Cefiderocol vs Best Available Therapy for Carbapenem-resistant Acinetobacter Baumannii-calcoaceticus Complex Infections: A Target Trial Emulation
Conditions: Carbapenem Resistant Bacterial Infection, Acinetobacter Baumannii Infection, Antimicrobial Drug Resistance
Sponsor: National Institutes of Health Clinical Center (CC)

COVER PAGE 
 
Cefiderocol versus best available therapy for treatment of carbapenem-resistant A. baumannii infections: A 
hypothetical target trial emulation study 
 
September 2, 2025 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Significance & Background  
In July 2024, the Centers for Disease Prevention and Control published new antimicrobial resistance 
surveillance data which demonstrated a significant increase in the number of hospital-onset carbapenem-
resistant Acinetobacter baumannii-calcoaceticus complex (CR-ABC) infections from 2019 to 2022[1]. This 
statistic is quite alarming given the high mortality associated with CR-ABC infections even among patients who 

receive in vitro active antibiotic therapy within 72 hours of culture collection[2]. Guidelines for treatment of 
severe CR-ABC infections remain broad, varied across professional societies, and based on limited high-
quality clinical trial data[3, 4]. As of recent, the Infectious Diseases Society of America (IDSA) suggested the 
optimal treatment regimen for severe CR-ABC is the combination of sulbactam-durlobactam with imipenem-
cilastatin[4]. This recommendation comes from findings of a recent randomized controlled trial comparing this 
combination to colistin and imipenem-cilastatin[5], a regimen which was previously demonstrated not to be 
superior to colistin alone[6]. Despite this revised recommendation, sulbactam-durlobactam is relatively new to 
the commercial market and not necessarily available at all institutions. Consequently, clinicians must rely on 
alternative treatment regimens which include combination antibiotic treatment with ampicillin-sulbactam and a 
second agent (i.e., polymyxin b, minocycline, tigecycline, or cefiderocol). However, much of the existing 
literature investigating the optimal regimen for CR-ABC is derived from observational studies and are biased by 
small sample sizes, heterogenous patient populations, inadequate antibiotic dosing, and variable combination 
regimens among comparison groups[7-12].  
 
Cefiderocol demonstrates in vitro activity against CR-ABC and a more favorable side effect profile compared to 
traditional CR-ABC agents such as tigecycline and polymyxin b. However, given the findings from CREDIBLE-
CR trial a black box warning was issued by the Food and Drug Administration due to a concern for an 
increased risk of mortality for the subgroup of patients with CR-ABC. These findings have not been confirmed 
in subsequent observational studies[13-18], but uncertainty remains regarding the clinical effectiveness of 
cefiderocol in this target population. While a large randomized controlled trial comparing cefiderocol to best 
available therapy would provide definitive answers, recruitment into a study of this type is often challenging due 
to the rarity of disease and severity of illness upon presentation. The use of large, observational databases in 
combination with causal inference techniques offer a powerful tool to investigate relevant clinical questions for 
which traditional randomized controlled trials are not possible.  
 
This study aims to use a target trial emulation framework to compare 28-day mortality among patients with CR-
ABC infection randomized to a hypothetical target trial to receive at least 7 days of a cefiderocol-based 
treatment strategy or at least 7 days of best available therapy if and when they receive an empiric gram-
negative antibiotic following culture collection using patient data collected from the PINC-AI healthcare 
database between 2018 and 2024.  
 
STUDY PROTOCOL 9-2-2025 
 
Eligibility  
Hospitalized adult (≥18 years of age) with clinical culture positive for carbapenem-resistant Acinetobacter 
baumannii-calcoaceticus complex (CR-ABC) in the PINC AI database[19] between 2018-2024 are be eligible for 
inclusion in the hypothetical target trial.  
 
Inclusion Criteria  
• 
Adult hospitalized patients (≥18 years of age) 
• 
Any clinical culture positive for carbapenem resistant A. baumannii-calcoaceticus complex  
 
Exclusion Criteria  
• 
Antibiotic susceptibility results are not available for A. baumannii-calcoaceticus complex culture 
• 
A. baumannii-calcoaceticus complex diagnosed by molecular testing only (i.e., multiplex polymerase 
chain reaction [PCR] 
 
Treatment strategy 
• 
Best available therapy: Patients will receive at least 7 days of best available therapy (i.e., any 
monotherapy or combination of ampicillin/sulbactam, minocycline, tigecycline, polymyxin B, colistin, 
aminoglycosides, fluoroquinolones, eravacycline, and/or trimethoprim/sulfamethoxazole) if and when 
they receive an empiric gram-negative antibiotic following culture collection.  
• 
Cefiderocol: Patients will receive at least 7 days of cefiderocol (as monotherapy or in combination) if 
and when they receive an empiric gram-negative antibiotic following culture collection.  
  
Primary Outcome measure 
• 
In-hospital mortality defined as death during hospitalization or discharge to hospice.  

 
Secondary outcome measures 
• 
Length of stay among survivors: duration of hospitalization among surviving patients 
• 
Recurrent carbapenem resistant A. baumannii infection: clinical culture positive for carbapenem 
resistant A. baumannii infection within the same encounter downstream of the index episode and within 
30 days.    
• 
Development of antibiotic resistance to initial antibiotic treatment: development of antibiotic resistance 
on a subsequent positive clinical culture to an antibiotic administered during prior infectious episode  
 
Statistical Analysis Plan  
We will use a target trial emulation framework to reduce confounding bias. In the hypothetical target trial, 
patients will be randomized to a hypothetical treatment strategy of receiving at least 7 days of best available 
therapy or at least 7 days of cefiderocol if and when a patient received an empiric gram-negative antibiotic 
following culture collection. This target trial will assume no loss to follow up. Under perfect adherence to the 
assigned treatment strategy, we will use a longitudinal g-computation formula [20] to estimate the per protocol 
average treatment effect between the two treatment strategies on 28-day mortality (defined as death or 
discharge to hospice) under standard causal assumptions (consistency, positivity, and exchangeability). The g-
computation formula determines the average treatment effect by estimating outcomes that would occur under 
the counterfactual treatment strategies. A sequentially doubly robust (SDR) estimator[21] will be used to 
estimate the g-computation formula. This method uses the probability of receiving a hypothetical treatment 
strategy, the probability of experiencing the outcome, and the probability of censoring at each time point (day 
0-day 28) to estimate a survival curve under each hypothetical treatment strategy. If at least one model is 
correctly specified at each time point, the average treatment effect estimate will remain correct and is, 
therefore, doubly robust against model misspecification. This method will minimize the presence of 
confounding that occurs in the absence of random allocation to either treatment strategy. Time-independent 
variables including age, gender, race, Elixhauser co-morbidity score[22], eSOFA (simplified sequential organ 
failure assessment simplified for use in observational data from electronic health records)[23], infection site, and 
polymicrobial culture will be included in baseline adjustments as well as time-dependent variables such as 
receipt of mechanical ventilation, receipt of vasopressors, ICU admission, and receipt of renal replacement 
therapy will be used for model specification. Subgroup analyses comparing cefiderocol-based antibiotic 
regimens to distinct combinations of BAT (i.e., ampicillin/sulbactam in combination with either minocycline, 
tigecycline, or polymyxins) will be performed to examine the heterogeneity of treatment effect.   
 
Statistical analysis will be performed using R version 4.5.0 within Rstudio version 2025.05.1+513 (R 
Foundation for Statistical Computing, Vienna, Austria). The reporting of the study will be in line with 
Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. 
 
Missing Data Plan 
Less than 5% missingness across key variables is expected. If >5% of missingness across key variables is 
identified, then predictors of missingness will be evaluated and hospitals which display a significant amount of 
missingness that does not conform to expectations may be excluded. We will impute missing data elements 
using multiple imputation approach for some variables, when feasible. Sensitivity analyses using only complete 
case records would be reported for analyses requiring multiple imputation for missing data elements. 
 
References 
 
1. 
Centers for Disease Control and Prevention, Antimicrobial Reistance Threats in the United States, 2021-
2022. 2024, Centers for Disease Control and Prevention. 
2. 
J. M. Pogue, Y. Zhou, H. Kanakamedala, and B. Cai, Burden of illness in carbapenem-resistant 
Acinetobacter baumannii infections in US hospitals between 2014 and 2019. BMC Infect Dis, 2022. 22(1): 
p. 36. DOI: 10.1186/s12879-021-07024-4. 
3. 
M. Paul, E. Carrara, P. Retamar, et al., European Society of Clinical Microbiology and Infectious Diseases 
(ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli 
(endorsed by European society of intensive care medicine). Clin Microbiol Infect, 2022. 28(4): p. 521-547. 
DOI: 10.1016/j.cmi.2021.11.025. 

4. 
P. D. Tamma, E. L. Heil, J. A. Justo, A. J. Mathers, M. J. Satlin, and R. A. Bonomo, Infectious Diseases Society 
of America 2024 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections. Clin 
Infect Dis, 2024. DOI: 10.1093/cid/ciae403. 
5. 
K. S. Kaye, A. F. Shorr, R. G. Wunderink, 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. DOI: 10.1016/S1473-3099(23)00184-6. 
6. 
M.D. Keith S. Kaye, M.P.H. kk1116@rwjms.rutgers.edu, Dror Marchaim, M.D., Visanu Thamlikitkul, M.D., 
Yehuda Carmeli, M.D., Cheng-Hsun Chiu, M.D., Ph.D., George Daikos, M.D., Sorabh Dhar, M.D., Emanuele 
Durante-Mangoni, M.D., Achilles Gikas, M.D., Anastasia Kotanidou, M.D., Mical Paul, M.D., Emmanuelle 
Roilides, M.D., Michael Rybak, Pharm.D., Ph.D., Michael Samarkos, M.D., Matthew Sims, M.D., Dora 
Tancheva, M.D., Sotirios Tsiodras, M.D., Daniel Kett, M.D., Gopi Patel, M.D., David Calfee, M.D., Leonard 
Leibovici, M.D., Laura Power, M.D., Sylvia Munoz-Price, M.D., Kurt Stevenson, M.D., Laura Susick, Katie 
Latack, Jolene Daniel, Christine Chiou, M.D., George W. Divine, Ph.D., Varduhi Ghazyaran, M.D., and Jason 
M. Pogue, Pharm.D, Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant 
Organisms. NEJM Evidence 2023. 2(1). DOI: 10.1056/EVIDoa2200131. 
7. 
H. Aydemir, D. Akduman, N. Piskin, 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): p. 1214-22. DOI: 10.1017/S095026881200194X. 
8. 
A. P. Betrosian, F. Frantzeskaki, A. Xanthaki, and E. E. Douzinas, 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): p. 432-6. DOI: 
10.1016/j.jinf.2008.04.002. 
9. 
E. Durante-Mangoni, G. Signoriello, R. Andini, 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): p. 349-58. DOI: 10.1093/cid/cit253. 
10. 
D. Makris, E. Petinaki, V. Tsolaki, 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): p. 67-77. DOI: 10.4103/ijccm.IJCCM_302_17. 
11. 
M. S. Oliveira, G. V. Prado, S. F. Costa, R. S. Grinbaum, and A. S. Levin, Ampicillin/sulbactam compared with 
polymyxins for the treatment of infections caused by carbapenem-resistant Acinetobacter spp. J 
Antimicrob Chemother, 2008. 61(6): p. 1369-75. DOI: 10.1093/jac/dkn128. 
12. 
R. Sirijatuphat and V. Thamlikitkul, Preliminary study of colistin versus colistin plus fosfomycin for 
treatment of carbapenem-resistant Acinetobacter baumannii infections. Antimicrob Agents Chemother, 
2014. 58(9): p. 5598-601. DOI: 10.1128/AAC.02435-13. 
13. 
S. Alosaimy, T. Morrisette, A. M. Lagnf, et al., Clinical Outcomes of Eravacycline in Patients Treated 
Predominately for Carbapenem-Resistant Acinetobacter baumannii. Microbiol Spectr, 2022. 10(5): p. 
e0047922. DOI: 10.1128/spectrum.00479-22. 
14. 
M. Falcone, G. Tiseo, A. Leonildi, et al., Cefiderocol- Compared to Colistin-Based Regimens for the 
Treatment of Severe Infections Caused by Carbapenem-Resistant Acinetobacter baumannii. Antimicrob 
Agents Chemother, 2022. 66(5): p. e0214221. DOI: 10.1128/aac.02142-21. 
15. 
D. M. Livermore, S. Mushtaq, M. Warner, and N. Woodford, In Vitro Activity of Eravacycline against 
Carbapenem-Resistant Enterobacteriaceae and Acinetobacter baumannii. Antimicrob Agents Chemother, 
2016. 60(6): p. 3840-4. DOI: 10.1128/AAC.00436-16. 
16. 
R. Pascale, Z. Pasquini, M. Bartoletti, et al., Cefiderocol treatment for carbapenem-resistant Acinetobacter 
baumannii infection in the ICU during the COVID-19 pandemic: a multicentre cohort study. JAC Antimicrob 
Resist, 2021. 3(4): p. dlab174. DOI: 10.1093/jacamr/dlab174. 
17. 
C. J. Scott, E. Zhu, R. A. Jayakumar, G. Shan, and V. Viswesh, Efficacy of Eravacycline Versus Best Previously 
Available Therapy for Adults With Pneumonia Due to Difficult-to-Treat Resistant (DTR) Acinetobacter 
baumannii. Ann Pharmacother, 2022. 56(12): p. 1299-1307. DOI: 10.1177/10600280221085551. 
18. 
H. Seifert, D. Stefanik, J. A. Sutcliffe, and P. G. Higgins, In-vitro activity of the novel fluorocycline 
eravacycline against carbapenem non-susceptible Acinetobacter baumannii. Int J Antimicrob Agents, 
2018. 51(1): p. 62-64. DOI: 10.1016/j.ijantimicag.2017.06.022. 

19. 
PINC AI™ Healthcare Database: Data that informs and performs (White Paper), Premier Inc. PINC AI™ 
Applied Sciences, Editor. 2023. 
20. 
J Robbins, A new approach to causal inference in mortality studies with a sustained exposure period - 
application to control of the healthy worker survivor effect. . Mathematical Modelling, 1986. 7(9-12): p. 
1393-1512. DOI:  
21. 
I. Diaz, N. Williams, K. L. Hoffman, and E.J. Schenck, Nonparametric causal effects based on longitudinal 
modified treatment policies. . Journal of the American Statistical Association 2021. 118(542): p. 846-857. 
DOI:  
22. 
A. Elixhauser, C. Steiner, D. R. Harris, and R. M. Coffey, Comorbidity measures for use with administrative 
data. Med Care, 1998. 36(1): p. 8-27. DOI: 10.1097/00005650-199801000-00004. 
23. 
C. Rhee, Z. Zhang, S. S. Kadri, et al., Sepsis Surveillance Using Adult Sepsis Events Simplified eSOFA 
Criteria Versus Sepsis-3 Sequential Organ Failure Assessment Criteria. Crit Care Med, 2019. 47(3): p. 307-
314. DOI: 10.1097/CCM.0000000000003521.