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Carbapenem Resistant Acinetobacter Baumannii: An Urgent Threat

By: Giavanna Carr, PharmD Candidate c/o 2025

Acinetobacter is a gram-negative organism typically found in soil and water, but it has been found to colonize intravenous fluids and irrigation solutions.1 Of the species of acinetobacter, A. baumannii is the most clinically significant.1 Acinetobacter is a slow growing organism with the potential to cause infections in immunocompromised and neutropenic patients, while also, commonly infecting those who are on ventilators, have catheters, open wounds from surgeries, in the intensive care unit (ICU), or prolonged stay in the hospital.1 A. baumannii is prone to causing infections in the blood, urinary tract, lungs colonizing as pneumonia, or in wounds in various parts of the body.2

Antibiotic Resistance

Acinetobacter gained clinical significance due to its ability to survive desiccation and sustain life in a healthcare setting for an extended period of time.1 This organism has the potential to acquire resistance to frequently used antibiotics and thus can be deemed  as multidrug resistant (MDR), when the organism is resistant to at least one agent in three or more antimicrobial classes, extensively drug resistant (XDR), when the organism is resistant to more than one agent in two or fewer antimicrobial classes and pan drug resistant (PDR), when the organism if resistant to all antimicrobial classes, when categorized by the Centers for Disease Control (CDC), antimicrobial resistance report.1 The 2013 CDC report classified Acinetobacter as MDR under a threat category “serious”.1

The typical agents used to fight A. baumannii include broad spectrum beta lactams such as ceftazidime, cefepime, ampicillin/sulbactam and piperacillin/tazobactam.3 Between the 1970s and the 1980s, widespread resistance of A. baumannii was experienced and by the late 1990s, the only drug of use against A. baumannii were the carbapenems: meropenem and imipenem.4 Due to the sudden emergence of Carbapenem Resistant Acinetobacter Baumannii (CRAB), the therapeutic choices for A. baumannii are decreasing. The CDC has classified CRAB as an urgent threat in antibiotic resistance.5

Mechanisms of Resistance

There are three main mechanisms by which acinetobacter acquires resistance to different antibiotics: enzymes inactivating antibiotics, reduced entry into the target sites of antibiotics, and alteration of the target or cellular functions due to mutation.6 Carbapenems are impacted by two of the three mechanisms of resistance, consistent with the fact that this is an urgent threat. The enzymes responsible for the inactivation of antibiotics, such as penicillins, synthetic cephalosporins, and carbapenems, are beta-lactamases.6 Beta lactamases are known to hydrolyze and confer resistance against various groups of antibiotics, most importantly the carbapenems.6 Class D, OXA-type inactivating enzymes, and class B, metallo-beta-lactamases (MBLs) are the most threatening.6 Carbapenems also deemed resistant to acinetobacter due to reduced entry into the target site of the bacteria. In the case of CRAB, the porin channels are too small in size and number to allow the delivery of the carbapenem to the target protein for it to complete its action, therefore resistance is conferred.6

Antimicrobial Susceptibility Testing

In order to determine if the patient is infected with CRAB, an antimicrobial susceptibility test would need to be conducted. Antimicrobial Susceptibility Testing (AST) is performed to identify the proper antimicrobial regimen for a specific patient based on what their specific infection is susceptible or resistant to.7 The first step is specimen collection, and the most common specimens used for culture and sensitivity (C&S) tests are urine, blood, cerebrospinal fluid, sputum, wound, or stool.7 The culture and sensitivity test will return and provide the minimum inhibitory concentration (MIC) and the MIC breakpoints, which will classify whether a specific antibiotic is susceptible or resistant to the organism.7 In the case of CRAB, the AST and C&S would disclose that the organism is resistant to carbapenems and not an appropriate antimicrobial regimen for that specific patient.

Treatment of CRAB

In cases of CRAB, clinicians often turn to combination therapy to combat resistant isolates. Colistin, administered in its prodrug form, colistimethate, is typically used in combination with other agents like vancomycin.8 Studies have shown that colistimethate yield low serum concentrations in the early stages of therapy, thus patients may experience subtherapeutic levels of the drug and not show signs of improvement.8 Colistimethate and vancomycin both have the potential for nephrotoxicity and may be seen as a limitation in the use of these medications to treat CRAB.8 Another drug which has shown bacteriostatic activity against Acinetobacter is tigecycline.6 Overtime resistance to this medication has been documented due to the overexpression of efflux pumps in Acinetobacter.The current regimen recommended within the IDSA guidelines include the use of high dose ampicillin-sulbactam with a total daily dose of 6-9 grams of the sulbactam component in combination with polymyxin B, minocycline, or tigecycline.9 Due to the adverse effects and resistance that current treatments pose, there is extensive research for new antibiotics to be introduced into the market to fight this urgent threat.

Emergence of Zosurabalpin

Following the classification of CRAB as a priority 1 pathogen, the need for a new antibiotic to fight this pathogen is abundantly necessary. No new antibiotic class with activity against Acinetobacter has been discovered within the last 50 years. Because of this,  the discovery of Zosurabalpin is ground breaking.10 The novel antibiotic is currently under phase 1 trials by F. Hoffmann-La Roche, a swiss pharmaceutical company.10 Currently, Roche has evidence that Zosurabalpin effectively treats CRAB in vitro and in mouse models.10 The mechanism of Zosurabalpin is completely unique to this drug, and also specific to CRAB and no other infection. This can be seen as both a pro and con to the drug. On the bright side, it is less likely to acquire resistance since it is only active against one organism. At the same time, clinicians need to be entirely sure the organism they’re fighting is CRAB because Zosurabalpin is  efficacious solely against CRAB.10 CRAB is such a difficult organism to defeat due to its protective outer layer of lipopolysaccharide (LPS). Zosurabalpin’s mechanism of action is to block the lipopolysaccharide transporter, LptB2FGC, which prevents the organism from transporting the LPS from the interior to the outer layer to protect it from antibiotics. Keeping the LPS inside of the organism itself will cause a self-destructive mechanism, resulting in bacterium death.10

Conclusion

Zosurabalpin is a revolutionary discovery in that no antibiotic has been found to have activity against Acinetobacter in the past 50 years! CRAB is a priority 1 pathogen as defined by both the World Health Organization and the Centers for Disease Control and Prevention, therefore indubitably at the top of all scientists list. This revelation will aid in antimicrobial resistance as well as save countless lives due to this destructible pathogen.

References

  1. Brady MF, Jamal Z, Pervin N. Acinetobacter – StatPearls – NCBI Bookshelf. August 8, 2023. Accessed January 28, 2024. https://www.ncbi.nlm.nih.gov/books/NBK430784/
  2. Acinetobacter in healthcare settings. Centers for Disease Control and Prevention. November 13, 2019. Accessed January 28, 2024. https://www.cdc.gov/hai/organisms/acinetobacter.html.   
  3. Kanafani ZA, Kanj SS. UpToDate. November 8, 2023. Accessed January 28, 2024. https://www.uptodate.com/contents/acinetobacter-infection-treatment-and-prevention.
  4. Manchanda V, Sanchaita S, Singh N. Multidrug Resistant Acinetobacter. Journal of global infectious diseases. September 2010. Accessed January 28, 2024. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946687/.  
  5. 2019 antibiotic resistance threats report. Centers for Disease Control and Prevention. November 23, 2021. Accessed January 28, 2024. https://www.cdc.gov/drugresistance/biggest-threats.html
  6. Acinetobacter in healthcare settings. Centers for Disease Control and Prevention. November 13, 2019. Accessed January 28, 2024. https://www.cdc.gov/hai/organisms/acinetobacter.html
  7. Singh H, Thangaraj P, Chakrabarti A. Acinetobacter baumannii: A brief account of mechanisms of multidrug resistance and current and future therapeutic management. Journal of clinical and diagnostic research : JCDR. November 10, 2013. Accessed January 28, 2024. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3879836/.
  8. Bayot ML, Bragg BN. Antimicrobial susceptibility testing – statpearls – NCBI bookshelf. October 10, 2022. Accessed January 28, 2024. https://www.ncbi.nlm.nih.gov/books/NBK539714/.
  9. Viehman JA, Nguyen MH, Doi Y. Treatment options for carbapenem-resistant and extensively drug-resistant Acinetobacter baumannii infections. Drugs. August 1, 2015. Accessed January 28, 2024. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4258832/
  10. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, David van Duin, Clancy CJ. Infectious Diseases Society of America 2023 Guidance on the Treatment of Antimicrobial Resistant Gram-Negative Infections. Clinical Infectious Diseases. Published online July 18, 2023. doi:https://doi.org/10.1093/cid/ciad428 
  11. Healthcare G. Zosurabalpin shows promise in the fight against antibacterial resistance. Clinical Trials Arena. January 16, 2024. Accessed January 28, 2024. https://www.clinicaltrialsarena.com/analyst-comment/zosurabalpin-promise-antibacterial-resistance/?cf-view.
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