Table of Contents
Credits
Host: Sara Dong
Guest: Fatimah Alshahrani, Abdullah Almohaizeie
Writing/Producing/Editing/Cover Art: Sara Dong
Our Guests
Dr. Fatimah Alshahrani
Dr. Fatimah Alshahrani is the Director of Infection Prevention & Control at King Saud University Medical City, an Assistant Professor of Infectious Diseases, and an adult Infectious Diseases Consultant.
Dr. Abdullah Almohaizeie
Dr. Abdullah Almohaizeie is a Consultant in Infectious Diseases Pharmacotherapy at King Faisal Specialist Hospital in Riyadh, KSA
Culture
Fatimah loves walking at night, swimming, traveling, and listening to music! She also loves spending time with her kids.
Abdullah likes to read and spend time with family
Consult Notes
Consult Q
Please assist in management of infection with Acinetobacter
Key Points
Welcome to a three episode series recorded live at the World Antimicrobial Resistance Awareness Week (WAAW) Forum held and organized by the Saudi Pediatric Infectious Diseases Society (SPIDS) in collaboration with Febrile and the King Abdulaziz Public Library
In addition to our guests that you’ll meet on episodes 86-88, a special thank you to:
- Dr. Rana Almaghrabi, President of SPIDS
- Dr. Fatimah Aldubisi, Head of Scientific and Research Committee
Key Resource
Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America Antimicrobial-Resistant Treatment Guidance: Gram-Negative Bacterial Infections. Infectious Diseases Society of America 2023; Version 3.0. Available at https://www.idsociety.org/practice-guideline/amr-guidance/.
The patient case
We meet a 10 year old child with leukemia receiving chemotherapy in the ICU. The ICU team lets you know that the Acinetobacter isolate appears to be CRAB (carbapenem-resistant Acinetobacter baumanii), which is meropenem resistant and only shows susceptibility to ampicillin/sulbactam, colistin, and minocycline
Isolate: Acinetobacter baumanii | |||
Antibiotic | Intrp | MIC | Intrp |
Ampicillin/sulbactam | S | ||
Ceftazidime | R | ||
Ciprofloxacin | R | ||
Cefepime | R | ||
Gentamicin | R | ||
Levofloxacin | R | ||
Meropenem | R | ||
Tobramycin | R | ||
Colistin | 0.25 | S | |
Minocycline | 4 | S | |
Initial management/evaluation
We initially noted the culture results were from a respiratory sample in a patient who was clinically stable without signs of respiratory infection
- The first step is to ensure that any culture growing CRAB represents true infection and not colonization – this is especially true for respiratory, urine, and wound cultures
- CRAB is commonly recovered from respiratory specimens or wounds – and its not always easy to tell if the organism is a pathogen or is colonizing this ill patient (which could be related to their underlying host status such as mechanical ventilation, patients with extensive burns)
- We know that CRAB as a pathogen can contribute to mortality which further makes decisions on antibiotic therapy challenging
- Bartal C, Rolston KVI, Nesher L. Carbapenem-resistant Acinetobacter baumannii: Colonization, Infection and Current Treatment Options. Infect Dis Ther. 2022;11(2):683-694. doi:10.1007/s40121-022-00597-w
Afterwards, the case was revised to represent blood cultures!
- We emphasized that source control and investigating for sources of infection are paramount
Antimicrobial therapy for CRAB
Initial therapy for CRAB infections is challenging – there is no clear standard of care regimen
- Generally will use high dose ampicillin-sulbactam in combination with at least one other agent
- Combination therapy with at least 2 agents is continued at least until clinical response since there is limited clinical data supporting effectiveness of any single agent
- Combo therapy only noted to improve outcomes in one of 8 clinical trials
- Paul M, Daikos GL, Durante-Mangoni E, 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. doi:10.1016/S1473-3099(18)30099-9
- 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):5598-5601. doi:10.1128/AAC.02435-13
- Durante-Mangoni E, Signoriello G, Andini R, 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):349-358. doi:10.1093/cid/cit253
- Aydemir H, Akduman D, Piskin N, 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):1214-1222. doi:10.1017/S095026881200194X
- Makris D, Petinaki E, Tsolaki V, et al. Colistin versus Colistin Combined with Ampicillin-Sulbactam for Multiresistant Acinetobacter baumannii Ventilator-associated Pneumonia Treatment: An Open-label Prospective Study. Indian J Crit Care Med. 2018;22(2):67-77. doi:10.4103/ijccm.IJCCM_302_17
- Park HJ, Cho JH, Kim HJ, Han SH, Jeong SH, Byun MK. Colistin monotherapy versus colistin/rifampicin combination therapy in pneumonia caused by colistin-resistant Acinetobacter baumannii: A randomised controlled trial. J Glob Antimicrob Resist. 2019;17:66-71. doi:10.1016/j.jgar.2018.11.016
- But the trial that demonstrated benefit was the only one that used high dose amp-sulbactam in combo therapy arm
- High dose amp-sulbactam is used given theoretical benefit of saturating sulbactam’s PBP targets with higher doses of sulbactam and potential inaccuracies with commonly used approaches for amp-sulbactam AST testing for CRAB
- Viana GF, Saalfeld SM, Moreira RR, et al. Can ampicillin/sulbactam resistance in Acinetobacter baumannii be predicted accurately by disk diffusion?. J Glob Antimicrob Resist. 2013;1(4):221-223. doi:10.1016/j.jgar.2013.07.001
- Fernández-Cuenca F, Tomás M, Caballero-Moyano FJ, Bou G, Pascual Á; Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC). Reporting antimicrobial susceptibilities and resistance phenotypes in Acinetobacter spp: a nationwide proficiency study. J Antimicrob Chemother. 2018;73(3):692-697. doi:10.1093/jac/dkx464
- Combo therapy only noted to improve outcomes in one of 8 clinical trials
- The additional agents that can be used as component of combo therapy include:
- Polymyxin B (IDSA guidance favors polymyxin B based on more favorable PK profile than colistin)
- Minocycline
- Tigecycline
- Cefiderocol
- Not suggested: fosfomycin, rifampin
- High dose extended infusion carbapenem therapy did not have benefit in two clinical trials
- Paul M, Daikos GL, Durante-Mangoni E, 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. doi:10.1016/S1473-3099(18)30099-9
- https://clinicaltrials.gov/study/NCT01597973
- High dose extended infusion carbapenem therapy did not have benefit in two clinical trials
- A brief note on CRAB pneumonia and nebulized therapy. There is concern regarding unequal distribution in infected lungs and potential for respiratory complications such as bronchorestriction with its use
What are the mechanisms of antibiotic resistance in Acinetobacter baumanii?
- Generally carbapenem resistance comes along with acquired resistance to many other antibiotics expected to be active against wild-type A.baumannii, leaving few remaining therapeutic options
- Production of OXA carbapenemases (eg OXA-24/40, OXA-23) mediate resistance to beta-lactams
- Vijayakumar S, Biswas I, Veeraraghavan B. Accurate identification of clinically important Acinetobacter spp.: an update. Future Sci OA. 2019;5(6):FSO395. Published 2019 Jun 27. doi:10.2144/fsoa-2018-0127
- Turton JF, Ward ME, Woodford N, et al. The role of ISAba1 in expression of OXA carbapenemase genes in Acinetobacter baumannii. FEMS Microbiol Lett. 2006;258(1):72-77. doi:10.1111/j.1574-6968.2006.00195.x
- Isolates may produce MBLs and additional serine carbapenemases (eg Acinetobacter baumannii-derived cephalosporinases, ADCs)
- Sulbactam resistance is not completely understood but appears to be driven via mutations targeting PBPs and beta-lactamase production may contribute
- Penwell WF, Shapiro AB, Giacobbe RA, et al. Molecular mechanisms of sulbactam antibacterial activity and resistance determinants in Acinetobacter baumannii. Antimicrob Agents Chemother. 2015;59(3):1680-1689. doi:10.1128/AAC.04808-14
- McLeod SM, Shapiro AB, Moussa SH, et al. Frequency and Mechanism of Spontaneous Resistance to Sulbactam Combined with the Novel β-Lactamase Inhibitor ETX2514 in Clinical Isolates of Acinetobacter baumannii. Antimicrob Agents Chemother. 2018;62(2):e01576-17. Published 2018 Jan 25. doi:10.1128/AAC.01576-17
- Krizova L, Poirel L, Nordmann P, Nemec A. TEM-1 β-lactamase as a source of resistance to sulbactam in clinical strains of Acinetobacter baumannii. J Antimicrob Chemother. 2013;68(12):2786-2791. doi:10.1093/jac/dkt275
- Aminoglycosides often are not an option due to aminoglycoside modifying enzymes or 16S rRNA methyltransferases
- Nemec A, Dolzani L, Brisse S, van den Broek P, Dijkshoorn L. Diversity of aminoglycoside-resistance genes and their association with class 1 integrons among strains of pan-European Acinetobacter baumannii clones. J Med Microbiol. 2004;53(Pt 12):1233-1240. doi:10.1099/jmm.0.45716-0
- Bonomo RA, Szabo D. Mechanisms of multidrug resistance in Acinetobacter species and Pseudomonas aeruginosa. Clin Infect Dis. 2006;43 Suppl 2:S49-S56. doi:10.1086/504477
- Castanheira M, Deshpande LM, Woosley LN, Serio AW, Krause KM, Flamm RK. Activity of plazomicin compared with other aminoglycosides against isolates from European and adjacent countries, including Enterobacteriaceae molecularly characterized for aminoglycoside-modifying enzymes and other resistance mechanisms. J Antimicrob Chemother. 2018;73(12):3346-3354. doi:10.1093/jac/dky344
- Fluoroquinolones: mutations in chromosomally encoded quinolone resistance determining regions
This patient does have a central venous line and ultimately the ICU team is able to remove this given ongoing bacteremia. They have cleared their blood cultures and are clinically improved? Do we stick with combination therapy?
- Our guests described their approach to step-down therapy
- If prolonged durations of therapy are needed (such as osteomyelitis), step-down to single agent might be considered
- There are various observational studies comparing combination therapy vs monotherapy but they are very heterogenous and challenging to interpret
Let’s say that this patient’s susceptibility results showed resistance to amp-sulbactam. How do you think about that?
- Fewer than half of CRAB isolates are going to test susceptible for amp-sulbactam
- Reddy T, Chopra T, Marchaim D, et al. Trends in antimicrobial resistance of Acinetobacter baumannii isolates from a metropolitan Detroit health system. Antimicrob Agents Chemother. 2010;54(5):2235-2238. doi:10.1128/AAC.01665-09
- Castanheira M, Mendes RE, Jones RN. Update on Acinetobacter species: mechanisms of antimicrobial resistance and contemporary in vitro activity of minocycline and other treatment options. Clin Infect Dis. 2014;59 Suppl 6:S367-S373. doi:10.1093/cid/ciu706
- Sulbactam is competitive, irreversible beta-lactamase inhibitor that can saturate PBP1a/1b and PBP3 of A.baumannii isolates
- This unique activity has been shown in various studies that are in vitro and clinical
- Makris D, Petinaki E, Tsolaki V, et al. Colistin versus Colistin Combined with Ampicillin-Sulbactam for Multiresistant Acinetobacter baumannii Ventilator-associated Pneumonia Treatment: An Open-label Prospective Study. Indian J Crit Care Med. 2018;22(2):67-77. doi:10.4103/ijccm.IJCCM_302_17
- 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
- Assimakopoulos SF, Karamouzos V, Lefkaditi A, et al. Triple combination therapy with high-dose ampicillin/sulbactam, high-dose tigecycline and colistin in the treatment of ventilator-associated pneumonia caused by pan-drug resistant Acinetobacter baumannii: a case series study. Infez Med. 2019;27(1):11-16.
- 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
- Jung SY, Lee SH, Lee SY, et al. Antimicrobials for the treatment of drug-resistant Acinetobacter baumannii pneumonia in critically ill patients: a systemic review and Bayesian network meta-analysis. Crit Care. 2017;21(1):319. Published 2017 Dec 20. doi:10.1186/s13054-017-1916-6
- So amp-sulbactam is often used despite whether susceptibility has been demonstrated
- Dr. Abdullah discussed the error rate comparing e-test with agar dilution with CRAB was 10%, which cast doubt on disk diffusion and etest techniques as appropriate methods for detecting resistance to SAM
- Disk diffusion and agar dilution are listed by CLSI as acceptable methods but some studies have found low accuracy
- Viana GF, Saalfeld SM, Moreira RR, et al. Can ampicillin/sulbactam resistance in Acinetobacter baumannii be predicted accurately by disk diffusion?. J Glob Antimicrob Resist. 2013;1(4):221-223. doi:10.1016/j.jgar.2013.07.001
- Fernández-Cuenca F, Tomás M, Caballero-Moyano FJ, Bou G, Pascual Á; Spanish Society of Clinical Microbiology and Infectious Diseases (SEIMC). Reporting antimicrobial susceptibilities and resistance phenotypes in Acinetobacter spp: a nationwide proficiency study. J Antimicrob Chemother. 2018;73(3):692-697. doi:10.1093/jac/dkx464
What is sulbactam-durlobactam?
- This was approved in by the US FDA in May of 2023 and is an exciting new option
- Studies investigate this agent against CRAB isolates using 4g of sulbactam component
- Sulbactam is a substrate for both ADCs (Class C enzymes) and OXA enzymes (Class D enzymes) that are produced by CRAB
- Durlobactam is a potent inhibitor of class A, C, and D enzymes commonly produced, enabling lower doses of sulbactam as sulbactam is more likely to successfully reach its PBP targets with the protection of durlobactam
- Findlay J, Poirel L, Bouvier M, Nordmann P. In vitro activity of sulbactam-durlobactam against carbapenem-resistant Acinetobacter baumannii and mechanisms of resistance. J Glob Antimicrob Resist. 2022;30:445-450. doi:10.1016/j.jgar.2022.05.011
- Karlowsky JA, Hackel MA, McLeod SM, Miller AA. In Vitro Activity of Sulbactam-Durlobactam against Global Isolates of Acinetobacter baumannii–calcoaceticus Complex Collected from 2016 to 2021. Antimicrob Agents Chemother. 2022;66(9):e0078122. doi:10.1128/aac.00781-22
- McLeod SM, Moussa SH, Hackel MA, Miller AA. In Vitro Activity of Sulbactam-Durlobactam against Acinetobacter baumannii-calcoaceticus Complex Isolates Collected Globally in 2016 and 2017. Antimicrob Agents Chemother. 2020;64(4):e02534-19. Published 2020 Mar 24. doi:10.1128/AAC.02534-19
Infographics
Goal
Listeners will be able to understand the management of CRAB infections
Learning Objectives
After listening to this episode, listeners will be able to:
- Identify the importance of investigating whether growth of CRAB in culture represents true infection vs colonization
- Describe the general antimicrobial treatment approaches for serious CRAB infection
- Discuss the mechanisms of antibiotic resistance in Acinetobacter baumanii
Disclosures
Our guests as well as Febrile podcast and hosts report no relevant financial disclosures
Citation
Alshahrani, F., Almohaizeie, A., Dong, S. “#87: WAAW with SPIDS – Catching CRABs”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/f7da75d6-048d-4c2c-bb24-391f38e9b920