Sulbactam for carbapenem-resistant Acinetobacter baumannii infections: a literature review

Abstract

Carbapenem-resistant Acinetobacter baumannii (CRAB) is characterized as a critical priority pathogen with restricted therapeutic options. To date, the most effective antimicrobial treatment against this difficult-to-treat bacterial strain has not been established. Sulbactam is a β-lactamase inhibitor with intrinsic activity against this pathogen, however, as a β-lactam, it can be hydrolysed by β-lactamases produced by A. baumannii. High-dose, extended-infusion treatment with sulbactam can overcome this hydrolysis by β-lactamases and is considered an effective therapeutic strategy against CRAB. The aim of this review is to analyse primary and secondary research studies that compare sulbactam-based with other regimens, such as polymyxin-containing regimens, tigecycline-containing regimens and other antimicrobial combinations against CRAB infections, especially ventilator-associated pneumonia (VAP), hospital-acquired pneumonia (HAP) and bacteraemia. Our findings suggest that results are conflicting, mostly because of high heterogeneity among studies. However, in most studies, sulbactam-based regimens have demonstrated comparable, and in several studies more favourable results in contrast to other antimicrobial treatments with respect to clinical cure and mortality in CRAB-associated pneumonia, yet without reaching statistical significance in most cases. The auspicious novel β-lactam/β-lactamase inhibitor combination sulbactam/durlobactam is also discussed, although real-world clinical data regarding its efficacy in CRAB infections are still scarce. More randomized controlled trials comparing sulbactam-based with other regimens are warranted to determine the most effective antimicrobial combination against CRAB infections. Nevertheless, current data suggest that sulbactam could play a major role in this combination treatment.

Introduction

The Acinetobacter baumannii–calcoaceticus complex (ABC) represents the species of the genus Acinetobacter with the greatest clinical relevance, causing numerous healthcare-associated infections, such as bacteraemia, respiratory tract, urinary tract and surgical wound infections.^1,2 Carbapenem-resistant A. baumannii (CRAB) poses a global threat to healthcare systems due to limited therapeutic options against infections caused by this bacterial strain, leading to its characterization by the WHO as a critical priority pathogen.³

Treating CRAB infections entails plenty of challenges for many reasons. CRAB is often isolated from respiratory and wound samples. It is extremely difficult to distinguish a colonization from a true infection, especially in critically ill hospitalized patients with underlying co-morbidities or those immunocompromised. This can lead to significant delay in treatment initiation and substantially to poor outcomes.⁴ On the other hand, this clinical conundrum may result to overtreatment, leading to delayed ICU and hospital discharges, more adverse drug reactions and increased antimicrobial resistance.⁵ Moreover, CRAB isolates usually develop different mechanisms of resistance, such as β-lactamases, antimicrobial target modifications, increased activity of efflux pumps and alterations in the structure and number of porins, rendering them resistant to multiple categories of antibiotics.⁶ These multiple mechanisms can lead to formation of pan-drug-resistant isolates, which can cause infections whose effective management requires antimicrobial combinations aiming for a possible synergistic action.⁷ Even the use of antimicrobial agents with the highest in vitro activity against CRAB, such as polymyxins (colistin and polymyxin B), tetracyclines (eravacycline, minocycline and tigecycline) and ampicillin-sulbactam, requires rigorous dose-optimization strategies to achieve pharmacokinetic-pharmacodynamic (PK-PD) targets in the context of invasive CRAB infections.⁸ Finally, large, randomized studies comparing the effectiveness of the abovementioned drugs are limited and, as a result, there is no ‘gold standard’ antibiotic regimen for CRAB infections.⁹

According to the Infectious Diseases Society of America 2024 Guidance on the treatment of CRAB infections, a combination of at least two agents is suggested. It is also suggested that at least one antimicrobial in the combination is sulbactam based.⁹ The practice of using sulbactam as the backbone of the therapeutic armamentarium against CRAB isolates is still up for debate. The aim of this review is to narratively summarize evidence from clinical studies comparing sulbactam-based regimens with others regarding treatment of CRAB infections.

Sulbactam’s activity against CRAB isolates

Sulbactam is an irreversible β-lactamase inhibitor with intrinsic activity against A. baumannii, saturating its PBP1a/1b and PBP3.¹⁰ As a β-lactamase inhibitor, this molecule exhibits variable inhibitory activity against only class A β-lactamases, whereas as a β-lactam, it can be hydrolysed by β-lactamases by all Ambler classes, including class A, Acinetobacter derived cephalosporinase (ADC)-type class C, OXA-type class D β-lactamases, and metallo-β-lactamases (MBL), which are commonly produced by the ABC complex.¹¹ Among these β-lactamases, class D OXA-type carbapenemases are the most clinically significant, with the gene bla_OXA-23 being the most widespread globally, detected in up to 74.5% of A. baumannii isolates in Europe and 39.5% in the USA.¹² Other OXA-type β-lactamase genes, such as bla_OXA-24/40 and bla_OXA-58, are also prevalent but at lower frequencies.¹² For instance, in Spain, bla_OXA-24/40-like genes were identified in 48.7% of CRAB isolates in 2000 and 51.6% in 2010.¹³ Additionally, bla_OXA-58 has been detected in various countries, including the USA, UK, Turkey, Greece, Argentina, Kuwait, Italy, Spain and Austria, with prevalence rates varying by region.¹⁴ Class B metallo-β-lactamases, including the gene bla_NDM-1, have been detected in A. baumannii isolates from Europe and the USA, although their prevalence remains relatively low (<2%).¹⁵ Although less common, the MBL genes bla_IMP and bla_VIM also contribute to broad-spectrum β-lactam resistance.¹² Finally, class C ADC enzymes are intrinsic to A. baumannii, with the bla_ADC gene playing a key role in cephalosporin resistance, however, mutations within this gene can broaden the hydrolytic activity of A. baumannii to include carbapenems.¹²

Over the years, sulbactam has been widely commercially available in the form of ampicillin-sulbactam with a ratio of 2:1 (2 g of ampicillin, 1 g of sulbactam).⁸ As in the case of other β-lactams, the main pharmacokinetic parameter regarding its effective action, is the time that free sulbactam concentrations remain above the MIC (fT > MIC).¹⁶ However, on a global basis, most CRAB isolates test resistant to ampicillin-sulbactam.¹⁷ High doses of sulbactam [i.e. an intravenous (IV) 4-hour infusion of 3 g sulbactam every 8 hours] are required to achieve sufficient fT > MIC in case of A. baumannii isolates with a sulbactam MIC 16 mg/L, as demonstrated in PK studies.^16,18 The rationale behind this therapeutic strategy is that high doses will allow more sulbactam molecules to reach their penicillin-binding protein (PBP) targets, overcoming the hydrolysis by β-lactamases (Figure 1).⁹

While high-dose sulbactam is necessary to achieve therapeutic efficacy against A. baumannii, critically ill patients and those with renal impairment may require augmented dosing to optimize drug exposure to minimize drug toxicity. However, the safe and optimal dosing of sulbactam/ampicillin in these populations remains poorly defined. Early pharmacokinetic studies demonstrated that renal impairment significantly prolongs sulbactam elimination, necessitating dose adjustments to prevent toxicity.^19,20 Blum et al. found that in severe renal failure, the half-life of sulbactam and ampicillin more than doubled, while haemodialysis enhanced drug clearance, underscoring the need for modified dosing.¹⁹ Lorenzen et al. demonstrated that in critically ill patients with acute kidney injury (AKI) on extended dialysis, standard sulbactam dosing resulted in underdosing, necessitating a twice-daily 2 g/1 g regimen to maintain therapeutic levels.²¹ Additionally, Yokoyama et al. found that sulbactam clearance was significantly associated with renal function, indicating the necessity for dosage adjustments based on creatinine clearance to maintain therapeutic efficacy while minimizing toxicity.²² Despite these findings, robust pharmacokinetic data guiding safe sulbactam dosing in renally impaired patients remain limited, which presents a challenge for the routine use in this population.

Beyond dosing optimization, sulbactam’s activity can be enhanced by combining it with β-lactamase inhibitors or other β-lactams to overcome resistance. For instance, lower doses of sulbactam can be used when combined with durlobactam, a potent inhibitor of class A, C and D β-lactamases produced by CRAB isolates, enabling sulbactam molecules to saturate PBPs before their inactivation.²³ Moreover, in vitro studies have demonstrated that other β-lactamase inhibitors, such as avibactam and relebactam, can also reduce the MIC of sulbactam against multidrug-resistant A. baumannii isolates.^24,25

Moreover, given sulbactam’s ability to achieve high epithelial lining fluid (ELF) concentrations, sulbactam presents a promising therapeutic option for pulmonary infections caused by CRAB. This was shown by a recent PK/PD analysis in the neutropenic murine pneumonia model, a 4-hour infusion of 3 g sulbactam every 8 hours achieved adequate ELF exposures (probability of target attainment >90%) for A. baumannii isolates with sulbactam MIC up to 8 mg/L.²⁶ On the other hand, the insufficient penetration of IV colistin into pulmonary ELF raises concerns regarding its efficacy against A. baumannii pneumonia.²⁷ Nevertheless, it is of the utmost importance to examine how these data are reflected in clinical studies.

Sulbactam-based versus other regimens against CRAB infections

Clinical safety of high-dose ampicillin-sulbactam in case of MDR-A. baumannii infections has been demonstrated formerly.²⁸ In a randomized controlled trial conducted in Greece, patients were randomly assigned to receive either 9 g (n = 14) or 12 g (n = 13) of sulbactam per day for the treatment of MDR-A. baumannii ventilator-associated pneumonia (VAP). According to the results, no major adverse events were reported.²⁸ However, clinical data are scarce with reference to direct comparison between sulbactam-based and other regimens in the context of CRAB infections. In this section studies comparing sulbactam-based with other therapeutic regimens in adult patients with CRAB infections are analysed. Primary clinical studies on sulbactam-based versus other treatments are also summarized in Table 1.

Sulbactam-based regimens versus other treatments against CRAB pneumonia

Sulbactam-polymyxins

A series of studies have been conducted, comparing the efficacy of sulbactam- and polymyxin-based regimens in various combinations against CRAB respiratory infections, especially VAP. A randomized controlled study performed at two ICUs in Greece, compared directly the efficacy and safety of high-dose ampicillin-sulbactam versus colistin as monotherapies for the treatment of MDR-A. baumannii VAP. A total of 28 patients were included and randomly assigned to receive either 3 MIU of colistin every 8 hours (n = 15) or 9 grams of ampicillin-sulbactam every 8 hours (n = 13). All isolates were resistant to sulbactam with an MIC > 16 mg/L. As regards clinical success, mortality and adverse event rates, there were no statistically significant differences between the two study arms, although fewer cases of nephrotoxicity were observed in the ampicillin-sulbactam subgroup of patients.³⁰ In a more recent retrospective study conducted in a single centre in Israel, ampicillin-sulbactam exhibited more favourable results.⁴⁷ Researchers evaluated 98 patients with CRAB-VAP who were treated with either colistin (n = 66) or ampicillin-sulbactam (n = 32). According to their findings, treatment with colistin was associated with higher 30-day mortality (25.8% versus 9.4%, P = 0.07), higher microbiological failure rates at 7 days of treatment (48% versus 18%, P = 0.03) and more significant elevation in creatinine levels. Clinical cure rates at 7 days were comparable between the two groups of patients (47% versus 56%, P = 0.39).⁴⁷

Another randomized study was carried out at two ICUs in Greece, including 39 patients with MDR-A. baumannii VAP, who received either colistin monotherapy or combination treatment with high-dose ampicillin-sulbactam (8 g of sulbactam per day). All isolates were susceptible to colistin and demonstrated at least intermediate susceptibility to ampicillin-sulbactam (MIC for ampicillin-sulbactam <16 mg/L). Early clinical response rates were significantly higher in the combination treatment group of patients (70% versus 15.8% in the monotherapy group P = 0.001) and in multiple regression analysis, initial favourable response was associated with survival and discharge from ICU.³⁸ These results are not compatible with the findings of a former retrospective study of 89 patients with MDR-A. baumannii VAP (>90% resistance to carbapenems) in Turkey. Researchers compared clinical cure and microbiological response rates between colistin monotherapy and colistin/sulbactam combination therapy, using 9 g of sulbactam daily. According to the results, at the end of treatment course they did not demonstrate significantly higher clinical response and microbiological eradication rates in favour of combination therapy. Additionally, when the mortality rates were adjusted for APACHE II score, no statistically significant difference was observed.³¹ Moreover, an observational study from Turkey of 70 VAP patients due to MDR or XDR-A. baumannii, did not reveal significant differences regarding clinical and microbiological efficacy, as well as mortality, among patients who received colistin monotherapy or colistin in combination with either sulbactam or carbapenems. It must be emphasized that according to study methodology, sulbactam’s daily dose was 3 g and only two isolates were susceptible to sulbactam.⁴⁶ Moreover, in a prospective cohort study of 182 patients with XDR-A. baumannii pneumonia (mainly VAP and to a lesser extent HAP) in Thailand, 92 patients received colistin plus 6 g of sulbactam, whereas 90 patients received colistin in combination with carbapenems. Despite the high sulbactam MIC for isolates and the use of 6 g of this agent per day, overall mortality rates at 7, 14 and 28 days were not significantly different between the two subgroups of patients.⁴⁸ Although controversial, these clinical findings about colistin/sulbactam combination may partially be in accordance with a pharmacokinetics/pharmacodynamics model, which has indicated enhanced bacterial killing of CRAB isolates by the use of both the abovementioned drugs.⁴⁹

Several randomized studies conducted in ICUs in Iran have compared high-dose ampicillin-sulbactam with colistin, each one of these drugs in combination with another agent, for the treatment of MDR-A. baumannii VAP. First, Khalili et al. studied 47 patients who received meropenem (2 g every 8 hours) combined with either colistin or ampicillin-sulbactam against CRAB-VAP. Clinical improvement of infection was proven in 18/24 and 16/23 of patients in the meropenem/colistin and meropenem/ampicillin-sulbactam group, respectively. Results were also comparable between the two subgroups of patients with respect to microbiological eradication and 28-day mortality rates. Of note, in this trial the total daily dose of administered sulbactam was 6 g.³³ In another study published in 2019, 28 patients were treated with nebulized colistin in combination with either IV high-dose ampicillin-sulbactam (8 g of sulbactam per day) or IV colistin for the treatment of MDR-A. baumannii VAP, with most isolates being sensitive only to colistin. Similar results were indicated regarding clinical efficacy, microbiological response, length of ICU and hospital stay, as well as survival rates among the two treatment arms, whereas a higher incidence of AKI was observed in the IV colistin group of participants.⁴² Finally, in an interim analysis of 23 patients with MDR-A. baumannii VAP, participants were randomized to receive colistin plus levofloxacin (n = 11) or continuous infusion of ampicillin-sulbactam (24 g daily, i.e. 8 g of sulbactam per day) plus levofloxacin (n = 12). Significantly higher clinical response rates (83% versus 27%), as well as significantly lower 28-day (42% versus 82%) and 14-day (8% versus 73%) mortality rates were observed in the ampicillin-sulbactam treatment group. Furthermore, a significantly lower incidence of nephrotoxicity was indicated in the same subgroup of patients.³⁹

Sulbactam—tigecycline

Limited data exist regarding direct comparison between sulbactam-based and tetracycline-based regimens against CRAB pneumonia. In a multicentre retrospective study including 238 ICU patients with CRAB pneumonia, tigecycline monotherapy and tigecycline-based treatment was compared with sulbactam-based regimens, as well as colistin monotherapy and colistin-combination therapies. The lowest crude ICU mortality (8.3%) was observed in patients treated with sulbactam-based regimens, although only 12 of 238 patients (5%) received this type of treatment, rendering them a small sample size. Overall, tigecycline-based therapy was associated with higher rates of ICU mortality and treatment failure.³⁶ Moreover, in a retrospective study conducted in Taiwan, 84 tigecycline-treated were matched to 84 sulbactam-treated individuals (maximum daily dose of sulbactam was 4 g), in combination with other antimicrobials, with respect to the treatment of MDR-A. baumannii pneumonia. In the tigecycline group, fewer patients received combination therapy, and more patients had delays in treatment initiation. Although microbiological eradication rate was significantly higher in the sulbactam group, there were no significant differences regarding clinical resolution and mortality rates among the two subgroups of patients.⁴⁵

Some trials have been performed examining combination treatment of tigecycline with cefoperazone-sulbactam. In a randomized controlled trial of 42 patients with XDR-A. baumannii VAP, participants received either tigecycline alone or combined with cefoperazone-sulbactam, and combination treatment was associated with higher clinical efficacy rates.⁴³ In another study, 114 patients with MDR-A. baumannii pulmonary infection were randomized to be treated with either cefoperazone-sulbactam alone or in combination with tigecycline. After 14 days of treatment, inflammatory markers were significantly lower in the combination group of patients.³⁷

Of note, the dose of tigecycline used in most of the abovementioned studies was 50 mg twice daily (standard dose). Higher doses (i.e. 200 mg daily) are required for adequate tigecycline concentrations in the ELF and achievement of PK/PD target (fAUC/MIC), whereas even these doses may not be appropriate in case of difficult-to-treat pathogens with higher tigecycline MICs.⁵⁰ According to a systematic review and meta-analysis published by Zha et al. in 2020, the use of high-dose tigecycline was associated with better clinical outcomes and reduced mortality in the context of severe infections.⁵¹

Comparison of multiple antimicrobial regimens against CRAB pneumonia

Other studies have been carried out, evaluating multiple therapeutic regimens against CRAB pneumonia. In a retrospective cohort study performed in Thailand, survival at 28 days was assessed in 166 patients with XDR-A. baumannii pneumonia, who received three different combination treatments. Ninety-three patients were treated with high-dose sulbactam (6 g of sulbactam per day), 43 were treated with 100 mg of tigecycline daily and 30 with a high-dose prolonged infusion of a carbapenem, all these antimicrobials in combination with nebulized or IV colistin. Survival rates at 28 days were not significantly different between the three subgroups of patients. Of note, all isolates were resistant to sulbactam.³⁴

Moreover, a systematic review and a Bayesian network meta-analysis (NMA) were performed by Jung et al., evaluating 15 different antimicrobial treatments against MDR- and XDR-A. baumannii pneumonia.⁵² Twenty-three studies and 2118 adult patients were included in the Bayesian NMA and IV colistin monotherapy was used as a common comparator. Researchers found that sulbactam monotherapy ranked first for reducing all-cause mortality, which was defined as the primary outcome of the study. Four additional therapeutic regimens ranked higher than IV colistin monotherapy, including high-dose sulbactam (i.e. 9 g/day or more), fosfomycin plus IV colistin, inhaled combined with IV colistin and high-dose tigecycline (i.e. 200 mg/day after a loading dose of 200 mg). These regimens also ranked higher than IV colistin monotherapy regarding the effect on clinical cure. Moreover, fosfomycin plus IV colistin ranked highest for microbiological eradication, followed by sulbactam and sulbactam plus inhaled colistin. Overall, sulbactam and inhaled plus IV colistin were found to be significantly superior to IV colistin monotherapy with regards to survival and clinical cure, respectively. Consequently, researchers characterized sulbactam as the most effective treatment to reduce all-cause mortality in critically ill patients with drug-resistant A. baumannii pneumonia.⁵²

Sulbactam-based regimens versus other treatments against CRAB bacteraemia

Contrary to pneumonia, evidence from comparative studies between sulbactam-based treatments and other agents against CRAB bacteraemia are limited. A multicentre retrospective study was conducted in 27 tertiary-care centres in Turkey, including 250 patients, who received colistin monotherapy, colistin plus a carbapenem, colistin plus sulbactam (4–6 g per day) or colistin in combination with other antimicrobials for the treatment of XDR-A. baumannii bacteraemia. Clinical response, microbiological eradication and 14-day survival rates were significantly higher in the combination than in the colistin-monotherapy group of patients, whereas no statistically significant differences were observed among the three combination subgroups.²⁹

Furthermore, in a comparative study of 210 patients with CRAB-bloodstream infection in China, researchers examined the therapeutic effect of tigecycline in contrast to cefoperazone-sulbactam, in combination with other antimicrobial agents. It was indicated that 28-day mortality was significantly lower in the cefoperazone-sulbactam group of patients, and more specifically, mortality seemed to be the lowest when this antimicrobial was combined with imipenem/cilastatin.⁴⁰

Evaluation of multiple antimicrobial regimens in multiple types of infection

In pursuit of the optimal antibiotic treatment strategy for CRAB infections, larger studies have been conducted, comparing the efficacy of multiple antimicrobial combinations in several types of infection. In a retrospective study of 167 patients with CRAB infections, most of whom had bloodstream infections (47% versus 32% pneumonia and 17% surgical site infections), 82 patients were treated with IV polymyxins and 85 with ampicillin-sulbactam, simultaneously with other antimicrobials. Higher clinical cure and improvement rates, as well as lower mortality rates were observed in the ampicillin-sulbactam-treated group of patients. Multivariate analysis of risk factors associated with mortality indicated that polymyxin therapy, along with higher APACHE II score, septic shock, delays in treatment initiation and renal failure, were independent predictors of mortality until the end of treatment.⁴¹

In another retrospective cohort study in Taiwan, researchers evaluated 386 patients with healthcare-associated MDR-A. baumannii infections, including VAP, HAP, bacteraemia and other sites of infection. One hundred and twenty patients received sulbactam (1 g every 6 hours) plus imipenem/cilastatin, whereas 266 patients received either tigecycline alone or in combination with a carbapenem or piperacillin/tazobactam or a third-generation cephalosporin. Researchers found no significant differences in 30-day mortality and length of hospital and ICU stay between the two subgroups of patients.³⁵

Moreover, a retrospective cohort study was carried out in 10 large Korean clinical centres, including 282 ICU adult patients with CRAB infections and evaluating the impact of colistin-, carbapenem- and sulbactam-based regimens and other treatments (i.e. tigecycline-, minocycline- and amikacin-containing regimens) on 7- and 28-day mortality, as well as on clinical and microbiological response.⁴⁴ The most common type of infection was pneumonia (91.1%), followed by primary bacteraemia (7.1%) and urinary tract infection (1.4%). In multivariate analysis, combination treatment of colistin and carbapenem significantly reduced 7-day mortality, sulbactam-containing regimen significantly decreased 28-day mortality, whereas colistin monotherapy significantly increased 28-day mortality. According to subgroup analysis, sulbactam-containing regimen also significantly reduced 28-day mortality in CRAB pneumonia. With respect to clinical improvement, amikacin-containing regimens, sulbactam monotherapy and combination therapy of sulbactam and minocycline were associated with the highest clinical response rates at the end of treatment, although only amikacin-containing regimens exhibited statistically significant results. Moreover, minocycline-containing regimens were associated with the highest microbiological response rates at 14 days, 28 days and at the end of treatment. Of note, all CRAB isolates except one were susceptible to colistin and ∼80% of them to minocycline, whereas the susceptibility rate to ampicillin/sulbactam was <10%. Finally, colistin-containing regimens and tigecyline were associated with increased nephrotoxicity and hepatotoxicity, respectively. Overall, researchers concluded that combination therapy of colistin and carbapenem and sulbactam-based regimens may improve survival rates in CRAB infections.⁴⁴

A series of systematic reviews and meta-analyses have been carried out, assessing the efficacy of sulbactam-based and multiple other regimens in the treatment of CRAB infections. A systematic review and meta-analysis published by Chu et al. in 2013, included four studies (three retrospective and one prospective), directly comparing sulbactam-based regimens with other comparator drugs with respect to clinical response rate in CRAB infections.⁵³ Two of the studies included patients with CRAB-associated VAP, one study included patients with CRAB-associated bloodstream infections, whereas the researchers in the remaining study did not specify the type of infection. A total of 112 patients received sulbactam in combination with ampicillin, carbapenem or cefoperazone, whereas 107 patients were treated with other regimens, such as colistin, cephalosporins, anti-pseudomonal penicillin agents, fluoroquinolones, minocycline/doxycycline, aminoglycosides, tigecycline, imipenem/cilastatin and combination treatment. According to the results, sulbactam-based therapy did not significantly outperform comparator therapy in terms of the combined clinical response rate odds ratio. However, this study has several limitations because of the small sample size, as well as the heterogeneity in the drugs administered with sulbactam.⁵³

In another systematic review, which included 29 studies (4 RCTs and 25 cohort studies) and 2529 patients, researchers thoroughly compared and ranked the efficacy and safety of multiple treatment options in MDR- and XDR-A. baumannii infections.⁵⁴ Seventeen studies were carried out on pneumonia (VAP alone or HAP/VAP) and the remaining 12 studies on several types of infection, such as bacteraemia, pneumonia and intra-abdominal infections. According to NMA of 17 studies (1476 patients), there were no statistically significant differences between treatment options regarding clinical cure rate, although the triple combination of colistin, sulbactam and tigecycline had the highest rank among all regimens. As regards microbiological cure rate, the NMA of 20 studies (1863 patients) revealed no significant differences for colistin in combination with other antimicrobials versus colistin in combination with sulbactam, and sulbactam in combination with other agents. Combined treatment of colistin with rifampicin, sulbactam or other antimicrobials, such as carbapenems, exhibited significantly higher microbiological cure rate contrasted to colistin monotherapy. Moreover, tigecycline in monotherapy or in combination with other treatments was found to be less effective than other therapeutic options in terms of microbiological cure rate. Finally, with respect to all-cause mortality as a secondary outcome, colistin combined with other antibiotics was associated with a significantly lower all-cause mortality compared with sulbactam in combination with other agents. Overall, researchers concluded that colistin-combination therapy, especially with sulbactam, indicated an important microbiological benefit, supporting the use of this combination in the treatment of MDR- and XDR-A. baumannii infections.⁵⁴

Finally, in a more recent systematic review published by Liu et al., researchers compared the efficacy and safety of high-dose sulbactam (i.e. ≥4 g/day) or colistin in combination with other antimicrobials for MDR- and XDR-A. baumannii infections.⁵⁵ They included 18 studies (7 RCTs and 11 retrospective studies) and 1835 patients. Eleven studies were performed on pneumonia (VAP alone, HAP alone or VAP/HAP) and seven studies on multiple types of infection, such as pneumonia, as well as bloodstream, urinary tract and post-surgical intra-abdominal infections. Primary outcomes were clinical improvement, clinical cure, microbiological cure and all-cause mortality, whereas a secondary outcome was drug-related nephrotoxicity. The NMAs to evaluate clinical improvement and clinical cure, showed that high-dose sulbactam in combination with another antimicrobial (levofloxacin or tigecycline) were the highest ranking when compared to colistin-based regimens. According to the results of the NMA that assessed the impact of multiple combination therapies on microbiological eradication, there were no statistically significant differences between various colistin-based regimens and high-dose sulbactam in combination with colistin or carbapenems. However, colistin combined with rifampicin, fosfomycin or high-dose sulbactam was significantly superior to colistin monotherapy and high-dose sulbactam in combination with levofloxacin or tigecycline, in terms of microbiological eradication. Moreover, there were no statistically significant differences in all-cause mortality among patients treated with the different antimicrobial agents. As regards the secondary outcome, combination of colistin with high-dose sulbactam or carbapenems was associated with less nephrotoxicity compared with combination of this agent with other antimicrobials. Researchers interpreted their findings, emphasizing that high-dose sulbactam combined with other agents (including colistin) might be a favourable therapeutic option for MDR- and XDR-A. baumannii infections.⁵⁵

The novel β-lactam/β-lactamase inhibitor combination sulbactam/durlobactam

Sulbactam/durlobactam was approved in 2023 by the FDA in the USA for treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by suspectable ABC complex.⁵⁶ As detailed previously, sulbactam’s activity against ABC can be limited as multiple β-lactamases found in Acinetobacter spp. can degrade sulbactam.¹¹ Durlobactam’s ability to inhibit a wide range of β-lactamases, including the OXA carbapenemases that are prevalent in MDR-A. baumannii, allows for the restoration of sulbactam’s intrinsic activity.^11,23 Furthermore, due to the improved structure of durlobactam, these enzymes may be bound and inactivated more effectively, resulting in the combination treatment having potent antibacterial activity.⁵⁷

There is a limited number of trials that assessed the role of sulbactam/durlobactam in CRAB infections. The first trial was a multicentre phase 2 trial that compared sulbactam/durlobactam versus placebo in 80 hospitalized patients with complicated urinary tract infections.⁵⁸ Background therapy in both groups consisted of imipenem-cilastatin. Their findings showed that sulbactam/durlobactam was with limited serious side effects, and microbiological success in the modified intent-to-treat participants was similar between both groups (76.6% in the sulbactam/durlobactam group and 81.0% in the placebo group at test-of-care visit). Interestingly, this trial included seven patients with imipenem non-susceptible Gram-negative microbes in which the success rate was 100% for the sulbactam/durlobactam group compared to 75% in the placebo group, however, it is important to note that this was a small and limited sample of patients.⁵⁸ In a separate phase 3 multicentre trial (ATTACK trial), 125 patients with confirmed carbapenem-resistant ABC infections were randomized to receive either colistin or sulbactam–durlobactam, both in combination with imipenem-cilastatin. Compared to the colistin group, patients receiving sulbactam–durlobactam exhibited a lower 28-day all-cause mortality rate (19% versus 32%, CI: −30.0 to 3.5), meeting the trial’s criteria for non-inferiority. The colistin group demonstrated significantly higher number of nephrotoxicity (38% versus 13%, P < 0.001) and reported more adverse events leading to antibiotic cessation (16% versus 11%).³² This trial formed the basis for the Infectious Diseases Society of America recommendation that sulbactam/durlobactam is the preferred agent, in combination with meropenem or imipenem/cilastatin, for the treatment of CRAB infections.⁹ The rationale behind studying the combination of sulbactam–durlobactam with imipenem could be explained by their synergetic activity against Acinetobacter spp. This combination has been shown to effectively inhibits multiple PBPs in Acinetobacter spp. Specifically, sulbactam primarily targets PBP1a and PBP3, while imipenem targets PBP1a, PBP2 and PBP3 leading to disruption various stages of cell wall synthesis, thus, enhancing antibacterial efficacy.⁵⁹ Additionally, durlobactam protects both sulbactam and imipenem from degradation by OXA-type carbapenemases by targeting OXA-23 and OXA-51, further contributing to the combination’s effectiveness.⁵⁹ In case that sulbactam/durlobactam is not available, the panel recommends high-dose ampicillin-sulbactam (9 g of sulbactam daily) in combination with at least one other agent, such as polymyxin, minocycline, tigecycline or cefiderocol, as an alternative therapeutic option.⁹

Additionally, several case reports were sought from the literature that demonstrated the role of sulbactam–durlobactam combination therapy in treating CRAB infections. In one case, multiple antibiotic regimens, including polymixins and meropenem, failed to achieve clinical cure in one patient with VAP due to XDR-A. baumannii. However, the patient was able to demonstrate rapid and significant improvement once treated with sulbactam–durlobactam and cefiderocol.⁶⁰ A second case reported successful management of necrotizing pneumonia and empyema after the patient received sulbactam–durlobactam combined with meropenem.⁶¹ In another challenging case, a patient with CRAB meningitis resistant to cefiderocol and high-dose ampicillin-sulbactam was able to achieve clinical recovery and microbiological clearance following administration of sulbactam–durlobactam combined with meropenem.⁶² Another case also discussed the successful use of sulbactam–durlobactam in a patient with CRAB-associated neurosurgical infection and meningitis following emergent left hemicraniectomy requiring ICU admission.⁶³ In that case, the patient culture data revealed OXA-producing A. baumannii that was first treated with a combination of cefiderocol and polymyxin B and attempts at surgical source controlled, however, with clinical and imaging evidence of worsening infection; therefore, sulbactam–durlobactam was used in combination with cefiderocol and minocycline, which achieved clinical resolution of the infection.⁶³

Finally, another case highlighted the role of encoded β-lactamases, such as blaADC-30, blaOXA-23 and blaOXA-66, and mutations in siderophore receptor genes, piuA and fepA, that contributed to significant resistance and affected iron transport mechanisms carried by cefiderocol. Despite these resistance mechanisms to cefiderocol, sulbactam–durlobactam could achieve complete microbiological clearance of the CRAB infection in a burn patient with VAP, due to durlobactam protecting sulbactam from β-lactamase degradation.⁶⁴ Although these cases provide limited insight, they still highlight the important role sulbactam–durlobactam could play in the treatment of CRAB infections.

Cefiderocol and sulbactam-based regimens: future perspective for CRAB therapy

A promising combination for infections secondary to CRAB is cefiderocol with sulbactam, albeit, with very limited reports on its utility in clinical practice. However, there are promising data from in vitro and in vivo studies regarding the role of this combination. An in vitro study by Lewis et al., assessed the synergistic effect of cefiderocol with other antimicrobial regimens including sulbactam against two strains of CRAB (one strain was cefiderocol resistant and the other was cefiderocol susceptible) using a time–kill curve assay.⁶⁵ The combination of cefiderocol and sulbactam exhibited significant synergistic activity against both cefiderocol-susceptible and cefiderocol-resistant CRAB isolates by showing a significant reduction in bacterial count, indicating a potential role against CRAB infections.⁶⁵ Similar results were also shown in an in vivo study by Gill et al., using a murine thigh infection model with human-simulated dosing regimens to assess the efficacy of cefiderocol with ampicillin/sulbactam against 15 CRAB isolates.⁶⁶ They showed that this combination resulted in bacterial reduction and prevented the emergence of resistance against cefiderocol when compared to cefiderocol monotherapy.⁶⁶ Finally, a case series by Bavaro et al., describes cefiderocol-based combinations in 13 patients for multiresistant Gram-negative infections including CRAB, and three patients received cefiderocol at 2 g every 8 hours, combined with ampicillin/sulbactam at 3 g every 6 hours.⁶⁷ Two of the patients had VAP and one had bacteraemia secondary to CRAB infection with all three achieving microbiological eradication and clinical cure.⁶⁷ These studies highlight the promising potential of combining cefiderocol with sulbactam-based regimens. However, given the limited available data, further studies are warranted to comprehensively assess the safety and efficacy of this combination in larger patient populations.

Conclusion

Clinical studies that compare sulbactam-based versus other regimens against CRAB infections exhibit diverse results. The main reason is the high heterogeneity between these studies in various parameters, such as sulbactam dosage, sulbactam MICs for A. baumannii isolates and antimicrobial combinations used. High-dose sulbactam combined with other agents has demonstrated more encouraging results in some cases, especially against CRAB-associated pneumonia. Its sufficient penetration into pulmonary ELF may render sulbactam a most attractive therapeutic option than other antimicrobials, such as polymyxins, in cases of CRAB-associated VAP or HAP. Sulbactam/durlobactam combined with a carbapenem also constitutes a preferred therapeutic strategy against these difficult-to-treat infections, although clinical data are still limited. More randomized clinical trials comparing sulbactam-based with other regimens are warranted for the purpose of answering several questions regarding the most effective combination, the appropriate dose of the agents used and the number of antimicrobials that should be combined. However, current evidence already suggests that sulbactam may play a significant role in the combination therapy of CRAB infections.

Funding

No funding was received to support this work.

Transparency declarations

None to declare.

References