What is the evidence for high-dose ampicillin/sulbactam for carbapenem resistant Acinetobacter baumanii infections? Does this always need to be combination therapy? ?

Comment by InpharmD Researcher

Based on available evidence, high-dose ampicillin/sulbactam (with daily sulbactam doses of 6-9 grams) is a rational and effective treatment for carbapenem-resistant Acinetobacter baumannii (CRAB), as the sulbactam component has intrinsic antibacterial activity against the bacterium. Clinical studies, including randomized trials, show that regimens based on high-dose ampicillin/sulbactam have success rates comparable to colistin, often with a better safety profile. However, due to the high resistance levels of CRAB, current guidelines and expert opinion recommend that high-dose ampicillin/sulbactam be used as a core component of combination therapy, rather than as monotherapy, to improve efficacy and prevent further resistance.

Background

A 2024 review provides an overview on current treatments for carbapenem-resistant A. baumannii (CRAB). Ampicillin-sulbactam is a unique β-lactam/β-lactamase inhibitor where the sulbactam component itself has direct, intrinsic antibacterial activity against Acinetobacter baumannii by binding to its penicillin-binding proteins. For CRAB infections, which are typically highly resistant, high-dose ampicillin-sulbactam (with daily sulbactam doses of 6 g to 9 g) is a valuable therapeutic strategy. This approach is pharmacologically rational, as sulbactam exhibits time-dependent activity, and high-dose, extended-infusion regimens are designed to maximize the time that drug concentrations remain above the pathogen's elevated minimum inhibitory concentration (MIC). Clinical evidence, primarily from smaller randomized trials and observational studies, shows that high-dose ampicillin-sulbactam-based regimens have clinical success and mortality rates comparable to, and sometimes better than, colistin-based regimens, often with a more favorable nephrotoxicity profile. These regimens are frequently used in combination with another agent like a polymyxin or carbapenem, as combination therapy is recommended to improve efficacy and prevent resistance. However, the evidence is not yet sufficient to establish a single standardized regimen, and high-dose ampicillin-sulbactam is best considered a core component of combination therapy rather than a monotherapy, pending further large-scale clinical trials to solidify its role and optimize dosing. [1]

A 2021 systematic review and network meta-analysis aimed to evaluate the comparative efficacy and safety of high-dose sulbactam or colistin combined with additional antibacterial agents for treating multidrug-resistant (MDR) and extensively drug-resistant (XDR) Acinetobacter baumannii infections. This analysis synthesized data from 18 studies involving 1,835 patients, utilizing a mix of randomized controlled trials and observational studies. The research systematically searched multiple databases, including PubMed, Embase, and Cochrane, through March 2020, to identify studies relevant to the treatment of MDR-AB and XDR-AB infections using these combination therapies. Key findings from the network meta-analysis indicated that high-dose sulbactam (≥ 6 g/day) combined with a single antibacterial agent, such as levofloxacin or tigecycline, ranked highest concerning clinical improvement and clinical cure. Despite colistin-based combinations being prevalent in the studies analyzed, they were associated with a higher risk of nephrotoxicity compared to other treatments. The results suggest that regimens including high-dose sulbactam with additional antibacterial agents might offer a promising therapeutic option for MDR-AB or XDR-AB infections, although further high-quality studies are needed to confirm these findings. [2]

References:

[1] Choi SJ, Kim ES. Optimizing Treatment for Carbapenem-Resistant Acinetobacter baumannii Complex Infections: A Review of Current Evidence. Infect Chemother. 2024;56(2):171-187. doi:10.3947/ic.2024.0055
[2] Liu J, Shu Y, Zhu F, et al. Comparative efficacy and safety of combination therapy with high-dose sulbactam or colistin with additional antibacterial agents for multiple drug-resistant and extensively drug-resistant Acinetobacter baumannii infections: A systematic review and network meta-analysis. J Glob Antimicrob Resist. 2021;24:136-147. doi:10.1016/j.jgar.2020.08.021
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What is the evidence for high-dose ampicillin/sulbactam for carbapenem resistant Acinetobacter baumanii infections? Does this always need to be combination therapy? ?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

High-dose ampicillin-sulbactam as an alternative treatment of late-onset VAP from multidrug-resistant Acinetobacter baumannii
Design

Randomized, prospective trial

N= 27
Objective To evaluate the efficacy and safety of high-dose treatment regimens of ampicillin-sulbactam for MDR Acinetobacter baumannii VAP
Study Groups

Group A (18/9 g daily dose, n= 14)

Group B (24/12 g daily dose, n= 13)
Inclusion Criteria Patients mechanically ventilated for more than 72 h with positive tracheal aspirates for A. baumannii and quantitative culture of bronchoalveolar lavage (≥104 cfu/ml)
Exclusion Criteria Episodes of VAP in which A. baumannii was isolated in conjunction with another microorganism
Methods Patients were randomly assigned to receive A/S at a rate of 2:1 every 8 h for 7-10 days. Dosage was adjusted according to creatinine clearance. Evaluation of efficacy was based on clinical and bacteriological responses. Clinical success was defined as resolution of symptoms and signs of VAP. Bacteriological success was defined as eradication of isolates on follow-up BAL
Duration October 2004 to February 2006
Outcome Measures Clinical (resolution of symptoms and signs of VAP at the end of therapy) and bacteriological (eradication of the isolates on the follow-up) success, 14-day and 30-day mortality rates
Baseline Characteristics Characteristic Group A (n= 14) Group B (n= 13)
Age (median ± SEM) 67 ± 4.5 72 ± 2.8
Gender (male/female) 7/7 8/5
APACHE II score (median ± SEM) 15 ± 0.94 15 ± 0.58
Primary diagnosis - Postoperative respiratory failure 2 (14.3%) 4 (30.8%)
Primary diagnosis - Pneumonia 8 (57.2%) 3 (23.1%)
Primary diagnosis - Acute pulmonary oedema 0 (0%) 3 (23.1%)
Primary diagnosis - Acute pancreatitis + ARDS 1 (7.2%) 1 (7.7%)
Primary diagnosis - COPD 1 (7.2%) 2 (15.4%)
Primary diagnosis - Subarachnoid haemorrhage 1 (7.2%) 0 (0%)
Primary diagnosis - Guillain-Barre 1 (7.2%) 0 (0%)
Mechanical ventilation prior VAP (median of days ± SEM) 6.5 ± 8.3 10 ± 4.1
Mean duration of ICU stay (median of days ± SEM) 31 ± 11.6 35 ± 5.9
Results Outcome Group A (n= 14) Group B (n= 13) p-Value
Clinical Success 9 (64.3%) 9 (69.2%) 0.785
Clinical Failure 5 (35.7%) 4 (30.8%) 0.785
Bacteriological Success 12 (85.7%) 9 (69.2%) 0.303
Bacteriological Eradication 9 (75%) 6 (66.7%) 0.676
Bacteriological Suppression 3 (25%) 3 (33.3%) 0.676
Bacteriological Failure 2 (14.3%) 4 (30.8%) 0.303
14-day Mortality 3 (21.4%) 4 (30.8%) 0.580
30-day Mortality 6 (42.9%) 7 (53.8%) 0.568
Adverse Effects 2 (14.3%) 2 (15.4%) 0.936
Adverse Events No major adverse reactions were recorded. Adverse effects included transient renal deterioration, temporary skin rash, and diarrhea
Study Author Conclusions Clinical and bacteriological results support the use of high-dose regimen of ampicillin-sulbactam for MDR Acinetobacter baumannii VAP. Both regimens were effective and well-tolerated.
Critique The study's strengths include its prospective design and accurate definition of VAP using quantitative cultures. Limitations include the small sample size and lack of pharmacokinetic studies. The study also highlights discrepancies in susceptibility testing methods.
References:

Betrosian AP, Frantzeskaki F, Xanthaki A, Georgiadis G. High-dose ampicillin-sulbactam as an alternative treatment of late-onset VAP from multidrug-resistant Acinetobacter baumannii. Scand J Infect Dis. 2007;39(1):38-43. doi:10.1080/00365540600951184

Efficacy and safety of high-dose ampicillin/sulbactam vs. colistin as monotherapy for the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia
Design

Prospective cohort study

N= 28
Objective To compare the safety and efficacy of ampicillin/sulbactam (Amp/Sulb) and colistin (COL) in the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia (VAP)
Study Groups COL group (n= 15) Amp/Sulb group (n= 13)
Inclusion Criteria All mechanically ventilated patients for >72 h who developed VAP with A. baumannii isolated and quantitative culture of bronchoscopic bronchoalveolar lavage (BAL) achieved
Exclusion Criteria Cases of VAP with mixed isolated microorganisms, combination antibiotic therapy, allergy to b-lactamase or penicillin, or previous enrolment to similar studies
Methods Patients were randomly assigned to receive Amp/Sulb (9 g every 8 h) or COL (3 MIU every 8 h) intravenously. Dosage was adjusted according to creatinine clearance. Treatment duration was 8-10 days, extended as needed. Follow-up BAL was performed on the 5th day after treatment initiation
Duration One-year period
Outcome Measures

Primary: Clinical cure of VAP

Secondary: Microbiological cure, 14-day mortality, 28-day all-cause mortality
Baseline Characteristics   COL group (n= 15) Amp/Sulb group (n= 13)
Age (mean ± SD) 67 ± 9 72 ± 5
Sex (male/female) 7/8 7/6
APACHE II score (mean ± SD) 14 ± 2 14 ± 5
Primary diagnosis - Postoperative respiratory failure 4 (26.6%) 3 (23%)
Primary diagnosis - COPD acute respiratory failure 7 (46.6%) 6 (46.1%)
Primary diagnosis - Acute pancreatitis ARDS 1 (6.6%) 2 (15.3%)
Primary diagnosis - Subarachnoid hemorrhage 2 (13.3%) 2 (15.3%)
Primary diagnosis - GuillaineBarre syndrome 1 (6.6%) 0 (0%)
Mechanical ventilation prior VAP (mean ± SD) 10 ± 4 11 ± 5
Mean duration of ICU stay (mean ± SD) 24 ± 13 31 ± 14
Results   COL group (n= 15) Amp/Sulb group (n= 13) p-value
Clinical success 9 (60%) 9 (61.5%) NS
Improvement 2 (13.3%) 1 (7.6%) NS
Failure 4 (26.6%) 3 (23%) NS
Bacteriological success 10 (66.6%) 8 (61.5%) NS
Eradication 7 (46.6%) 6 (46.1%) NS
Suppression 3 (20%) 2 (15.3%) NS
14-day mortality 3 (20%) 2 (15.3%) NS
28-day mortality 5 (33.3%) 3 (30.0%) NS
Nephrotoxicity 5 (33%) 2 (15.3%) NS
Other adverse effects 1 (6.6%) 2 (15.3%) NS
Adverse Events Adverse events were 39.6% (including 33% nephrotoxicity) for the COL group and 30.7% (15.3% nephrotoxicity) for the Amp/Sulb group
Study Author Conclusions Colistin and high-dose ampicillin/sulbactam were comparably safe and effective treatments for critically ill patients with MDR A. baumannii VAP.
Critique The study's small sample size limits the power to detect significant differences between treatments. The prospective design and use of quantitative cultures from BAL are strengths, but the lack of pharmacokinetic analysis is a limitation. The study's findings should be interpreted with caution due to the limited number of patients.
References:

Betrosian AP, Frantzeskaki F, Xanthaki A, Douzinas EE. Efficacy and safety of high-dose ampicillin/sulbactam vs. colistin as monotherapy for the treatment of multidrug resistant Acinetobacter baumannii ventilator-associated pneumonia. J Infect. 2008;56(6):432-436. doi:10.1016/j.jinf.2008.04.002