therefore slow down the metabolism of any other drugs that are metabolized by CYP3A4. This can increase the effect of these other drugs.
The interaction with warfarin is particularly important. The dose of warfarin may need to be reduced when these drugs are started. Remember also that the dose may need to be increased again when they are stopped.
These may be affected if they are co-administered with drugs that inhibit CYP3A4 (see second list).
Antihistamines
Benzodiazepines
Calcium channel blockers
Carbamazepine
Ciclosporin
Clarithromycin
Clozapine
Corticosteroids
Ergotamine
Erythromycin
HIV protease inhibitors
HMG CoA reductase inhibitors (‘statins’)
Phenytoin
Quinidine
Saint John’s wort
Sildenafil
Tacrolimus
Theophylline
Warfarin
Amiodarone
Cimetidine
Clarithromycin
Diltiazem
Fluvoxamine
Grapefruit juice
HIV protease inhibitors
Itraconazole
Antibacterial Drugs: Sulfonamides and trimethoprim (including co-trimoxazole) BNF 5.1.8 and 13.10.1.1
Antimicrobial drugs that act by interfering with bacterial folate metabolism
Sulfamethoxazole
Sulfadiazine
Silver sulfadiazine (Flamazine®)
Co-trimoxazole
Trimethoprim plus sulfamethoxazole (Septrin®)
Potential uses
Trimethoprim is most commonly used for the treatment of urinary tract infections.
It can also be used for the treatment of prostatitis, shigellosis, and invasive Salmonella infections. Seek specialist advice.
Co-trimoxazole is associated with rare but severe and potentially serious adverse effects. For this reason, its use should be restricted to the following indications.
Drug of choice for Pneumocysitis jirovecii (carinii) pneumonia.
Also given for toxoplasmosis and nocardiasis (seek specialist advice).
Sulfadiazine is used for the treatment of toxoplasmic encephalitis.
It is also used for the prevention of recurrence of rheumatic fever (specialized use).
Silver sulfadiazine is used topically for prevention of infections in wounds (commonly after burns).
Contraindications and cautions
Avoid all these drugs if the patient has severe hepatic or renal insufficiency.
These drugs can cause crystalluria; ensure an adequate fluid intake in all patients, but especially those with any degree of renal insufficiency.
Avoid all these drugs if the patient has an existing haematological disease; they can suppress the bone marrow.
All these drugs should be avoided during pregnancy—trimethoprim is teratogenic during the 1st trimester; sulfonamides cause fetotoxic effects in the 3rd trimester.
Avoid all these drugs if the patient is folate deficient.
See teaching point box, p. 408 , if the patient reports an allergy to sulphur-containing drugs.
How to use
Urinary tract infection
Trimethoprim is commonly used empirically for urinary tract infections, but resistance is increasing and nitrofurantoin is an alternative. Check your local guidelines for empirical therapy.
Always consider the likely causative organisms when treating infections empirically.
Trimethoprim is sometimes given long term. In this case special monitoring is required; see later notes.
Pneumocystis jirovecii (carinii)
Treatment of toxoplasmic encephalitis and Pneumocystis jirovecii (carinii) should be under the direction of a specialist. These infections are sometimes the first presentation of AIDS. Consider these diagnoses in patients at risk from HIV infection and AIDS.
Co-trimoxazole is the drug of choice for prophylaxis and treatment of Pneumocystis jirovecii infection.
Pneumocystis is an opportunistic pathogen and is usually only a cause of disease in immunocompromised patients; the largest group are those with AIDS.
Prophylaxis is usually given to those patients with a white cell CD4 count <200 × 106/L
Toxoplasmic encephalitis
This serious infection occurs most commonly in patients with AIDS.
Sulfadiazine is used in combination with pyrimethamine (a folate antagonist), although it is unlicensed for this indication.
Alternatives include the combination of a macrolide antibiotic with pyrimethamine (specialist use only)
Topical treatment
Silver sulfadiazine is commonly used in the prophylaxis and treatment of infections in burns wounds. The care of extensive burns requires specialized nursing and medical supervision.
Systemic absorption can be significant if this drug is applied over large areas. See adverse effects and interactions notes.
Most common and most serious adverse effects
The adverse effects of trimethoprim are similar to those of co-trimoxazole, but are less common and usually less severe.
The most serious adverse effects are severe rashes and Stevens–Johnson syndrome.
These are hypersensitivity phenomena.
Other hypersensitivity phenomena include anaphylaxis, serum sickness, systemic vasculitis, and pneumonitis.
Bone marrow depression (usually agranulocytosis) can also occur.
An antifolate effect; see mechanism of action earleir; the drug should be withdrawn immediately if this occurs.
Patients with G6PD deficiency or abnormal haemoglobins are at risk of haemolytic anaemia.
Gastrointestinal disturbances, headache, and drowsiness tend to be dose-related.
Crystalluria can occur, but urinary tract obstruction is uncommon; a high fluid intake is recommended.
These drugs can cause antibiotic-associated diarrhoea (see Cephalosporins, p. 383 ).
Major drug-drug interactions
Co-trimoxazole
Increased risk of ventricular arrhythmias with amiodarone; avoid concomitant use.
Effect of warfarin increased.*
Antifolate effect and plasma concentration of phenytoin increased.
Increase risk of nephrotoxicity when given with ciclosporin.*
Increased risk of toxicity when given with other drugs that have an antifolate action.*
Pyrimethamine (includes Fansidar®).*
Azathioprine and mercaptopurine.*
Methotrexate*.
Phenytoin*.
Trimethoprim
The interactions earlier marked * also apply to trimethoprim.
Monitoring
Safety and efficacy
Measures of clinical improvement are the most important, but inflammatory markers, such as the ESR and CRP, are often helpful. Arterial blood gas measurements indicate the severity of Pneumocystis jirovecii (carinii) infection.
Whenever possible, take cultures before staring antibiotic treatment. Advise the laboratory if you suspect that the patient has HIV.
This is to protect the laboratory staff, and to ensure that special cultures for opportunistic organisms are set up.
Check the sensitivities of the causative organism. Discuss any unusual results with a microbiologist.
No specific monitoring is required if trimethoprim is given in a short course for a urinary tract infection.
If used for long-term treatment, patients should be advised how to recognize the symptoms and signs of bone marrow suppression (see later notes).
Patients given sulfadiazine and pyrimethamine should also be given folinic acid and should have a full blood count measured at least weekly.
Patients given co-trimoxazole for long-term prophylaxis against Pneumocystis jirovecii (carinii) should have a full blood count measured monthly.
Patient information
Advise patients how to recognize the symptoms and signs of bone marrow suppression (easy bruising, unexpected sore throat, bleeding). Advise them that they should seek immediate medical attention if these occur.
Advise patients that they should seek immediate medical attention if they develop a rash.
Warn female patients that if they develop diarrhoea, the oral contraceptive may be ineffective.
Prescribing information: Sulfonamides and trimethoprim
There are many formulations of these drugs. The following are given as examples. Dosages and duration of treatment will depend on the indication. Check your local antibiotics policy.
Trimethoprim
For urinary tract infections.
By mouth, 200 mg bd.
Co-trimoxazole
Note: co-trimoxazole contains trimethoprim and sulfamethoxazole in the proportion of 1 part to 5 parts (960 mg of co-trimoxazole contains sulfamethoxazole 800 mg and trimethoprim 160 mg).
Prophylaxis against Pneumocystis jiroveci (carinii) infection.
By mouth, usually 960 mg daily.
Treatment of Pneumocystis jiroveci (carinii) infection.
By mouth or by intravenous infusion, usually 120 mg/kg daily in 2–4 divided doses for 14 days.
Sulfadiazine
Treatment of toxoplasmic encephalitis, seek specialist advice.
Prophylaxis and treatment of infection in burns wounds.
Cream 1%; apply with sterile applicator.
Note earlier cautions about applying to large areas.
There are two distinct forms of ‘sulphur’ allergy:
Allergy to sulfonamides.
Allergy to sulphiting agents; these are present in foods, beverages, and some pharmaceutical formulations.
| Drugs that contain sulfonamide groups | Drugs that are commonly formulated with sulfiting agents |
|---|---|
• Antibacterial sulfonamides • Sulfasalazine • Sulfonylureas (allergy rare) • Thiazide diuretics (e.g. hydrochlorothiazide; allergy rare) • Thiazide-like diuretics (e.g. chlortalidone; allergy rare) • Loop diuretics (bumetanide, furosemide; allergy rare) • Acetazolamide (carbonic anhydrase inhibitor) • Celecoxib • Probenecid • Sumatriptan | • Adrenaline (epinephrine) • Amino acids • Aminoglycosides • Dexamethasone • Dopamine • Isoprenaline • Phenylephrine |
• The risk of cross-reactivity is relatively low. • Re-exposure to the causative drug after a period time will not cause a reaction in up to 50% of cases, especially if the initial reaction was a mild rash. • However, do not reintroduce the drug unless it is absolutely necessary and ensure that facilities to treat anaphylaxis are available. • Patients with an allergy to sulfonamides do not usually have an allergy to sulphiting agents. | • Patients who are allergic to these agents commonly have a history of atopy and asthma. • The risk of cross-reactivity with sulfonamides is low. |
| Drugs that contain sulfonamide groups | Drugs that are commonly formulated with sulfiting agents |
|---|---|
• Antibacterial sulfonamides • Sulfasalazine • Sulfonylureas (allergy rare) • Thiazide diuretics (e.g. hydrochlorothiazide; allergy rare) • Thiazide-like diuretics (e.g. chlortalidone; allergy rare) • Loop diuretics (bumetanide, furosemide; allergy rare) • Acetazolamide (carbonic anhydrase inhibitor) • Celecoxib • Probenecid • Sumatriptan | • Adrenaline (epinephrine) • Amino acids • Aminoglycosides • Dexamethasone • Dopamine • Isoprenaline • Phenylephrine |
• The risk of cross-reactivity is relatively low. • Re-exposure to the causative drug after a period time will not cause a reaction in up to 50% of cases, especially if the initial reaction was a mild rash. • However, do not reintroduce the drug unless it is absolutely necessary and ensure that facilities to treat anaphylaxis are available. • Patients with an allergy to sulfonamides do not usually have an allergy to sulphiting agents. | • Patients who are allergic to these agents commonly have a history of atopy and asthma. • The risk of cross-reactivity with sulfonamides is low. |
Antibacterial Drugs: Metronidazole and tinidazole BNF 5.1.11
Nitroimidazole antibiotics
Metronidazole
Tinidazole
Similar spectrum of activity to metronidazole but has a longer duration of action
Metronidazole
Tinidazole
Tazocin
Imipenem
Clindamycin
Potential uses
Treatment of infection by anaerobic (and microaerophilic) bacteria and protozoa.
Prophylaxis and treatment of infection from colonic anaerobes, especially Bacteroides fragilis.
Commonly used for prophylaxis during abdominal surgery.
Metronidazole is used for the treatment of antibiotic-associated diarrhoea (Clostridium difficile).
Treatment of amoebiasis (Amoeba enterohepatica) and amoebic abscess.
Treatment of giardiasis (Giardia lamblia).
Treatment of tetanus (Clostridium tetani); specialized use; seek expert advice.
Treatment of trichomonal vaginitis and bacterial vaginosis.
Metronidazole is a component of several regimens for the eradication of Helicobacter pylori (see Proton pump inhibitors, p. 36 ).
Metronidazole can be used topically to reduce the odour from fungating tumours.
Contraindications and cautions
Dosage adjustment is not usually required in renal insufficiency.
These drugs are metabolized by the liver; reduce the dose to one-third and give it once daily in severe hepatic insufficiency.
The manufacturers of tinidazole recommend that it should be avoided during the 1st trimester of pregnancy.
The manufacturers of metronidazole recommend that high dosages should be avoided during pregnancy.
How to use
Always consider the likely causative organisms when treating infections empirically; is an anaerobic organism likely to be the cause?
Advise the laboratory that you suspect an anaerobic infection, to ensure that the samples are cultured appropriately.
Metronidazole is preferably given by mouth or rectum for the treatment of antibiotic-associated diarrhoea. Intravenous metronidazole is sometimes used in practice, as the excretion of drug into bile and exudation from the inflamed colon may be effective. Seek local antibiotic protocols for the preferred treatment options.
Most common and most serious adverse effects
These drugs are usually well-tolerated.
Gastrointestinal adverse effects are the most common: nausea and vomiting, unpleasant taste in the mouth.
A rash can occur and can be severe. Anaphylactic reactions also occur rarely.
Liver function test abnormalities occur occasionally.
Prolonged treatment can cause a peripheral neuropathy.
The prophylactic use of antibiotics (commonly a cephalosporin plus metronidazole) has an important role in the prevention of postoperative infection. However, if the patient develops a postoperative infection, it is unlikely that the organism responsible will be sensitive to the antibiotics used for prophylaxis. Take appropriate cultures and discuss a change in antibiotic regimen with a microbiologist or specialist in infection.
Do not continue prophylactic antibiotic treatment for inappropriately long periods.
Guidelines on the use of prophylactic antibiotics during surgery are provided by the Scottish Intercollegiate Guidelines Network ( http://www.sign.ac.uk/guidelines).
Major drug-drug interactions
Metronidazole enhances the effect of warfarin; take care to adjust the dose when starting or stopping a course of metronidazole.
Metronidazole inhibits the metabolism of phenytoin and fluorouracil (5-FU), increasing the risk of toxicity.
Both metronidazole and tinidazole can cause a disulfiram-like reaction (disulfiram = Antabuse®) if the patient also takes alcohol.
Monitoring
Safety and efficacy
Measures of clinical improvement are the most important, but inflammatory markers, such as the ESR and CRP, are often helpful.
Whenever possible, take cultures before staring antibiotic treatment. Check the sensitivities of the causative organism. Discuss any unusual results with a microbiologist.
Measure liver function tests if long-term treatment is required (>10 days).
Patient information
Patients taking these antibiotics should be advised to avoid alcohol, since they can cause a disulfiram-like reaction, which is very unpleasant and potentially harmful.
Warn women that if they develop diarrhoea, the oral contraceptive may be ineffective.
Prescribing information: Metronidazole and tinidazole
There are many formulations of these drugs. The following are given as examples. Dosages and duration of treatment will depend on the indication. Check your local antibiotics policy.
Metronidazole
Treatment of anaerobic infections.
By mouth, 800 mg initially then 400 mg tds; some recommend 500 mg tds.
By rectum, 1 g tds.
By intravenous infusion, 500 mg tds.
Surgical prophylaxis.
By mouth, 400–500 mg 2 hours before surgery. Up to three further doses can be given every 8 hours after high-risk procedures.
By rectum, 1 g 2 hours before surgery. Up to three further doses can be given every 8 hours after high-risk procedures.
By intravenous infusion, 500 mg at induction. Up to three further doses can be given every 8 hours after high-risk procedures.
Treatment of antibiotic-associated diarrhoea.
By mouth, 400 mg tds for 10 days (see also Cephalosporins, p. 383 ).
By rectum, 1 g tds.
Tinidazole
Treatment of anaerobic infections.
By mouth, either 2 g initially then 1 g daily, or 500 mg bd.
Tetanus is an acute, often fatal, disease caused by a toxin produced by the bacillus Clostridium tetani. The bacterium is found in soil, street dust, and animal and human faeces. Infection results from an injury or puncture wound; however, these may be trivial or unnoticed cuts/abrasions. Less commonly, it can result from injection using contaminated needles.
Symptoms occur within 3–21 days, usually 8 days, after exposure to tetanus spores. Most cases require hospitalization.
The outcome once the disease is established is often poor; prevention is therefore particularly important.
In the UK, children are offered immunization with tetanus toxoid (as part of DTaP vaccine). This is a course of 3 injections every 4 weeks, starting at 2 months of age.
This is then boosted before school entry (DTaP vaccine) and before leaving school.
In most circumstances, a total of five doses of tetanus vaccine is considered sufficient for long-term protection.
Give a booster injection to any patient who presents with a potentially contaminated wound whose primary immunization is incomplete or whose immunization status is unknown.
Stiffness and contraction of muscles, especially those of the abdomen, back, and jaw. This can be painful. Death can result from asphyxiation.
Symptoms of systemic infection, fever, tachycardia, sweating.
Seek specialist advice.
Supportive:
Paralysis and mechanical ventilation.
Diazepam for muscle spasm.
Specific:
Metronidazole.
(Anti)tetanus immunoglobulin.
Antibacterial Drugs: Quinolone antibiotics BNF 5.1.12
Antibiotics
Ciprofloxacin
Levofloxacin
Ofloxacin
Nalidixic acid
Norfloxacin
Moxifloxacin
For treatment and prophylaxis against anthrax.
As a component of some regimens for the treatment of multi-resistant Mycobacterium tuberculosis (TB) and other atypical mycobacteria.
As an alterative to rifampicin for meningococcal disease prophylaxis.
Potential uses
Treatment of infection by both Gram-positive and Gram-negative organisms, especially:
Urinary tract sepsis.
Biliary tract sepsis.
Food poisoning due to Campylobacter (if antibiotics indicated), Shigella, and Salmonella species.
Food poisoning is a notifiable disease (see Antituberculosis drugs, p. 421 , for more information about notifiable diseases).
Ciprofloxacin is the only drug currently available that has good activity against Pseudomonas aeruginosa and can be given by mouth.
Ciprofloxacin is not active against Streptococcus pneumoniae; levofloxacin and moxifloxacin give better pneumococcal cover.
All these drugs have relatively poor activity against staphylococci; they are therefore not ideal choices for the treatment of skin and soft-tissue infections.
Contraindications and cautions
Quinolones are excreted by the kidney; halve the dose in renal insufficiency.
Quinolones can cause hepatotoxicity; reduce the dose in hepatic insufficiency.
Quinolones lower the seizure threshold; avoid them if possible in patients with epilepsy.
Avoid quinolones during pregnancy; there is a theoretical risk of causing an arthropathy in the baby.
Animal studies suggest that children and adolescents are also at risk of arthropathy; avoid these drugs if possible; but short-term use may be justified in some circumstances
Quinolones can cause tendon rupture; avoid them if the patient has tendonitis. The elderly and those taking corticosteroids are at increased risk.
Avoid quinolones if the patient has G6PD deficiency. See teaching point box in Antimalarial drugs, p. 449 .
How to use
Always consider the likely causative organisms when treating infection empirically.
Avoid using a broad-spectrum drug when one with a narrow spectrum will cover the causative organism.
Quinolones are very well absorbed when given by mouth. Intravenous administration is expensive and usually not justified unless the patient cannot take drugs by mouth.
Ciprofloxacin is available as eye drops/ointment for local application.
Most common and most serious adverse effects
Gastrointestinal adverse effects are common (8% of patients). These are usually nausea, vomiting, and abdominal pain.
A photosensitive rash occurs in 1–2% of patients; it can be severe.
Anaphylactic reactions also occur.
Liver function test abnormalities occur in 5% of patients. In a small number this will progress to hepatitis.
Quinolones can cause tendon rupture; the risk is greater if there is existing tendonitis, or if the patient is elderly or taking corticosteroids; the Achilles tendon is often affected.
Quinolones have effects on the CNS. These include convulsions, restlessness, confusion, and hallucinations. If any of these occur, the drug should be withdrawn.
Rare adverse effects include haemolytic anaemia and hypoglycaemia.
Major drug-drug interactions
Quinolones enhance the effect of warfarin.
The risk of nephrotoxicity from ciclosporin is increased if it is given with quinolones.
Quinolones increase the plasma theophylline concentration; dosage reduction may be required.
There is an increased risk of convulsions from quinolones if they are given with NSAIDs.
Antacids significantly reduce the absorption of ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, and norfloxacin.
Monitoring
Safety and efficacy
Measures of clinical improvement are the most important, but inflammatory markers, such as the ESR and CRP, are often helpful.
Whenever possible, take cultures before staring antibiotic treatment. Check the sensitivities of the causative organism. Discuss any unusual results with a microbiologist.
Measure liver function tests, especially if long-term treatment is required (>7 days).
Patient information
Warn the patient of the risk of a rash and other hypersensitivity phenomena.
Warn women that if they develop diarrhoea, the oral contraceptive may be ineffective.
Prescribing information: Quinolones
There are many formulations of these drugs. The following are given as examples. Dosages and duration of treatment will depend on the indication. Check your local antibiotics policy.
Ciprofloxacin
By mouth, 250–750 mg twice daily.
By intravenous infusion, 200–400 mg twice daily. Infuse over 60 minutes.
Levofloxacin
By mouth, 250–500 mg once or twice daily.
By intravenous infusion, 500 mg once or twice daily. Infuse over 60 minutes.
Moxifloxacin
By mouth, 400 mg once daily.
By intravenous infusion, 400 mg once daily: infuse over 60 minutes.
Nalidixic acid (for urinary tract infections only)
By mouth, 900 mg every 6 hours.
Norfloxacin
By mouth, 400 mg twice daily.
Ofloxacin
By mouth, 200–400 mg once or twice daily.
By intravenous infusion, 200–400 mg once or twice daily. Infuse over 30–60 minutes.
Antituberculosis drugs BNF 5.1.9
A group of various anti-infective drugs that are effective against Mycobacterium tuberculosis
Fully-sensitive organisms
Rifampicin
Isoniazid
Pyrazinamide
(Ethambutol)
(Streptomycin; specialist used only)
Multidrug-resistant organisms
Streptomycin
Capreomycin
Cycloserine
Rifabutin (for prophylaxis in patients with a low CD4 count)
Immunization is recommended for:
Contacts of those with active respiratory TB
Immigrants from areas of high prevalence
Children aged 10–14
Healthcare workers
Laboratory staff
Veterinary staff
Prison/hostel workers
Those staying for more than 1 month in an area of high prevalence
Potential uses
Many drugs are available for the treatment of Mycobacterium tuberculosis (TB).
Treatment regimens are complex. Seek expert advice.
If the patient is immunocompromised (e.g. HIV infection), infection may be due to atypical mycobacteria. Seek expert advice.
Rifampicin is used to treat brucellosis and Legionnaires’ disease.
Always in combination with other drugs.
Contraindications and cautions
The standard treatment regimen can be given during pregnancy, but omitting streptomycin.
Ethambutol and streptomycin are best avoided in renal insufficiency.
If their use is essential, measure plasma concentrations to guide the dosage regimen.
These drugs can cause liver damage; take care in patients with hepatic insufficiency.
How to use
Take care to protect yourself and other contacts if TB is suspected.
TB is a notifiable disease (see teaching point box, p. 421 ).
The principle of standard treatment is that of an initial killing phase (triple therapy) followed by a long continuation phase.
The challenge of treating TB is that the bacteria divide slowly, so the kill rate is low.
The initial phase is usually for 2 months (after which sensitivities should be available).
The continuation phase is usually for 4 months; treatment is required for longer durations in some circumstances (e.g. non-pulmonary TB, resistant organisms).
Combination formulations are preferred for long-term treatment.
Multidrug resistance is an increasing problem, especially in some Eastern European countries (e.g. Latvia), parts of China, and Iran. Seek expert advice immediately.
Prevention of reactivation of latent TB
In those given chemotherapy or who are immunosuppressed.
Patients given steroids alone do not need prophylaxis.
The usual treatment is isoniazid alone for 6 months, or in combination with rifampicin for 3 months.
Contact prophylaxis
Give this to close contacts of those with established TB and to those who become tuberculin positive on testing.
See prescribing information for a dosage regimen.
Most common and most serious adverse effects
Rifampicin
Commonly causes a transient rise in transaminases.
Can cause a number of other recognized syndromes; these are rare.
Flu-like syndrome, abdominal and respiratory symptoms, shock, renal insufficiency, and thrombocytopenic purpura.
Isoniazid
Can cause a peripheral neuropathy.
This is more common in those with HIV infection, with chronic renal failure, who are malnourished, or who drink excess alcohol.
The incidence is reduced by giving pyridoxine 10 mg daily, which should be routine therapy with isoniazid.
Can also cause optic atrophy, convulsions, and psychosis.
The incidence can be reduced by giving pyridoxine.
Isoniazid can cause hepatitis; this is rare.
Pyrazinamide
Can cause rare but serious liver toxicity.
Ethambutol
This can damage visual acuity, especially if given in doses >25 mg/kg/day, or if the patient has renal insufficiency.
Major drug-drug interactions
Rifampicin is a classic example of a drug that induces hepatic enzymes. It will induce its own metabolism and that of a large number of other drugs.
See Carbamazepine, p. 285 for more information and a list.
Bacterial resistance to rifampicin develops very rapidly if it is given on its own; rifampicin should always be given in combination with other anti-infective drugs for treatment of active infection.
Isoniazid inhibits the metabolism of carbamazepine, phenytoin, diazepam, and theophylline. This will enhance their effect.
Monitoring
Safety and efficacy
Measures of clinical improvement are the most important.
Whenever possible, take cultures before starting antibiotic treatment. Sensitivities of the causative organism can take a month or more to be determined. Discuss your treatment strategy with an expert.
Measure the patient’s liver function tests weekly during the first 2 months of treatment, and thereafter only if there is any suggestion of liver toxicity.
Measure the patient’s visual acuity with a Snellen chart and colour vision using an Ishihara chart before starting treatment with ethambutol. Remeasure them if the patient complains of any visual symptoms.
Close supervision of patients given antituberculosis therapy is essential. If you think that there is a risk that they will not take the medication as directed, consider directly observed therapy (DOT) or admission to hospital.
Plasma concentration measurement is recommended for patients with renal insufficiency who are taking ethambutol or streptomycin. These are specialist assays; liaise with your laboratory before sending samples.
Ethambutol target peak concentration 2–6 mg/L (7–22 micromol/L) 2–5 hours after the dose; trough <1 mg/L (4 micromol/L).
Streptomycin target peak concentration 15–40 mg/L 1 hour after the dose; trough <5 mg/L.
Monitoring
Warn women that rifampicin reduces the effectiveness of the oral contraceptive. They should take additional precautions.
Warn the patient that rifampicin will make their urine and tears orange (and will stain soft contact lenses).
Advise the patient how to recognize the symptoms and signs of liver toxicity: jaundice, vomiting, and malaise. They should seek medical attention if any of these develop.
Prescribing information: Antituberculosis drugs
There are many formulations and regimens of these drugs. The following are given as examples only. Dosages and duration of treatment will depend on the precise clinical circumstances. A frequent cause of treatment failure is incorrect dosing by the prescriber. Seek expert advice and supervision.
Standard unsupervised treatment
Initial 2 month phase.
Rifampicin, isoniazid, and pyrazinamide, given as combination tablets (e.g. Rifater®); the doses vary according to weight (see product information).
rifampicin 600 mg daily
isoniazid 250 mg daily
pyrazinamide 1.5 g daily
ethambutol (if given) 15 mg/kg daily.
Continuation phase (4 months).
Rifampicin and isoniazid in combination tablets (e.g. Rifinah®); doses vary according to weight (see product information):
rifampicin 600 mg daily
isoniazid 300 mg daily.
Prevention of reactivation of latent TB or contact prophylaxis
Isoniazid 300 mg daily for 6 months or
Isoniazid 300 mg daily and rifampicin 600 mg daily for 3 months.
Supervised treatment (DOT)
This must be observed directly throughout.
Patients are given isoniazid, rifampicin, pyrazinamide, and ethambutol (or streptomycin) 3 times a week for the first 2 months, followed by isoniazid and rifampicin 3 times a week for a further 4 months.
Doses:
Rifampicin 600–900 mg 3 times a week.
Isoniazid 15 mg/kg (maximum 900 mg) 3 times a week.
Pyrazinamide 2.5 g 3 times a week.
Ethambutol 30 mg/kg 3 times a week.
Doctors in England and Wales have a statutory duty to notify a ‘proper officer’ of the local authority of suspected cases of certain infectious diseases. The proper officers are required every week to give the Communicable Disease Surveillance Centre (CDSC) details of each case of each disease that has been notified. The CDSC has responsibility for collating these weekly returns and publishing analyses of local and national trends. This is important, as it is a method of detecting, and so limiting, outbreaks.
List of notifiable diseases under the Public Health (Infectious Diseases) Regulations 1988: Some of the more common ones are highlighted in bold.
Acute encephalitis Acute poliomyelitis Anthrax Cholera Diphtheria Dysentery Food poisoning Leptospirosis Malaria Measles | Meningitis Meningococcal Pneumococcal Haemophilus influenzae Viral Other specified Unspecified Meningococcal septicaemia (without meningitis) Mumps | Ophthalmia neonatorum Paratyphoid fever Plague Rabies Relapsing fever Rubella Scarlet fever Smallpox Tetanus Tuberculosis | Typhoid fever Typhus fever Viral haemorrhagic fever Whooping cough Viral hepatitis Hepatitis A Hepatitis B Hepatitis C Other Yellow fever |
Acute encephalitis Acute poliomyelitis Anthrax Cholera Diphtheria Dysentery Food poisoning Leptospirosis Malaria Measles | Meningitis Meningococcal Pneumococcal Haemophilus influenzae Viral Other specified Unspecified Meningococcal septicaemia (without meningitis) Mumps | Ophthalmia neonatorum Paratyphoid fever Plague Rabies Relapsing fever Rubella Scarlet fever Smallpox Tetanus Tuberculosis | Typhoid fever Typhus fever Viral haemorrhagic fever Whooping cough Viral hepatitis Hepatitis A Hepatitis B Hepatitis C Other Yellow fever |
Antiviral Drugs: Antiviral guanine derivatives BNF 5.3, 11.3.3, and 13.10.3
Inhibit the replication of herpesviruses
Aciclovir
Valaciclovir (prodrug of aciclovir)
Penciclovir
Famciclovir (prodrug of penciclovir)
Ganciclovir is active against cytomegalovirus (CMV) (the other drugs are not) but is considerably more toxic. It is therefore reserved for the treatment of CMV infections
Valganciclovir (prodrug of ganciclovir)
Potential uses
Treatment and prophylaxis against herpesvirus (HSV 1 and 2) infection.
Ganciclovir only: treatment and prophylaxis against cytomegalovirus (CMV) infection.
Contraindications and cautions
Avoid the combination of ganciclovir with zidovudine, as this can cause profound myelosuppression.
The combination of ganciclovir with didanosine is better tolerated.
These drugs are given during pregnancy, but experience is limited. Seek expert advice.
No dosage adjustment is usually required in hepatic insufficiency.
Aciclovir is renally excreted. Reduce the dose in moderate to severe renal impairment.
Aciclovir can crystallize in the renal tubules if the patient is not adequately hydrated during treatment.
Ganciclovir:
Pregnancy (ensure effective contraception during treatment and barrier contraception for men during and for at least 90 days after treatment).
Breastfeeding (until 72 hours after last dose).
Caution if the neutrophil or platelet count is low; see adverse effects section.
How to use
See later notes for an approach to viral infections and the treatment of influenza.
Herpesvirus infection
These drugs are effective against HSV, but they do not eradicate the virus and so are only really effective when used early.
Valaciclovir is a prodrug of aciclovir. It is much better absorbed than aciclovir after oral administration.
Famciclovir is a prodrug of penciclovir; it is 70% available after oral administration.
The dosages of these drugs are different for each indication (see prescribing information for details) but they can be used for:
Treatment of:
generalized/systemic HSV infection, including encephalitis
skin and mucous membrane infections, including shingles and genital infection
chickenpox in adults; not usually necessary in children, in whom the disease is milder
keratitis and corneal ulcer; ganciclovir ophthalmic gel is available for acute herpetic keratitis.
Prophylaxis against:
HSV infection in immunocompromised patients
recurrent HSV infection, especially genital infections.
CMV infection (ganciclovir only)
CMV retinitis in patients with AIDS.
Initially, treatment is by intravenous infusion, followed by oral maintenance therapy.
Slow-release ocular implants containing ganciclovir can be inserted surgically to treat immediate sight-threatening CMV retinitis.
Local treatments do not protect against systemic infection or infection in the other eye.
Oral prophylaxis in liver and renal transplant patients.
Most common and most serious adverse effects
Ganciclovir is considerably more toxic than the other guanine derivatives.
About one-third of patients need to have the drug withdrawn owing to adverse effects.
Neutropenia is the most frequent adverse effect; suppression of production of the other blood components is also seen; these effects are usually reversible on withdrawal of the drug.
Patients who develop neutropenia and require continuing treatment with ganciclovir may benefit from therapy with G-CSF (granulocyte colony-stimulating factor).
5% of patients taking ganciclovir develop neurological adverse effects. These range from headache to confusion, hallucinations, and seizures.
Treatment with the other guanine derivatives is usually associated with few adverse effects.
Aciclovir can cause severe local inflammation at the site of intravenous infusion.
Neurological reactions are rarely seen and are associated with high plasma drug concentrations.
Major drug-drug interactions
Topical formulations do not usually cause drug interactions.
Ganciclovir is subject to more drug interactions than the other drugs in this class.
Ganciclovir can cause myelosuppression; the risk of this is increased when it is given with other drugs that can cause myelosuppression (e.g. didanosine, zidovudine, lamivudine).
Avoid these drugs with Primaxin® (imipenem with cilastatin); convulsions have been reported.
Monitoring
Safety
Ensure that patients who receive guanine derivatives by intravenous infusion are adequately hydrated.
Measure the full blood count (especially neutrophil and platelet counts) in patients receiving ganciclovir. The greatest risk is during intravenous treatment, but patients taking maintenance therapy should also have periodic checks.
Efficacy
Review patients with HSV infection to ensure the episode has resolved.
Consider prophylaxis when the disease is recurrent.
Arrange regular expert eye examinations for patients with CMV retinitis.
Patient information
Teach the patient taking long-term ganciclovir to recognize the signs of neutropenia (sore throat, skin infections) and thrombocytopenia (unexpected bruising or bleeding).
Prescribing information: Guanine derivatives
The following are given as examples.
Aciclovir
Treatment by mouth:
Herpes simplex, treatment, 200 mg (400 mg in the immunocompromised) 5 times daily, usually for 5 days.
Herpes simplex, prevention of recurrence, 200 mg 4 times daily or 400 mg twice daily, possibly reduced to 200 mg 2 or 3 times daily, and interrupted every 6–12 months.
Herpes simplex, prophylaxis in the immunocompromised, 200–400 mg 4 times daily.
Varicella zoster, treatment, 800 mg 5 times daily for 7 days.
Treatment by intravenous infusion:
Treatment of herpes simplex in the immunocompromised, severe initial genital herpes, and varicella zoster: 5 mg/kg every 8 hours usually for 5 days, doubled to 10 mg/kg every 8 hours in varicella zoster infection in immunocompromised patients and in herpes simplex encephalitis (usually given for 10 days in encephalitis).
Prophylaxis of herpes simplex in immunocompromised patients, 5 mg/kg every 8 hours.
Treatment by topical application:
Eye ointment, aciclovir 3%, apply 5 times daily (continue for at least 3 days after complete healing).
Skin cream, aciclovir 5%, apply to lesions every 4 hours (5 times daily) for 5–10 days, starting at the first sign of an attack.
Valaciclovir
Oral administration.
Herpes zoster, 1 g 3 times daily for 7 days.
Herpes simplex, first episode, 500 mg twice daily for 5 days (up to 10 days if severe); recurrent infection, 500 mg twice daily for 5 days.
Herpes simplex, suppression, 500 mg daily in 1–2 divided doses (in immunocompromised patients, 500 mg twice daily).
Ganciclovir
Intravenous infusion.
Initial (induction) treatment, 5 mg/kg every 12 hours for 14–21 days for treatment or for 7–14 days for prevention; maintenance (for patients at risk of relapse of retinitis) 6 mg/kg daily on 5 days per week or 5 mg/kg daily every day until adequate recovery of immunity; if retinitis progresses, initial induction treatment may be repeated.
Oral administration.
Maintenance treatment in AIDS patients when retinitis is stable (after at least 3 weeks of intravenous ganciclovir), use valganciclovir 900 mg daily with food.
Prevention of CMV disease in liver and kidney transplant patients, use valganciclovir 900 mg daily with food for 100 days.
Topical application for acute herpetic keratitis.
Ganciclovir 0.15% gel, apply 5 times daily until complete corneal re-epithelialization, then 3 times daily for 7 days (usual duration of treatment 21 days).
Most anti-infective drugs exploit the differences between human and infective cells; the relative simplicity of viruses and the fact that they incorporate themselves into human cells makes them difficult to treat.
For a long time treatment was entirely supportive, relying on the body’s immune system to clear the infection. However, better understanding of the processes of viral replication and the enzymes involved has led to the identification of several novel drug targets. The emergence of HIV infection as a global health problem accelerated this process.
Drugs used to treat viral infections are of several types:
Nucleoside analogues; these are incorporated into viral nuclear material and interfere with replication.
Zidovudine (and other nucleoside reverse transcriptase inhibitors).
Aciclovir.
Ribavirin.
Enzyme inhibitors; these exploit enzymes that are involved in viral replication only.
Non-nucleoside reverse transcriptase inhibitors.
Protease inhibitors.
Drugs that stimulate immune responses; these augment the body’s own defence processes.
Interferon alfa for hepatitis B.
Monoclonal antibodies directed against viral antigens.
Palivizumab for respiratory syncytial virus.
Patients often talk about ‘having the flu’, but this usually refers to infection with other viral causes of the common cold (e.g. adenoviruses). Infection with influenza virus is potentially life-threatening.
Prevention is more effective than treatment.
Influenza virus is antigenically unstable; the haemagglutinin (H) and neuraminidase (N) antigens on its surface change frequently. Large changes result in an epidemic as most people are not immune. The influenza vaccine available each year in the UK is different to provide cover for those strains that are considered most likely to be prevalent. For these reasons influenza vaccine cannot provide complete protection and will not control an epidemic. Immunization is only recommended for the following groups
Patients with:
chronic respiratory disease, including asthma
chronic heart disease
chronic renal failure
diabetes mellitus.
Patients who are immunosuppressed or who do not have a functioning spleen.
In anticipation of an outbreak that is expected to be widespread, key healthcare workers may also be immunized.
Prophylaxis with amantadine is of limited efficacy and is no longer recommended.
Treatment of influenza infection is largely supportive.
Zanamivir and oseltamivir are inhibitors of neuraminidase. If treatment with these drugs is started within 48 hours of the onset of symptoms, the duration of symptoms is shortened by 1 day. These drugs have not been convincingly to reduce morbidity or mortality. For this reason NICE has recommended that these drugs should not be prescribed in the NHS for otherwise healthy adults with influenza. Zanamivir can be given to patients in the high-risk groups (see earlier list) if treatment can be started within 48 hours of the onset of symptoms.
Antiviral Drugs: Drugs used to treat human immunodeficiency virus (HIV) infection BNF 5.3
Antiviral drugs
Nucleoside analogues (NRTI)
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stavudine
Tenofovir
Zalcitabine
Zidovudine
Non-nucleoside reverse transcriptase inhibitors (NNRTI)
Efavirenz
Nevirapine
Protease inhibitors (PI)
Amprenavir
Indinavir
Lopinavir plus ritonavir
Nelfinavir
Ritonavir
Saquinavir
Potential uses
Treatment of infection with HIV.
Remember that these drugs suppress viral replication but do not effect a cure.
They are not a treatment for opportunistic organisms that cause infections in patients with AIDS.
Contraindications and cautions
In hepatic insufficiency.
Avoid abacavir, ritonavir, saquinavir, nelfinavir, efavirenz, nevirapine, and zalcitabine.
Reduce the dose of indinavir from 800 mg tds to 600 mg tds.
Most of the nucleoside analogues can be used.
In renal insufficiency.
Avoid abacavir, amprenavir, ritonavir, lopinavir.
Reduce the dose of the nucleoside analogues.
Stavudine: give half the dose in mild to moderate insufficiency. Give one-quarter the dose if severe.
Zalcitabine: give two-thirds of the dose in mild insufficiency. Give one-third of the dose in moderate insufficiency.
Zidovudine: give half the dose in severe insufficiency.
Dosage reduction may also be required for didanosine and lamivudine.
Zidovudine is also known as AZT; avoid this abbreviation, as it can be confused with azathioprine.
These drugs are not recommended during pregnancy. However, they are sometimes given to pregnant women to reduce the risk of transmission of HIV to the baby. This is very a specialized area of practice; seek expert advice.
How to use
Treatment of HIV infection is complex and should be under the direction of a specialist. The following is offered as a general guide. It is based on the British HIV Association guidelines (see guidelines section at http://www.bhiva.org).
Acute seroconversion should usually be treated aggressively. The virus may be at its most vulnerable and least diverse at this point. However, treatment is unlikely to eradicate the virus.
The decision when to treat established infection is not straightforward. On the one hand, HIV is an infectious disease and should be treated hard and early. But in the asymptomatic patient this must be balanced against the toxicity of treatment, stringencies of the treatment regimen, and uncertainty as to whether early treatment will improve long-term outcome or simply drive the emergence of resistant virus. See box, p. 430 , for current suggested guidelines on when to treat.
There are several highly active antiretroviral treatment regimens (HAART). None has been shown to be definitively better than any other. See Table 5.1 for guidance about choice of regimen.
It is beyond our scope to discuss the appropriate strategy in the event of virological failure of treatment.
It is generally considered to be better to continue treatment, even if there has been virological failure; withdrawal of drug treatment causes a significant rebound in viral replication.
The formulations of these drugs are not interchangeable.
Many of these drugs have been developed and licensed on the basis of surrogate rather than clinical outcome data. See teaching point box, p. 433 , for a discussion of this.
Primary HIV infection
Treat as soon as possible, ideally within 6 months.
Asymptomatic HIV infection
CD4 count >350 × 106 cells/L: defer treatment.
CD4 count 200–300 × 106 cells/L: offer treatment.
CD4 count <200 × 106 cells/L: treatment recommended.
Symptomatic HIV infection
Treat whatever the CD4 count or viral load.
| Regimen | Advantages | Disadvantages |
|---|---|---|
2NTRIs + NNRTI | Good surrogate data (recommended) | Lack of clinical endpoint outcome data |
2NRTI + PI | Long-term | Toxicity common |
Complex regimen | ||
2NTRI + 2PI | Good surrogate outcome data | Lack of clinical endpoint data |
Potential for drug interactions | ||
3NRTI | Few drug interactions | May be less effective |
| Regimen | Advantages | Disadvantages |
|---|---|---|
2NTRIs + NNRTI | Good surrogate data (recommended) | Lack of clinical endpoint outcome data |
2NRTI + PI | Long-term | Toxicity common |
Complex regimen | ||
2NTRI + 2PI | Good surrogate outcome data | Lack of clinical endpoint data |
Potential for drug interactions | ||
3NRTI | Few drug interactions | May be less effective |
Most common and most serious adverse effects
Adverse effects of these drugs are very common.
Protease inhibitors
As a group, these drugs are associated with metabolic abnormalities.
Abnormalities of lipid metabolism, characterized by raised cholesterol and triglycerides; consider switching to a non-protease inhibitor, or giving a statin or fibrate as appropriate.
Lipodystrophy, characterized by atrophy and hypertrophy (fat redistribution), which can be very distressing; the incidence of this has been very variable between studies.
Insulin resistance and worsening of diabetic control; If treatment is required, metformin is preferred.
If the patient is co-infected with hepatitis C virus there is an increased risk of liver abnormalities.
Notes on specific drugs:
nelfinavir, mild to moderate diarrhoea
indinavir, risk of renal stones and crystalluria, hyperbilirubinaemia
ritonavir, taste changes, nausea, diarrhoea, perioral tingling
saquinavir, nausea, diarrhoea, abdominal pain, and headache
amprenavir, nausea, diarrhoea, rash (usually in the first 2 weeks), perioral tingling.
Nucleoside analogues (NRTI)
As a group these can cause:
Lactic acidosis, which can be fatal and is most associated with long-term treatment; it is difficult to predict those at greatest risk.
Hepatic steatosis.
Notes on individual drugs:
Abacavir, life-threatening hypersensitivity (for information on HLA B*5701 and pharmacogenetic testing, see p. 586 ); pancreatitis.
Didanosine, pancreatitis.
Lamivudine, hepatic steatosis.
Stavudine, peripheral neuropathy.
Tenofovir, renal impairment and hypophosphataemia.
Zalcitabine, peripheral neuroathy, pancreatitis.
Zidovudine, hepatic impairment, anaemia.
Non-nucleoside reverse transcriptase inhibitors
As a group, these drugs are better tolerated than other antiretroviral drugs.
Efavirenz:
can cause dysphoria
rash, usually in the first 2 weeks and resolving after 1 month; withdraw the drug if it is very severe
hypercholesterolaemia.
Nevirapine:
rash, which can be severe (Stevens–Johnson syndrome)
hepatitis, which can be fulminant.
Major drug-drug interactions
Drug interactions are common, both with drugs for other indications and with other HIV drugs. This is not always detrimental. For example, ritonavir inhibits the metabolism of other protease inhibitors, increasing their effect.
Protease inhibitors
The protease inhibitors are inhibitors of hepatic CYP3A4 (see Macrolides, p. 402 , for more information).
Ritonavir is a particularly potent inhibitor and also increases the effects of opioids, tricyclic antidepressants, SSRIs, triptans, antifungal drugs, antipsychotic drugs, and bupropion (amfebutamone).
Ritonavir and some other protease inhibitors increase the metabolism of the oral contraceptive. This may make it less effective. Warn women about this.
Nucleoside analogues (NRTI)
Do not give with co-trimoxazole (increases lamivudine concentration).
Do not give ganciclovir with zidovudine; this can cause bone marrow suppression.
Non-nucleoside reverse transcriptase inhibitors
These drugs can interact with grapefruit juice; avoid this (see p. 401 ).
Enzyme-inducing drugs (see Carbamazepine, p. 286 ); reduce the concentrations of these drugs.
These drugs can affect the metabolism of other anti-HIV drugs; use an established regimen.
These drugs increase metabolism of the oral contraceptive. This may make it less effective. Warn women about this.
Monitoring
Safety
Zidovudine—measure a full blood count every 2 weeks for the first 3 months of treatment, and monthly thereafter.
Tenofovir—measure renal function and the serum phosphate concentration monthly.
Nevirapine—measure liver function tests every 2 weeks for 2 months, and every 3–6 months thereafter.
It has been suggested that patients taking long-term nucleoside analogues should have their anion gap, pyruvate, and lactate measured. However, it has not been established that this predicts the onset of lactic acidosis, so it is not routinely recommended.
Efficacy
This is complex. In general, the patient’s CD4 count is more predictive of the outcome in late disease, whereas the viral load (HIV-1 RNA copies/mL) is more predictive in early disease.
Plasma drug concentration monitoring is still under development and is not routinely recommended. However, it may be useful, given that low plasma concentrations of drugs are associated with failure of treatment. At present, consider it for patients with liver insufficiency and those with adverse effects other than hypersusceptibility reactions ( p. 16 ).
Patient information
HAART regimens are complex and require considerable self-discipline to take correctly. These drugs will not be effective if taken randomly. Incorrect administration will promote viral resistance.
These drugs can reduce the effectiveness of the oral contraceptive. Patients infected with HIV should use barrier methods of contraception to reduce the risk of transmission of HIV.
Nelfinavir, saquinanvir, and lopinovir (with ritonavir) must be taken with food.
Indinavir and didanosine must be taken on an empty stomach.
Warn women about interactions with oral contraceptives.
A 32-year-old man with HIV infection had been taking zidovudine with lamivudine (Combivir®) for 5 years, prescribed by a specialist HIV centre. He attended his GP because he felt tired most of the time and the GP requested a full blood count. The result showed a borderline anaemia with a haemoglobin concentration of 11.2 g/dL, but the mean cell volume (MCV) was markedly raised at 119 fl.
Macrocytosis is very common in patients taking zidovudine. It is worth establishing that there is no vitamin B12 deficiency, which can also occur with zidovudine therapy, but macrocytosis in this setting usually does not require further investigation.
A 26-year-old woman with HIV infection was admitted to hospital with a severe generalized maculopapular rash and mucositis. 2 weeks earlier she had started to take a single tablet a day of the combination product Atripla®, containing efavirenz, emtricitabine, and tenofovir. A drug-induced rash was suspected, and because of a concern about Stevens–Johnson syndrome she was admitted to hospital. Despite withdrawal of the antiretroviral drugs, the rash showed little sign of subsiding 10 days later.
Efavirenz was the most likely culprit in this case. It has a very long half-life, and adverse effects can persist for up to a month.
Prescribing information: Drugs used to treat HIV infection
There are many regimens. Seek expert advice.
It is often difficult to measure the therapeutic effect of a drug directly.
For example, the effect of an antihypertensive drug on BP may appear to be a simple outcome measure. However, it is not the BP per se that we are most interested in, but rather the long-term reduction in risk of stroke or cardiovascular disease. These cannot be measured directly, and may not appear clinically for many years. BP is a useful surrogate, because we know that lowering BP lowers the risk of stroke.
The situation in many other disease states is less clear. Many of the drugs used to treat HIV infection were granted licences quickly on the basis of effects on CD4 count and viral load rather than long-term clinical outcome. This may be appropriate when there are no effective treatments for a fatal disease, but it is essential to try to identify surrogates that are clinically relevant. Ideally, these should also include some measures of functional outcome, not just changes in biochemical markers.
Another disadvantage of the surrogate approach is that it may not take into account the morbidity/mortality effect of late adverse effects of the drug. Drugs used to treat HIV carry a considerable risk of serious adverse effects. Always consider these along with the potential benefits.
Plasma drug concentration measurement is often neglected in clinical trials, but it can give useful information about exposure in individuals who do not respond or who develop adverse effects.
Based on the UK guidelines from the Department of Health ( http://www.advisorybodies.doh.gov.uk/eaga).
Prevention is more important than post-exposure prophylaxis. HIV is not the only virus that can be transmitted (e.g. hepatitis B and C).
Always follow guidelines when dealing with blood and other potentially contaminated material. Note that vomit, faeces, and urine are not considered high-risk unless they are blood-stained. Dispose of any sharps yourself. Do not expose others to risk by negligent behaviour.
Percutaneous injury This carries the greatest risk, especially when there is frank contamination of the needle by blood. The risk of transmission is about 3 in 1000.
Exposure of broken skin Eczema, abrasions.
Exposure of mucous membranes (e.g. the eyes). The risk of transmission is about 1 in 1000.
Encourage any wound to bleed, but do not suck it. Wash with water. Irrigate mucous membranes with water. Do not use antiseptics.
Contact the appropriate person (e.g. microbiologist, infectious diseases consultant, virologist) to discuss post-exposure drug treatment. This should include a discussion of the risk that the contaminated material poses. If the source is known, consider testing for HIV. This request should NOT be made by the person who has been exposed. Not all exposures are high-risk and drug treatment is not always necessary.
If drug treatment is deemed appropriate it should be readily available. Ideally, this should start as soon as possible after exposure, but it is worth considering up to 2 weeks after exposure.
A typical regimen consists of:
One Truvada® tablet—245 mg tenofovir plus 200 mg emtricitabine (FTC) once a day.
Plus two Kaletra® film-coated tablets (200 mg lopinavir plus 50 mg ritonavir) twice a day.
Make sure that the exposed individual has appropriate follow-up and support (e.g. with occupational health).
Investigate the circumstance of the exposure and change practice if mistakes have been made.
Antifungal Drugs: Imidazole and triazole antifungal drugs BNF 5.2, 7.2.2, 12.3.2, and 13.10.2
Inhibitors of fungal ergosterol synthesis
Triazoles
Fluconazole
Itraconazole
Voriconazole
Imidazoles
Ketoconazole
Miconazole
Drugs used topically
Clotrimazole
Fenticonazole
Sulconazole
Tioconazole
Polyenes (see p. 440 ).
Caspofungin and anidulafungin. Belong to a group of echinocandin antifungal agents which are lipopeptide agents that inhibit fungal cell wall growth. Caspofungin is active against Aspergillus spp., and both agents are used for the treatment of invasive candidiasis.
Flucytosine. Converted to fluouracil in fungal cells. Synergistic with amphotericin. Can cause bone marrow depression. Resistance is common.
Griseofulvin. Largely replaced by newer drugs. Binds to keratin, making it more resistant to fungal infection.
Terbinafine Used for fungal nail infections, and treatment of ringworm. Seek specialist advice.
Potential uses
Treatment of infection by Candida spp.
Mucosal and skin infections—commonly treated topically.
Invasive infections—fluconazole first-line; alternatively, give amphotericin with flucytosine.
Cryptococcal infection
Treatment (e.g. meningitis).
Prevention in patients with AIDS—fluconazole; alternatively, give amphotericin with flucytosine.
Aspergillus infection. Itraconazole is a second-line option.
Histoplasmosis (rare in temperate climates).
Indolent infection—itraconazole or ketoconazole.
Severe infection—can be life threatening in patients with AIDS; itraconazole, given intravenously, is an option.
Fungal skin and nail infections—treatment usually topical.
Prevention of fungal disease in immunocompromised patients—fluconazole.
Contraindications and cautions
Most of the following cautions apply to systemic rather than topical administration of these drugs.
Miconazole is given topically for oral infections, but is absorbed systemically and can cause drug interactions (see later notes).
Ketoconazole and itraconazole carry a particular risk of liver damage; the risk from fluconazole is much lower.
Itraconazole or ketoconazole should not be used unless the potential benefits are significant (see earlier notes).
Avoid systemic administration of these drugs if there is a history of liver disease; if treatment is essential use lower doses.
If the patient has renal insufficiency, avoid giving itraconazole or ketoconazole; give the usual first dose of fluconazole, but halve subsequent doses if the patient has mild or moderate renal insufficiency.
Long-term use of these drugs can cause congenital abnormalities if given during pregnancy.
Antifungal drugs can precipitate heart failure. Avoid them in patients with cardiac disease, especially if they are taking drugs with negative inotropic actions (e.g. calcium channel blockers).
How to use
Antifungal drugs are used for two types of clinical problem:
Non-invasive local infections; in this case, topical treatment is usually appropriate.
Invasive disease, often in vulnerable patients (e.g. those with AIDS); in this case, specialist advice and supervision is essential.
Infection by fungi is commonly an indication of immunocompromise.
Investigate the underlying cause.
Culture and identification of fungi is a specialized procedure.
Tell the laboratory if you suspect fungal infection and take advice about what sort of samples to send.
Topical treatment
Genital infection (especially vaginal candidiasis) Topical treatment with a pessary, or fluconazole by mouth, is appropriate. Recurrence is more common in diabetes mellitus. If recurrent, consider the partner as a possible source.
Eyes Infection is uncommon but can occur after agricultural injuries. There are no licensed topical formulations for application to the eye. Seek specialist advice. Can also present with metastatic endophthalmitis.
Ears For treatment of fungal otitis externa.
Oropharynx The decision to treat topically or systemically will depend on the extent of the infection.
Skin Systemic treatment is usually necessary for scalp or nail infections. Seek specialist advice and take skin scrapings to confirm the diagnosis.
Most common and most serious adverse effects
The following adverse effects are usually associated with systemic administration.
Adverse effects from local administration are rare. The most common is local irritation.
Antifungal drugs can cause a rash and other hypersensitivity phenomena.
Rashes can be severe (including Stevens–Johnson syndrome) and are more common in patients with AIDS.
Antifungal drugs commonly cause nausea, vomiting, and abdominal pain.
Antifungal drugs can cause bone marrow suppression.
Antifungal drugs can cause hepatotoxicity; this is characterized by cholestatic jaundice.
The risk is lower with fluconazole.
The risk is increased if treatment exceeds 1 month.
Itraconazole can cause heart failure. This risk is increased if it is given in high doses for long periods.
Long-term oral treatment with these drugs can cause hypokalaemia, oedema, and peripheral neuropathy.
Major drug-drug interactions
Antifungal drugs interact with many other drugs, the following refers to systemic administration.
Antifungal drugs inhibit cytochrome P450 enzymes (see Macrolides, p. 401 ); this means that they increase the actions of many other drugs.
The absorption of ketoconazole depends on an acid environment in the stomach. Antacids will reduce its absorption.
Ketoconazole can cause a disulfiram-like (Antabuse®) reaction if taken with alcohol.
Monitoring
Safety and efficacy
Specific monitoring is not usually required for topical treatment, other than appropriate clinical review.
Measures of clinical improvement are the most important, but inflammatory markers, such as the ESR and CRP, are often helpful.
Whenever possible, take cultures before starting antifungal treatment. Check the sensitivities of the causative organism. Discuss any unusual results with a microbiologist.
Long-term treatment with itraconazole or ketoconazole.
Measure liver function tests after 14 days of treatment and monthly thereafter.
Measure the full blood count and plasma electrolytes regularly if long-term systemic treatment is required.
Monitoring
Advise the patient to seek urgent medical attention if they develop symptoms of:
Liver toxicity (jaundice, pale stools, dark urine).
Bone marrow suppression (easy bruising, bleeding).
Topical vaginal formulations damage latex condoms and diaphragms.
Prescribing information: Antifungal drugs
The following are given as examples. Dosages and durations of treatment will depend on the indication. Check your local antibiotics policy.
Fluconazole
By mouth for mucosal candidiasis, 50 mg daily for 7–14 days.
By mouth or by intravenous infusion, for invasive candidal infections, initially 400 mg daily.
Long-term treatment usually 200 mg daily.
By mouth, for prevention of fungal infections in the immunocompromised, 50–400 mg daily.
Itraconazole
By mouth or intravenous infusion for systemic aspergillosis, 200 mg twice daily.
Reduced to 200 mg once-daily if responding.
Clotrimazole (Canesten®)
1% cream, spray, powder, and solution for topical application for skin infections.
For vaginal candidiasis:
Pessary 500 mg, one daily.
Vaginal cream 10%.
Safe and effective (balanced) prescribing is all about establishing a balance between potential harm and benefit. It requires a multi-dimensional assessment, which takes into account:
The severity of the underlying disease.
The size and nature of the benefit of the treatment proposed.
The likelihood that the patient will benefit.
The extent and nature of harm attributable to the treatment proposed.
The frequency of adverse outcomes attributable to the treatment.
The extent to which the information available reliably answers these questions in the patient.
The cost effectiveness of the treatment.
The management of fungal toenail infection with terbinafine is a good test case. The condition is rarely anything more than a cosmetic problem in non-diabetics and non-immunocompromised people. Treatment is usually for at least 3 months, and cure rates of around 75% are reported compared with a placebo cure rate of 20% at best. Minor adverse effects are relatively common (gastrointestinal disturbances, headache) and major adverse effects are rare but can be severe (liver toxicity and even fulminant liver failure). Treatment costs around £150. It is a difficult balance to strike, and some Primary Care Trusts have attempted to outlaw its use on the grounds that it is a ‘lifestyle’ treatment rather than a medical necessity (see also p. 238 ). Patients, however, continue to demand treatment and they must be given the correct information to make a difficult decision.
Antifungal Drugs: Polyene antifungal drugs BNF 5.2, 7.2.2, 12.3.2, and 13.10.2
Antifungal drugs
Nystatin
Amphotericin: standard and lipid formulations
Amphotericin in a lipid complex (Abelcet®)
Amphotericin encapsulated in liposomes (AmBisome®)
Potential uses
Nystatin is used only for superficial infections. Amphotericin is generally used for systemic infections.
Treatment of infection by Candida spp.
Mucosal and skin infections commonly treated topically, nystatin and amphotericin.
Invasive infections, intravenous amphotericin plus flucytosine.
Cryptococcal infection.
Treatment of meningitis, intravenous amphotericin plus flucytosine.
Aspergillus infection, amphotericin first-line.
Histoplasmosis (rare in temperate climates).
Severe infection can be life threatening in patients with AIDS; intravenous amphotericin, first-line.
Contraindications and cautions
Most cautions apply to systemic rather than topical administration of these drugs.
Nystatin and amphotericin are not absorbed systemically when given by mouth.
If the patient has renal insufficiency, do not use unless there is no alternative.
These drugs are not known to be harmful during pregnancy, but do not use them unless the potential benefits are clear.
How to use
These drugs are used for two types of clinical problem:
Non-invasive local infections, for which topical treatment is usually appropriate.
Invasive disease, often in vulnerable patients (e.g. immunosuppressed patients or those in intensive care); in these cases, specialist advice and supervision is essential.
Infection by fungi is commonly an indication of immunocompromise.
Investigate the underlying cause.
Culture and identification of fungi is a specialized procedure.
Tell the laboratory if you suspect fungal infection and take advice about what sort of samples to send.
Amphotericin penetrates tissues poorly; the doses required commonly cause nephrotoxicity.
Lipid formulations allow higher doses to be given without toxicity, but are considerably more expensive.
Keeping the patient well hydrated will reduce the risk of nephrotoxicity.
The doses of conventional and lipid formulations vary considerably; serious errors have occurred (see case history box, p. 443 ); check the dose form and calculation carefully.
Topical treatment
Genital infections (especially vaginal candidiasis) Topical treatment with a nystatin pessary or cream is appropriate. Recurrence is more common in diabetes mellitus. If there is recurrence, consider the partner as a possible source.
Treatment is usually for 14–28 days.
Oral and perioral infections The decision to treat topically or systemically (with an imidazole) will depend on the extent of the infection. Nystatin is available as a suspension for local treatment of oral infections.
Skin infections Seek specialist advice and take skin scrapings to confirm the diagnosis. Nystatin is effective for skin infections due to Candida spp., but not those due to dermatophytes. See Imidazoles, p. 436 .
Most common and most serious adverse effects
Nystatin is too toxic to be given systemically, but adverse effects after topical administration are rare. The most common is local irritation.
Adverse effects due to amphotericin given systemically are common.
Amphotericin can cause anaphylactic reactions, both IgE-mediated reactions and non-IgE-mediated (i.e. anaphylactoid) reactions (see Acetylcysteine, p. 703 .
give a test dose before starting regular treatment (e.g. 1 mg in 10 mL of 5% glucose over 30 minutes).
Febrile reactions, nausea, and vomiting are common.
Amphotericin can cause rashes, which can be severe (including the Stevens–Johnson syndrome); these reactions can be treated with hydrocortisone and antipyretics, which should be reserved for those with severe symptoms, as steroids can exacerbate hypokalaemia due to amphotericin.
Rapid infusion of amphotericin can cause cardiac arrhythmias; give the dose over 2–4 hours.
Nephrotoxicity is almost universal and usually dose-limiting; it is due to renal vasoconstriction and a direct toxic effect on the renal tubules; lipid formulations are less nephrotoxic.
hypokalaemia and hypomagnesaemia can occur.
Other adverse effects include convulsions, peripheral neuropathy, hearing loss, and hepatotoxicity; amphotericin should be withdrawn if these occur.
Major drug-drug interactions
The following refers to systemic administration of amphotericin.
Avoid giving amphotericin with cytotoxic or other nephrotoxic drugs (e.g. ciclosporin); the risk of nephrotoxicity is very great.
Amphotericin can cause hypokalaemia.
Corticosteroids can exacerbate this.
Avoid diuretics.
Hypokalaemia can precipitate digitalis toxicity.
Monitoring
Safety and efficacy
Specific monitoring is not usually required for topical treatment, other than appropriate clinical review.
Measures of clinical improvement are the most important, but inflammatory markers, such as the ESR and CRP, are often helpful in systemic infections.
Whenever possible, take cultures before starting antifungal drug treatment. Check the sensitivities of the causative organism. Discuss any unusual results with a microbiologist.
Treatment of a systemic fungal infection often requires a long course.
Monitor renal function closely. The manufacturers advise that treatment should be suspended if the serum creatinine rises above 260 micromol/L.
Monitoring should include electrolytes; treat hypokalaemia, which can be accompanied by hypomagnesaemia.
Measure a full blood count and liver function tests at least weekly; withdraw amphotericin if liver function tests become abnormal.
Patient information
Topical vaginal creams, but not pessaries, damage latex condoms and diaphragms.
Nystatin cream stains clothing yellow.
Prescribing information: Polyene antifungal drugs
The following are given as examples. Dosages and durations of treatment will depend on the indication. Check your local antibiotics policy.
Amphotericin
Conventional injection form (e.g. Fungizone®). By intravenous infusion, for systemic fungal infections.
Initially 250 micrograms/kg daily, gradually increased to 1 mg/kg over 2–4 days.
Can be increased to a maximum of 1.5 mg/kg daily in severe infections, if tolerated.
Consider lipid formulations if nephrotoxicity is dose-limiting. Seek specialist advice.
Nystatin
For skin infections due to Candida spp.
Cream or ointment 100 000 units/g, apply 2–4 times daily.
For oral or perioral fungal infections.
Oral suspension (100 000 units/mL), 100 000 units 4 times daily after food.
In 2007, two patients with cancers were due to be given amphotericin intravenously for presumed fungal infections. The prescribing doctor was not experienced in the use of amphotericin and tried to get help, but eventually prescribed it using the data available in the BNF. What the doctor did not know was that whereas the dose of conventional amphotericin (Fungizone®) is 1 mg/kg, lipid formulations are used in a dose of 5 mg/kg. Confusion arose between the products, and Fungizone® was given in a dosage that was appropriate for the lipid formulations (i.e. at five times the correct dose). Both patients died.
Many drugs are available in different formulations, and confusion between them can give rise to serious problems. Amphotericin is used in the treatment of systemic fungal infections, but its toxicity is high. Lipid formulations reduce some of the toxicity (particularly in the kidneys), but they are expensive and many hospitals reserve their use for patients who are unable to tolerate standard formulations or who are at a high risk of nephrotoxicity. The dosage regimens are significantly different between the formulations, and deaths have occurred when the wrong product was prescribed or dispensed.
Antimalarial drugs BNF 5.4.1
The drugs listed here are not interchangeable. The choice of drug should be directed by a specialist familiar with resistance patterns.
Drugs used for prophylaxis
(Note the importance of protection from bites)
Chloroquine and proguanil
Mefloquine (Lariam®)
Proguanil with atovaquone (Malarone®)
Doxycycline
Drugs used for treatment of malaria
‘Benign’ malarias P. vivax, malariae, and ovale
Chloroquine followed by primaquine
Acute uncomplicated falciparum malaria
Quinine (followed by pyrimethamine with sulfadoxine (Fansidar®) or doxycycline
Artemether with lumefantrine
Mefloquine
Proguanil with atovaquone
Complicated falciparum malaria
Intravenous quinine
Intravenous artesunate (artemisinin derivative)
Intramuscular artemether (artemisinin derivative)
Potential uses
Contraindications and cautions
The choice of drug for treatment or prophylaxis depends on the risk and resistance patterns for the area of proposed travel.
Patterns of resistance are constantly changing; seek up-to-date advice
The risk of malaria varies widely, depending on the proposed area of travel; the risk is often low in large cities; take a detailed history of the proposed itinerary so that the risk can be evaluated fully
Pregnancy.
Quinine is preferred because there is considerable experience of its use.
Do not give doxycycline; it stains the baby’s teeth.
Do not give primaquine during pregnancy; continue chloroquine until after delivery.
If proguanil is required, give it with folic acid 5 mg daily.
Avoid Maloprim® (pyrimethamine plus dapsone) and Malarone® (proguanil plus atovaquone); mefloquine may be safe.
Epilepsy.
Avoid chloroquine and mefloquine.
Doxycycline interacts with some antiepileptic drugs.
If pyrimethamine is required, and the patient is taking phenytoin or phenobarbital, give folic acid 5 mg daily.
Mefloquine lowers the seizure threshold.
Renal insufficiency.
Proguanil is renally excreted; avoid it.
Avoid Malarone® and chloroquine in moderate to severe renal insufficiency.
Mefloquine and doxycycline are usually safe.
G6PD deficiency.
Take care with chloroquine, primaquine, pyrimethamine plus dapsone, and quinine; see teaching point box, p. 449 .
Cardiac conduction defects.
Avoid quinine and artemether plus lumefantrine; they can prolong the QT interval.
Clinical features
Impaired consciousness, convulsions
Respiratory distress
Jaundice
Bleeding
Shock
Biochemical features
Renal impairment (serum creatinine >265 micromol/L or urine output <400 mL/day)
Acidosis (plasma bicarbonate <15 mmol/L)
Hepatic impairment (transaminases >3 times normal)
Hypoglycaemia (blood glucose <2.2 mmol/L)
Hypoxia (PO 2 <8 kPa on room air)
Haematological features
Parasitaemia >5%
Haemoglobin <6 g/L or haematocrit <20%
Evidence of disseminated intravascular coagulation (DIC)
How to use
Malaria prophylaxis
Always seek up-to-date specialist advice, as patterns of malarial resistance are constantly changing.
Other measures, such as avoidance, bed nets, and repellent sprays (diethyltoluamide/DEET), are as important for the prophylaxis of malaria as drug treatment. You cannot catch malaria unless you are bitten.
Treatment of malaria
Infection by P. falciparum can be fatal (see box on features of severe malaria). In most cases, patients suspected of having P. falciparum infection should be admitted to hospital for investigation and treatment.
Symptoms and signs of malaria may present as early as 7 days after exposure (average 10–21 days). Longer incubation periods can occur in patients who have been taking chemoprophylaxis or selected antibacterial drugs (e.g. co-trimoxazole, tetracycline, macrolides, chloramphenicol, and quinolones). Incubation periods for P. falciparum of 6–18 months are unusual, but are on record. Malaria due to infections with P. vivax, P. ovale, or P. malariae can take up to 12 months to the first manifestation.
The presentation of P. falciparum malaria is very variable and it can mimic many other diseases.
Have a high index of suspicion in anyone who has returned from a malarious region.
The diagnosis is usually made from examination of a blood smear.
A negative smear does not exclude the diagnosis.
The box indicates the suitable treatments, but seek expert advice in each case.
Most common and most serious adverse effects
| Drug | |||||||
|---|---|---|---|---|---|---|---|
| Quinine | Mefloquine | Primaquine | Proguanil | Proguanil plus atovaquone | Pyrimethamine (commonly combined with other drugs e.g. dapsone, sulfadoxine) | Artemisinin derivatives | |
Relatively common | ‘Cinchonism’ (tinnitus, hot flushed skin, abdominal pain, rash) | Sleep disorders (insomnia, abnormal dreams) | Mouth ulcers, stomatitis, hair loss | Mouth ulcers, stomatitis, hair loss Abnormal dreams and insomnia | Sleep disturbances Myalgia Rashes | ||
Rare but serious | Angio-oedema Temporary blindness and other visual disorders Thrombocytopenia (can cause DIC) | Neurological symptoms (<1%) Sensory and motor neuropathy Tremor and ataxia Anxiety, depression, panic, and psychosis Convulsions Rashes (urticaria most common, but can cause Stevens–Johnson syndrome) | Methaemo-globinaemia Haemolytic anaemia Leucopenia | Urticaria and angio-oedema | Urticaria and angio-oedema Visual disturbances | Methaemo-globinaemia Thrombocytopenia Psychosis Jaundice Eosinophilic pulmonary infiltrates | |
| Drug | |||||||
|---|---|---|---|---|---|---|---|
| Quinine | Mefloquine | Primaquine | Proguanil | Proguanil plus atovaquone | Pyrimethamine (commonly combined with other drugs e.g. dapsone, sulfadoxine) | Artemisinin derivatives | |
Relatively common | ‘Cinchonism’ (tinnitus, hot flushed skin, abdominal pain, rash) | Sleep disorders (insomnia, abnormal dreams) | Mouth ulcers, stomatitis, hair loss | Mouth ulcers, stomatitis, hair loss Abnormal dreams and insomnia | Sleep disturbances Myalgia Rashes | ||
Rare but serious | Angio-oedema Temporary blindness and other visual disorders Thrombocytopenia (can cause DIC) | Neurological symptoms (<1%) Sensory and motor neuropathy Tremor and ataxia Anxiety, depression, panic, and psychosis Convulsions Rashes (urticaria most common, but can cause Stevens–Johnson syndrome) | Methaemo-globinaemia Haemolytic anaemia Leucopenia | Urticaria and angio-oedema | Urticaria and angio-oedema Visual disturbances | Methaemo-globinaemia Thrombocytopenia Psychosis Jaundice Eosinophilic pulmonary infiltrates | |
Major drug-drug interactions
Drugs that prolong the QT interval (quinine and artemether plus lumefantrine) should not be given with other drugs that prolong the QT interval: antiarrhythmic drugs, some antihistamines (e.g. terfenadine), macrolide and quinolone antibiotics, imidazole and triazole antifungal drugs, and antipsychotic drugs.
Many of these drugs lower the seizure threshold (see earlier notes); this will reduce the efficacy of antiepileptic drugs.
Quinine increases the plasma digoxin concentration and can cause digoxin toxicity.
Monitoring
Safety
Patients who require quinine for the treatment of malaria are usually very ill.
Measure the blood glucose concentration before and often during treatment. Treat hypoglycaemia.
Measure the patient’s core temperature, respiratory rate, BP, level of consciousness.
Laboratory measurements should include: regular measurement of haemoglobin, glucose, urea and creatinine, electrolytes, liver function, and acid–base status.
Monitor fluid balance carefully. Avoid over- and underhydration. Fluid overload is dangerous; it can precipitate potentially fatal respiratory failure. However, hypovolaemia can potentiate renal failure, metabolic acidosis, and circulatory collapse. Accurate recording of fluid input and output is essential. Frequent central venous pressure (CVP) monitoring is recommended; maintain the CVP at 0–5 cm of water.
Monitor urine output constantly and carefully observe for the appearance of haemoglobinuria.
Reduce high body temperatures (>39°C) by vigorous tepid sponging and fanning. Paracetamol can be given as an antipyretic; avoid aspirin-containing compounds and NSAIDs.
Efficacy
Measure the parasite density at least daily.
Patient information
Malaria prophylaxis.
Drug treatment alone is not sufficient. Do not forget to cover up and to use an impregnated bed net and repellent spray.
Report any feverish illness especially within 3 months of return; say if you have been to a malarious region.
Prescribing information: Antimalarial drugs
The following is offered as a general guide only; seek expert advice in all cases.
Quinine
Treatment of malaria. By mouth, 600 mg tds for 7 days (usually followed by pyrimethamine plus sulfadoxine (Fansidar®)).
Treatment by intravenous infusion for severe malaria.
Loading dose of 20 mg/kg over 4 hours.
Followed by 10 mg/kg every 8–12 hours (given over 4 hours), until able to take treatment by mouth (or for 7 days).
Usually followed by pyrimethamine plus sulfadoxine (Fansidar®).
Pyrimethamine plus sulfadoxine (Fansidar®)
Treatment of malaria, following quinine. Tablets contain pyrimethamine 25 mg plus sulfadoxine 500 mg. Give 3 tablets as a single dose.
If resistant to Fansidar®, give doxycycline 200 mg for 7 days.
Mefloquine
Chemoprophylaxis. By mouth, 250 mg once weekly. See earlier notes.
Treatment of malaria (now rarely used). Daily dose 20–25 mg/kg given as three doses 8 hours apart.
Proguanil plus atovaquone (Malarone®)
Treatment of malaria. By mouth, 4 tablets once daily, for 3 days.
Tablets contain proguanil 100 mg plus atovaquone 250 mg.
Proguanil
Chemoprophylaxis. By mouth, 200 mg daily.
Given with chloroquine.
Primaquine
Adjunct to treatment of P. vivax and P. ovale (eradication of liver stages). By mouth, 30 mg (P. vivax) or 15 mg (P. ovale) daily for 14–21 days, following chloroquine treatment.
Artemisinin derivatives
Seek expert advice.
G6PD is an important component of the oxidative pathways in cells. Deficiency is common among people from most of Africa, most of Asia, Oceania, and Southern Europe (400 million people affected worldwide).
These patients are liable to develop an acute haemolytic anaemia when given an acute oxidative stress. Severe illness is a cause, as are several drugs.
Avoid the following drugs in patients with G6PD deficiency:
Dapsone and other sulfones.
Nitrofurantoin.
Primaquine (low doses may be safe).
Quinolone antibiotics.
Sulfonamides (including co-trimoxazole); some sulfonamides (e.g. sulfadiazine) have been tested and found not to be haemolytic in many G6PD-deficient individuals).
The following drugs carry a possible risk:
Aspirin (acceptable up to a dose of at least 1 g daily in most G6PD-deficient individuals).
Chloroquine (acceptable in acute malaria).
Menadione, water-soluble derivatives (e.g. menadiol sodium phosphate).
Quinine (acceptable in acute malaria).
Note. Mothballs containing naphthalene can cause haemolysis.
