IDSA Guideline Recommendations for Carbapenem-Resistant Acinetobacter Baumannii

Introduction

Carbapenem-resistant Acinetobacter baumannii (CRAB) infections are particularly challenging due to complex resistance mechanisms and the frequent difficulty in distinguishing colonization from actual infection, especially in patients with multiple comorbidities. Successful management requires carefully selected antibiotic regimens, and recent therapeutic advances have contributed to improved clinical outcomes.

CRAB infections most commonly arise from respiratory or wound sites, further complicating differentiation between colonization and active infection. Treatment options remain limited owing to resistance mechanisms such as OXA carbapenemases and various other b-lactamases.

The preferred regimen involves sulbactam-durlobactam in combination with carbapenems, which have demonstrated superior mortality and safety profiles compared to colistin. Alternative therapies include ampicillin-sulbactam in combination with agents such as polymyxin B, minocycline, or cefiderocol. Current Infectious Diseases Society of America (IDSA) guidelines advise against the use of meropenem or imipenem-cilastatin, rifamycins, or nebulized antibiotics in treating CRAB infections.

CRAB infections present significant challenges in health care.^1,2 Diagnosing and managing CRAB is difficult because isolates often come from respiratory or wound samples, making it hard to distinguish colonization from actual infection, particularly in patients with mechanical ventilation or extensive burns. This ambiguity complicates antibiotic treatment decisions and makes it challenging to determine whether poor outcomes result from inadequate therapy or patient-related factors.³

CRAB typically acquires resistance to multiple antibiotics, significantly limiting therapeutic options. The presence of OXA-type carbapenemase enzymes (such as OXA-23 and OXA-24/40) is responsible for resistance to beta-lactams, including carbapenems and sulbactam.^4,5 Additionally, CRAB isolates often produce other serine b-lactamases, such as Acinetobacter baumannii-derived cephalosporinases (ADC), further diminishing the efficacy of commonly used b-lactam agents. According to the IDSA Guidelines, the effectiveness of these agents is primarily compromised due to the expression of various b-lactamases and mutations in penicillin-binding proteins (PBPs), particularly PBP1a/b and PBP3.^6-8 Furthermore, the production of aminoglycoside-modifying enzymes or 16S rRNA methyltransferases typically renders aminoglycosides ineffective as treatment options for CRAB.9-11 CRAB also develops fluoroquinolone resistance through mutations within the chromosomal quinolone resistance-determining region.¹⁰

Sulbactam-durlobactam

Sulbactam-durlobactam received FDA approval in May 2023. Durlobactam serves as a b-lactamase inhibitor, exhibiting activity against class A enzymes (eg, TEM-1), class C enzymes (eg, ADC), and class D b-lactamases (eg, OXA-24/40, OXA-23).^4,5 Notably, it does not inhibit class B Metallo-b-lactamases such as New Delhi metallo-beta-lactamase. The recommended dosing for sulbactam-durlobactam is 1 g of each component (2 g total) every 6 hours, administered over a 3-hour infusion.³ This regimen achieves pharmacokinetic and pharmacodynamic targets in over 90% of Acinetobacter baumannii isolates with minimum inhibitory concentrations (MICs) ≤4/4 mcg/mL, as established by FDA and Clinical and Laboratory Standards Institute (CLSI) breakpoints.¹²

A clinical trial compared sulbactam-durlobactam to colistin, both combined with imipenem-cilastatin, in 125 patients with CRAB pneumonia or bloodstream infections.¹³ The 28-day mortality rate was 19% (12/63) for the sulbactam-durlobactam group versus 32% (20/62) for the colistin group. Additionally, sulbactam-durlobactam demonstrated higher clinical cure rates (62% vs 40%), superior microbiological response (68% vs 42%), and a lower risk of nephrotoxicity (13% vs 38%).¹³ Colistin with imipenem-cilastatin is therefore not recommended for CRAB infections.

Currently, it remains unclear whether the addition of imipenem-cilastatin to sulbactam-durlobactam confers further clinical benefit, though some studies suggest the combination may reduce sulbactam-durlobactam MICs or target more penicillin-binding proteins (PBP), whereas imipenem might act as a substrate for OXA-carbapenemase, increasing sulbactam access to its PBP target.^14,15 For cases needing extended therapy (eg, CRAB osteomyelitis), discontinuing carbapenem after clinical improvement may be appropriate.³

Ampicillin-sulbactam

High-dose ampicillin-sulbactam is an alternative for CRAB infections when sulbactam-durlobactam is unavailable and should be used in combination therapy. At high doses, sulbactam, a competitive and irreversible b-lactamase inhibitor, targets PBP1a/1b and PBP3 in A. baumannii isolates.^16,17 It is proven effective by pharmacokinetic/pharmacodynamic studies, animal models, and clinical outcomes. The recommended dosage is 9 g of sulbactam daily as part of combination therapy. Ampicillin-sulbactam has total daily doses of 27 g administered as an extended continuous infusion of ampicillin 9 g/sulbactam 3 g given intravenously every 8 hours infused over 4 hours.^18-21

A 2021 meta-analysis of 18 studies with 1835 patients found that ampicillin-sulbactam (with at least 6 g of sulbactam daily) combined with a second agent was the most effective regimen for reducing mortality in critically ill CRAB-infected patients.22 Similarly, a 2017 meta-analysis of 23 studies and 2118 patients identified sulbactam regimens as having the greatest impact on lowering mortality compared to polymyxin or tetracycline-based treatments.²³

Combination Therapy

When managing CRAB infections, using 2 or more agents is an option, especially until clinical improvement occurs. Although in vitro and animal studies have yielded mixed findings, several studies have reported improved bacterial eradication using various combinations of regimens.^19,24-26

The IDSA panel supports combination therapy for CRAB infections for the following reasons³:

1. Most clinical trials utilize combination treatments not commonly implemented in routine practice, limiting the generalizability of their findings;
2. There is insufficient clinical evidence supporting monotherapy using any single agent with in vitro activity against CRAB;
3. A high bacterial load is typically present in CRAB infections due to frequent delays in initiating effective treatment

Potential agents to consider as part of combination therapy, in addition to high-dose ampicillin-sulbactam, including minocycline, polymyxin B, or cefiderocol.

Polymyxins

Polymyxin B may be utilized in conjunction with at least 1 additional antibiotic for the management of CRAB infections. The polymyxin class comprises both colistin and polymyxin B; the IDSA panel recommends polymyxin B due to its more favorable pharmacokinetic properties compared to colistin.^27-29 However, colistin is preferred for treating CRAB urinary tract infections, given that polymyxin B exhibits minimal urinary excretion.³

Polymyxin monotherapy is not recommended for several reasons^27,30-35:

1. Serum concentrations of polymyxins achieved through standard dosing are highly variable and may be insufficient to ensure effective bactericidal activity. Additionally, the penetration of intravenous polymyxins into the pulmonary epithelial lining fluid is limited, typically resulting in suboptimal bacterial eradication within the lungs;
2. The dosage required to manage systemic infections approaches levels associated with nephrotoxicity;
3. In the 2 most extensive clinical trials, each involving over 300 patients, colistin monotherapy was associated with relatively high mortality rates of 46% in both studies.

Tetracyclines

High-dose minocycline or high-dose tigecycline may be considered in combination with at least 1 additional antibiotic for the treatment of CRAB infections. The IDSA panel notes a preference for minocycline due to established clinical experience and the existence of CLSI breakpoints.³ Tetracycline derivatives generally exhibit rapid tissue distribution after administration, leading to limited concentrations in urine and blood. Consequently, the IDSA panel does not recommend tetracycline derivatives as monotherapy for bloodstream infections.

Minocycline’ clinical use has been extensive since its introduction in the 1960s.³⁶ Data from critically ill patients who received a single minocycline dose of 200 mg was used to develop a population pharmacokinetic model. A dose of 200 mg administered intravenously every 12 hours was predicted to result in a suboptimal pharmacokinetic and pharmacodynamic profile for organisms with MIC greater than 1 mcg/ml. Notably, the CLSI breakpoint for minocycline against A. baumannii is less than 4 mcg/ml.^37,38 Despite the limitations of available data, the IDSA panel still considers minocycline a treatment option dosed 200 mg twice daily either intravenously or orally.³

An alternative to minocycline is high dose tigecycline; however, there are currently no CLSI or FDA breakpoints for tigecycline against A. baumannii isolates, and minocycline MICs cannot be used to predict tigecycline MICs due to differences among tetracycline derivatives. Studies have indicated that tigecycline monotherapy is linked to higher mortality rates compared to other regimens used for pneumonia treatment, including but not limited to CRAB pneumonia.^39-42 When administered at higher doses—an initial loading dose of 200 mg followed by 100 mg twice daily—the mortality difference between tigecycline and comparator agents is no longer observed.^43-45 Both minocycline and tigecycline are associated with nausea incidence rates ranging from 20% to 50%, with higher doses likely increasing the frequency.^46-48

Cefiderocol

International surveillance studies indicate that about 95% of CRAB isolates are susceptible to cefiderocol based on the CLSI breakpoint of ≤4 mcg/ml.49,50 Preclinical data, however, suggest that pharmacokinetic and pharmacodynamic targets for A. baumannii may be higher than those required for other gram-negative organisms. Additionally, studies using animal models have shown variability in bactericidal activity of cefiderocol against A. baumannii.^51-54 A clinical trial involving 54 patients with CRAB infections reported mortality rates of 49% in the cefiderocol group compared to 18% in the alternative therapy group, primarily treated with polymyxin-based regimens.⁵⁵ Another study with 47 patients diagnosed with CRAB pneumonia demonstrated a 14-day mortality rate of 22% for cefiderocol and 17% for meropenem, indicating comparable outcomes.⁵⁶ The IDSA panel suggests that cefiderocol should be used cautiously for CRAB infections, preferably as part of combination therapy when no other alternatives are available.

Antimicrobials Not Recommended

Meropenem and imipenem-cilastatin are generally not advised for treating CRAB infections unless administered with sulbactam-durlobactam, since MICs for these drugs against CRAB isolates are typically above 8 mcg/ml.^57,58 These agents are unlikely to provide benefit as components of combination therapy except when used with sulbactam-durlobactam.³ Rifampin and other rifamycins are also not recommended for CRAB infections. Three clinical trials did not demonstrate a survival benefit from adding rifampin to colistin compared to colistin alone.^59-61 There is similarly no evidence supporting an advantage for rifabutin.⁶² Owing to their potential toxicities, drug interactions, and lack of observed clinical benefit, the IDSA panel advises against using rifamycins.^3,63 The use of nebulized antibiotics as adjunctive therapy for CRAB pneumonia is not advised by the IDSA panel due to insufficient clinical benefit, inconsistent lung distribution, and documented respiratory risks, including bronchoconstriction.^64-67

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