AST News Update January 2024: Acinetobacter – the Bad, the Awful, and the Downright Ugly

By Sara Blosser, PhD, D(ABMM) 

Between 2018-2021, the National Healthcare Safety Network (NHSN) reported that 0.4% (n=1,951) of hospital-acquired infections (HAIs) in the United States were caused by Acinetobacter spp. Of these, 28-45% were not susceptible to carbapenem antibiotics (ie, intermediate or resistant).¹ CDC’s 2019 Antibiotic Resistance Threats Report estimated that there were 8,500 carbapenem-resistant Acinetobacter cases in hospitalized patients in 2017.² Consistently, the A. calcoaceticus-A. baumannii complex (A. baumannii) is the largest cause of clinical Acinetobacter spp. infections and is most often recovered from respiratory specimens. 

Mortality for severe A. baumannii infection ranges from 14-73%3-9 It is no wonder then, that A.baumannii, particularly carbapenem-resistant A. baumannii (CRAB), is one of the top antibiotic resistance threats the US faces today.² Several studies have documented global carbapenem resistance rates for A. baumannii—and they agree, as bad as the resistance rates are in the United States (36-45%), they are even worse in Asia and Latin America (66-86%).^10-11 Additionally, many CRAB isolates harbor carbapenemases, with OXA-23 being the most common.^10-12 

In Many Cases, Acinetobacter is Simply a Colonizer 

Colonization indicates that an organism resides on or within an individual, but that the organism is not causing an active infection. Colonization with Acinetobacter spp. is relatively common in healthy individuals (15-43%)^13-16, but increases substantially in hospitalized or other at-risk patients (up to 75%).¹⁵ Risk factors for A. baumannii colonization include intensive care unit (ICU) stay, recent surgery, mechanical ventilation, cancer, immunosuppressive treatment, presence of a central venous catheter, dialysis, and previous treatment with β-lactams (especially carbapenems) or fluoroquinolones.¹⁷ Differentiating between colonization and infection, however, is quite complex—especially in individuals in the ICU or who are on ventilators.¹⁷ 

When identified in culture from a non-sterile source without other signs or symptoms of infection, A. baumannii is generally considered to represent colonization, but this clinical information is often not available to the microbiology laboratory. From an infection prevention and control perspective, colonization presents challenges, as patient-to-patient transmission can occur whether the patient is infected or colonized. 

So, Why is CRAB so Hard to Treat? 

First, A. baumannii is intrinsically resistant to penicillins, ampicillin, amoxicillin-clavulanate, 1st and 2nd generation cephalosporins, cephamycins, aztreonam, ertapenem, macrolides, and more^18-19; therefore, treatment options are few. Second, it has an “unrivaled adaptive nature,” to cite one source²⁰ – due to a “plethora of mechanisms,” including a predilection for developing heteroresistance, and an ability to acquire (by plasmid or transposon) resistance markers. In other words, A. baumannii truly is bad news. Finally, as previously stated, it is difficult to distinguish colonization from infection, confounding an already complex patient landscape and making it hard to draw solid conclusions from the outcomes of clinical trials.^17,21 

What are the Treatment Options for CRAB? Let’s ask an Expert! 

Note: Tremendous thanks to Dr. Pranita Tamma for her insight on the use of sulbactam-durlobactam in treating CRAB infections. Dr. Tamma is the lead author on the Infectious Disease Society of America (IDSA) Treatment Guidelines for AMR Infections. The information contained in this interview will be released in the 2024 update. 

Q: Dr. Tamma, what are some considerations for clinicians when considering treatment options for CRAB? 

A: The first step in managing CRAB is distinguishing colonization and infection. Recovery of CRAB in clinical isolates in-and-of itself does not signify infection without the proper clinical context. Once it is established that a patient indeed has a CRAB infection, use of sulbactam-based therapy is recommended. Sulbactam can be administered in the form of sulbactam-durlobactam, or as high-dose ampicillin-sulbactam. Sulbactam-durlobactam is preferred, whenever available. Of note, I have no conflicts of interest with any diagnostic or therapeutic companies. ² 

Q: Sulbactam-durlobactam or (XACDURO^®), is a relatively new agent in the fight against CRAB. Can you tell us some more about why and how it is used? 

A: Durlobactam, as a β-lactamase inhibitor, has the ability to protect sulbactam from hydrolysis from OXA carbapenemases so sulbactam can successfully reach its penicillin binding protein targets (PBP1 and 3). In the clinical trial from which sulbactam-durlobactam was FDA-approved,²² all patients who received sulbactam-durlobactam also received imipenem-cilastatin. 

If sulbactam-durlobactam is administered, it is generally suggested to be administered in combination with a carbapenem (either imipenem-cilastatin or meropenem), at least until clinical improvement is observed. It is possible the carbapenem is serving as a decoy as it is being hydrolyzed by any OXA-carbapenemases that may happen to escape inhibition by durlobactam, indirectly protecting sulbactam. Alternatively, since carbapenems and sulbactam have different PBP targets, it is also theoretically possible that some carbapenem molecules will reach their PBP2 target under the protection of durlobactam, enabling the targeting of multiple PBPs. Clinical outcomes data are not currently available describing the outcomes of patients with CRAB infections who received sulbactam-durlobactam in the absence of a carbapenem. 

Q: And if sulbactam-durlobactam is not available? Would clinicians defer to the previous IDSA recommendations? 

A: If sulbactam-durlobactam is not available, an alternate approach is the administration of high-dose ampicillin-sulbactam in combination with a second agent.²¹ The secondary agents to consider include minocycline, tigecycline, cefiderocol, or polymyxin B. 

A Few More Notes on Sulbactam-Durlobactam 

In a 16-country clinical trial of treatment options for CRAB pneumonia or bloodstream infection, patients receiving sulbactam-durlobactam, along with imipenem, had a 13.2% lower mortality rate than patients receiving colistin-imipenem regimens.²² Additionally, nephrotoxicity was 24.4% lower for patients receiving sulbactam-durlobactam than those who received colistin. Although ineffective against Class B metallo-β-lactamases, such as NDM or IMP, sulbactam-durlobactam has good efficacy against Class A and D carbapenemases, including OXA-23.²³ 

For more information on sulbactam-durlobactam (XACDURO^®), see the companion article in this issue. 

What About Colistin? 

Because of recent clinical trials, IDSA guidelines discourage use of colistin-containing regimens for the treatment of CRAB.²¹ But the truth is, colistin has been a mainstay of CRAB-therapy regimens for two decades, and much of the world continues to use colistin. So, should you be testing and reporting colistin? The answer is, maybe. It’s not preferred, but sometimes it is all we have in the fight against CRAB. Here is some guidance, directly from the Rationale Document CLSI MR01 that may assist your decision-making process: “Polymyxins are last-resort agents, and if they are available, alternative agents are preferred. A susceptible category for polymyxins cannot be established because there is no MIC for which likely clinical efficacy can be predicted. When used, polymyxins should be administered at maximally tolerated doses and in combination with a second agent.”²⁴ Work with your antimicrobial stewardship program to determine the appropriate lab testing and reporting strategy for your facility. If you are going to use a polymyxin as part of your treatment regimen, polymyxin B is preferred over colistin given its more favorable pharmacokinetic profile.²⁵ 

Other AST Challenges 

Minocycline and tigecycline are IDSA-recommended agents for treatment of CRAB, yet tigecycline continues to be a challenge from an AST-perspective due to the absence of breakpoints. No breakpoint-setting organizations—neither CLSI, FDA, nor EUCAST— provide tigecycline breakpoints for Acinetobacter spp. So, tigecycline and Acinetobacter will continue to be another clinical microbiology conundrum—used clinically—but given the absence of breakpoints, there are substantial technical challenges in performing MIC-based testing and its interpretation.^26-28

CRAB and Public Health 

Finally, what is being done to combat CRAB and other multidrug-resistant A. baumannii infections? CRAB presents some unique challenges to prevention and detection, especially due to its tremendous abundance in long-term care facilities, its ability to survive on surfaces for long periods of time, and its poor performance on assays for phenotypic carbapenemase detection. This last point is a good one to reiterate: unlike Enterobacterales or Pseudomonas aeruginosa, the modified carbapenemase inactivation method (mCIM) and CarbaNP perform poorly with A. baumannii, and thus are not approved for use for CRAB isolates.¹⁹ Many commercially available molecular methods also do not include OXA-23 and OXA-24, the two most common acquired carbapenemases identified in CRAB in the US. 

CRAB is one of the priority targets for testing in the Centers for Disease Control and Prevention’s (CDC) Antimicrobial Resistance Laboratory Network (AR Lab Network).²⁹ State and local public health laboratories (PHLs) actively recruit clinical labs to submit clinical isolates of A. baumannii resistant to imipenem, meropenem, or doripenem (MIC ≥ 8 μg/mL). At PHLs, these isolates are tested for carbapenemase activity and mechanisms (including KPC, NDM, VIM, IMP, OXA-48, OXA-23, and OXA-24) and evaluated against a broad panel of anti-gram-negative antimicrobial agents. Whole genome sequencing is utilized in the identification of additional carbapenemases, tracing intra- and inter- facility transmission, and understanding the molecular epidemiology of submitted isolates. Seven AR Lab Network Regional labs also perform colonization screening for specific carbapenemase-producing CRAB. This screening is a pillar of the prevention, infection control, and response arms of the AR Lab Network. 

Conclusion 

We can all agree, infections caused by A. baumannii are tricky to treat, test, and detect. The drugs used to treat these infections are complicated to test and determining whether a culture result represents colonization or infection only compounds the challenge. Whether a cause of colonization or infection, A. baumannii, particularly CRAB, can spread rapidly within health care facilities, highlighting the incredible importance of the microbiology laboratory to detect this organism and perform AST. 

We have a few glimmers of hope though: public health is ramping up their support for infection control and response efforts to mitigate CRAB transmission, and sulbactam-durlobactam is giving clinicians new therapeutic options to combat infections. Our work is far from over, though, as we still need additional therapeutic options and improved test methods for existing therapies like tigecycline and polymyxin b. 

Use What You Read: 

• Follow the recommendations from the 33rd edition of CLSI M100-S33, including: 

– Tiered antimicrobial testing and reporting for Acinetobacter spp. (Table 1D). 

– Current Acinetobacter spp. breakpoints (Table 2B-2). 

– If testing cefiderocol, colistin, or polymyxin b, make a special note of the reporting comments (Table 2B-2). 

– Follow the recommendations in Appendix A: confirming AST, following up with your public health laboratory, and saving isolates, as appropriate. 

• Work with your antimicrobial stewardship program to harmonize testing challenges and clinical practice for treating CRAB infections. 

• Be familiar with the current IDSA treatment guidelines. If you are not routinely testing the drugs recommended for CRAB treatment, develop a strategy for when/how these drugs can be ordered and tested in your facility. 

• Submit CRAB isolates to your local or state public health lab.

 

References 

1 CDC, HAI Pathogens and Antimicrobial Resistance Report, 2018–2021. 2023, US Department of Health and Human Services: Atlanta, GA. 

2 CDC, Antibiotic Resistance Threats in the United States, 2019. US Department of Health and Human Services, CDC: Atlanta, GA. 

3 Durante-Mangoni E, et al. Colistin and rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized clinical trial. Clin Infect Dis., 2013;57(3)349-58. 

4 Aydemir H, et al. Colistin vs. the combination of colistin and rifampicin for the treatment of carbapenem-resistant Acinetobacter baumannii ventilator-associated pneumonia. Epidemiol Infect. 2013;141(6)1214-22. 

5 Sirijatuphat R, Thamlikitkul V. Preliminary study of colistin versus colistin plus fosfomycin for treatment of carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Agents Chemother. 2014;58(9)5598-601. 

6 Paul M, et al. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis. 2018;18(4)391-400. 

7 Kaye KS, et al. Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms. NEJM Evid. 2023;2(1). 

8 Betrosian, AP, et al. 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)432-6. 

9 Bassetti M, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021;21(2)226-240. 

10 Wang M, et al. Clinical Outcomes and Bacterial Characteristics of Carbapenem-Resistant Acinetobacter baumannii Among Patients from Different Global Regions. Clin Infect Dis. 2023. 

11 Ma C, McClean S. Mapping Global Prevalence of Acinetobacter baumannii and Recent Vaccine Development to Tackle It. Vaccines (Basel);2021;9(6). 

12 Muller CC, et al. A global view on carbapenem-resistant Acinetobacter baumannii. mBio, 2023:p. e0226023. 

13 Chu YW, et al. Skin carriage of acinetobacters in Hong Kong. J Clin Microbiol. 1999;37(9):2962-7. 

14 Berlau J, et al. Distribution of Acinetobacter species on skin of healthy humans. Eur J Clin Microbiol Infect Dis. 1999;18(3)179- 83. 

15 Seifert H, et al. Distribution of Acinetobacter species on human skin: comparison of phenotypic and genotypic identification methods. J Clin Microbiol. 1997;35(11)2819-25. 

16 Taplin D, Zaias N. The Human Skin as a Source of Mima-Herellea Infections. JAMA. 1963;186:952-5. 

17 Bartal, C, Rolston KVI, Nesher L. Carbapenem-resistant Acinetobacter baumannii: Colonization, Infection, and Current Treatment Options. Infect Dis Ther. 2022;11(2)683-694. 

18 Kyriakidis, I, et al. Acinetobacter baumannii Antibiotic Resistance Mechanisms. Pathogens. 2021;10(3). 

19 CLSI. Performance Standards for Antimicrobial Susceptibility Testing. 33rd ed. CLSI supplement M100. Clinical and Laboratory Standards Institute; 2023. 

20 Castanheira M, Mendes RE, Gales AC. Global Epidemiology and Mechanisms of Resistance of Acinetobacter baumannii-calcoaceticus Complex. Clin Infect Dis. 2023;76(Suppl 2)S166-S178. 

21 Tamma, PD, et al. Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram- Negative Infections. Clin Infect Dis. 2023. 

22 Kaye, KS, et al. Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK). Lancet Infect Dis. 2023;23(9)1072-1084.