Early Multicenter Experience With Imipenem-Cilastatin-Relebactam for Multidrug-Resistant Gram-Negative Infections

Nicholas Rebold; Taylor Morrisette; Abdalhamid M Lagnf; Sara Alosaimy; Dana Holger; Katie Barber; Julie Ann Justo; Kayla Antosz; Travis J Carlson; Jeremy J Frens; Mark Biagi; Wesley D Kufel; William J Moore; Nicholas Mercuro; Brian R Raux; Michael J Rybak

doi:10.1093/ofid/ofab554

. 2021 Dec 9;8(12):ofab554. doi: 10.1093/ofid/ofab554

Early Multicenter Experience With Imipenem-Cilastatin-Relebactam for Multidrug-Resistant Gram-Negative Infections

Nicholas Rebold ¹, Taylor Morrisette ^1,^2,³, Abdalhamid M Lagnf ¹, Sara Alosaimy ¹, Dana Holger ¹, Katie Barber ^4,⁵, Julie Ann Justo ^6,⁷, Kayla Antosz ⁷, Travis J Carlson ⁸, Jeremy J Frens ⁹, Mark Biagi ^10,¹¹, Wesley D Kufel ^12,¹³, William J Moore ¹⁴, Nicholas Mercuro ^15,¹⁶, Brian R Raux ², Michael J Rybak ^1,^17,^18,^✉

¹ Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan, USA

² Department of Pharmacy Services, Medical University of South Carolina, Charleston, South Carolina, USA

³ Department of Pharmacy & Outcomes Sciences, Medical University of South Carolina College of Pharmacy, Charleston, South Carolina, USA

⁴ Department of Pharmacy, University of Mississippi Medical Center, Jackson, Mississippi, USA

⁵ Department of Pharmacy Practice, University of Mississippi School of Pharmacy, Jackson, Mississippi, USA

⁶ Clinical Pharmacy and Outcomes Sciences, University of South Carolina College of Pharmacy, Columbia, South Carolina, USA

⁷ Department of Pharmacy, Prisma Health–Midlands, Columbia, South Carolina, USA

⁸ Department of Clinical Sciences, Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina, USA

⁹ Department of Pharmacy, Moses H. Cone Memorial Hospital, Cone Health, Greensboro, North Carolina, USA

¹⁰ College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA

¹¹ Department of Pharmacy, Swedish American Health System, Rockford, Illinois, USA

¹² Department of Pharmacy Practice, Binghamton University School of Pharmacy and Pharmaceutical Sciences, Binghamton, New York, USA

¹³ Department of Medicine, State University of New York Upstate Medical University, Syracuse, New York, USA

¹⁴ Department of Pharmacy, Northwestern Memorial Hospital, Chicago, Illinois, USA

¹⁵ Department of Pharmacy, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

¹⁶ Department of Pharmacy, Maine Medical Center, Portland, Maine, USA

¹⁷ Department of Pharmacy Services, Detroit Medical Center, Detroit, Michigan, USA

¹⁸ Division of Infectious Diseases, Department of Medicine, School of Medicine, Wayne State University, Detroit, Michigan, USA

^✉

Correspondence: Michael J. Rybak, PharmD, MPH, PhD, Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy & Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201 (m.rybak@wayne.edu).

PMCID: PMC8661073 PMID: 34901302

Abstract

A multicenter case series of 21 patients were treated with imipenem-cilastatin-relebactam. There were mixed infection sources, with pulmonary infections (11/21,52%) composing the majority. The primary pathogen was Pseudomonas aeruginosa (16/21, 76%), and 15/16 (94%) isolates were multidrug-resistant. Thirty-day survival occurred in 14/21 (67%) patients. Two patients experienced adverse effects.

Keywords: carbapenem-resistant Enterobacterales, imipenem-cilastatin-relebactam, multidrug-resistant, Pseudomonas aeruginosa

The increasing prevalence and spread of resistant gram-negative bacteria, such as multidrug-resistant (MDR) Pseudomonas aeruginosa and carbapenem-resistant Enterobacterales (CRE), are of high concern [1, 2]. Encouragingly, agents displaying in vitro and clinical activity against MDR gram-negative bacteria have recently been introduced to overcome several mechanisms of resistance and are now recommended in the Infectious Diseases Society of America CRE and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR P. aeruginosa) guidelines as preferred antibiotics [3–10].

Imipenem-cilastatin-relebactam (I-R; Recarbrio) is the combination of a carbapenem (imipenem), a renal dehydropeptidase-I inhibitor (cilastatin), and a dual-class A/C β-lactamase inhibitor (relebactam) that was Food and Drug Administration (FDA)–approved on July 17, 2019, for patients with complicated urinary tract infections and complicated intra-abdominal infections (IAIs). More recently, it was FDA-approved for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) [11–13]. This is the first antimicrobial that incorporates relebactam, a novel β-lactamase inhibitor that can restore the activity of imipenem in imipenem-resistant strains of Enterobacterales [14, 15]. Specifically, relebactam can inhibit class A β-lactamases including K. pneumoniae carbapenemase (KPC) and several extended-spectrum β-lactamases, as well as class C β-lactamases including several AmpC enzymes, and is unaffected by porin channel-mediated resistance due to OprD loss or efflux pump-mediated resistance (eg, MexAB, MexCD, MexXY) in P. aeruginosa [9, 16, 17]. Relebactam is based on a diazabicyclooctane core just like avibactam; however, relebactam has a piperidine ring for its R1 side chain and has been suggested to be more stable than avibactam when comparing active sites among KPC-2 complexes [18].

Although randomized controlled trials are considered to be the highest quality of scientific evidence, they often do not represent how agents are actually used in clinical practice [19]. The objective of this case series is to provide preliminary real-world evidence regarding the safety and efficacy of I-R in patients with drug-resistant gram-negative infections.

METHODS

This was a multicenter, retrospective, observational case series of hospitalized patients at 8 medical centers in 6 states treated with I-R between January 2020 and August 2021. Patients were included if they were ≥18 years old and received I-R for ≥48 hours. Patients were excluded if they were pregnant, a prisoner, or if they had received a prior I-R course within 60 days. Case sampling among collaborating centers was based on readiness and convenience sampling.

The primary outcome of all-cause 30-day mortality was assessed 30 days from the index culture collection date. The index culture was defined as the culture that necessitated I-R treatment. Secondary outcomes included clinical cure, defined as a resolution of signs and symptoms of infection within 7 days of antibiotic initiation, microbiological recurrence, defined as subsequent microbiological failure (growth of similar microbial species to index infection in a sterile site) with concomitant signs and symptoms of infection within 30 days after the end of antibiotic treatment and after initial microbiologic eradication, and adverse effects possibly attributable to I-R. Development of I-R nonsusceptibility during treatment was defined by an increase to minimum inhibitory concentration (MIC) ≥4/4mg/L or ≥2/4mg/L and a disk diffusion (DD) zone diameter of <23mm or <24mm (the Clinical and Laboratory Standards Institute [CLSI] intermediate to resistant break point ranges) for P. aeruginosa or Enterobacterales, respectively, up to 14 days after the end of I-R treatment [20, 21].

Creatinine clearance (CrCl) was calculated using the Cockcroft-Gault equation and serum creatinine (SCr), and acute kidney injury (AKI) was staged using the KDIGO 2012 guideline [22, 23]. MDR risk factors were defined using classical criteria in pneumonia: antimicrobials ≥24 hours within 90 days before index culture, hospitalization ≥48 hours within 90 days before index culture, admission from a nursing home or extended care facility, home infusion, chronic dialysis, home wound care, surgery within 30 days before index culture, and colonization and/or prior infection with resistant organisms [24]. Study data were collected and managed using the Research Electronic Data Capture (REDCap) tool hosted at Wayne State University [25]. Descriptive statistics were calculated using IBM SPSS Statistics, version 27.0 (IBM Corp., Armonk, NY, USA).

RESULTS

Twenty-one patients were included, as noted in Table 1, with a median age (interquartile range [IQR]) of 65 (48–75) years and a median BMI (IQR) of 29.2 (24.8–33.2) kg/m². Fifty-seven percent of patients were male, 48% were Caucasian, and 38% were African American. The most common comorbidities included heart failure (11/21, 52%) and diabetes (11/21, 52%). A majority of patients (14/21, 67%) had AKI on admission (at least 0.5 increase in SCr or 50% increase from baseline SCr), and most patients (14/21, 67%) received a renally adjusted dose of I-R. Sixty-seven percent of patients were admitted from home, followed by 3 patients from nursing homes and 2 patients each from long-term care facilities and transfers from outside hospitals. Patients had a median (IQR) of 3 (2–4) MDR risk factors [24]. Most patients (16/21, 76%) received antimicrobials for ≥24 hours in the 90 days before their index culture, and 67% had a hospitalization for ≥48 hours in the 90 days before their index admission. The median Charlson Comorbidity Index (CCI) score (IQR) was 4.0 (2.5–6.0), and the median APACHE II score (IQR) was 21.5 (13.0–28.0; n = 16). Most patients (16/21, 76%) were admitted to the intensive care unit at a median (IQR) of 0 (0–5.3) hospital-days from admission. Infectious diseases consultation was obtained in 95% of patients, surgery was consulted in 29% of patients, and 33% of patients received a source control procedure.

Table 1.

Clinical Characteristics of Patients and Infections Treated With Imipenem-Cilastatin-Relebactam

ID #	Age/Sex	CrCl at I-R Start, mL/min	APACHE/CCI	Infection	Index Organism(s)	Antibiotic(s) for Index Infection (Days used)^a	I-R Dose	I-R Selection Reason(S)	Clinical Cure	30-Day Mortality	I-R Nonsusceptibility on Tx?	Microbiologic Recurrence
1	79/M	81	13/10	SSTI	•\tProteus mirabilis •\tPseudomonas aeruginosa •\tStaphylococcus aureus (MRSA)	I-R (days 0–4) VAN (days 0–9) CZA (days 4–10) MZ (days 5–9)	1000mg q6 hours	•Double coverage for CRE/C-R Pseudomonas	Yes	No	No repeat MIC testing	No
2	73/F	128	10/6	UTI	•\tProteus mirabilis •\tPseudomonas aeruginosa •\tEnterococcus faecalis	I-R (days 4–18)	1000mg q6 hours	•\tConsolidation of regimen •\tNo other active agent for infection •\tAntibiotic shortage	Yes	No	No repeat MIC testing	No
3	70/F	17	22/5	IPD	•\tAchromobacter spp. •\tPseudomonas aeruginosa	I-R (days 6–10) MEV (days 10–103)	500mg q6 hours	•\tNo other active agent for infection	No	No	No repeat MIC testing	Yes
4	34/M	149	NA/0	PNA	•\tPseudomonas aeruginosa	I-R (days 5–12)	1250mg q6 hours	•\tNo other active agent for infection	Yes	No	No	No
5	64/M	72	NA/4	Bone/joint	•\tPseudomonas aeruginosa	I-R (days 13–48)	1250mg q6 hours	•\tAntibiotic shortage	Yes	No	No	No
6	77/F	49	NA/4	PNA	•\tPseudomonas aeruginosa	I-R (days 2–9)	750mg q6 hours	•\tNo other active agent for infection	Yes	No	No	No
7	42/F	116	21/1	PNA	•\tPseudomonas aeruginosa	Inhaled CST + Inh TOB (days 0–9) I-R (days 7–10)	1250mg q6 hours	•\tLack of PO access •\tNo other active agent for infection	No	Yes	No	NA
8	60/M	89	13/3	IPD + BSI	•\tPseudomonas aeruginosa	C/T (days 1–4) TOB (days 3–20) I-R (days 4–19) FDC (days 13–20) MEV (days 20–23)	1250mg q6 hours	•\tDouble coverage for CRE/C-R Pseudomonas	No	Yes	No repeat MIC testing	NA
9	83/M	15	26/7	UTI + BSI	•\tPseudomonas aeruginosa	CRO (days 0–1) FEP (day 2) I-R (days 2–8)	500mg q6 hours	•\tNo other active agent for infection	Yes	No	No repeat MIC testing	No
10	66/M	CRRT: 2L/h	46/6	PNA	•\tPseudomonas aeruginosa	FEP (days 0–1) I-R (days 1–9)	500mg q6 hours	•\tNo other active agent for infection	Yes	No	No repeat MIC testing	Yes
11	65/M	60	35/9	PNA	•\tPseudomonas aeruginosa	VAN (days 0–1) TZP (days 0–3) C/T (days 3–4) MZ (days 3–4) I-R (days 4–8)	750mg q6 hours	•\tNo other active agent for infection •\tAntibiotic shortage	Yes	No	No repeat MIC testing	Yes
12	57/F	82	10/5	IPD	•\tPseudomonas aeruginosa	CIP (days 0–22) MEM (days 0–1) I-R (days 10–22)	1000mg q6 hours	•\tNo other active agent for infection	Yes	Yes	No repeat MIC testing	Yes
13	44/M	CVVHD: 1.9L/h	17/2	PNA	•\tPseudomonas aeruginosa	TZP (days 123–149) Inhaled CST (days 123–171) SXT (days 150–165) I-R (days 150–186) TOB (days 150–) Inh TOB (days 178–)	500mg q6 hours	•\tDouble coverage for CRE/C-R Pseudomonas	No	No	Yes	Yes
14	71/F	16	NA/4	PNA	•\tPseudomonas aeruginosa •\tStenotrophomonas maltophilia	I-R (days 15–23)	500mg q6 hours	•\tNo other active agent for infection	No	No	No	No
15	77/M	286	23/4	PNA VP shunt	•\tPseudomonas aeruginosa •\tSerratia marcescens •\tAcinetobacter baumanii	I-R (days 35–42)	1250mg q6 hours	•\tOther: initial VAP P. aeruginosa susceptible to I-R 1 month prior	Yes	No	No repeat MIC testing	No
16	63/F	51	10/5	IAI	•\tKlebsiella oxytoca •\tPseudomonas aeruginosa •\tEnterococcus faecalis •\tGroup B Streptococcus	TZP (days 0–3) VAN (day 0) I-R (days 3–13)	1000mg q6 hours	•\tConsolidation of regimen •\tNo other active agent for infection	Yes	No	No repeat MIC testing	No
17	23/F	25	28/0	PNA	•\tKlebsiella pneumoniae •\tAcinetobacter baumanii •\tProteus mirabilis • \tStenotrophomonas maltophilia	MIN (days 2–6) I-R (days 2–6) Inh TOB (days 3–6)	500mg q6 hours	•\tDouble coverage for CRE/C-R Pseudomonas •\tNo other active agent for infection	Yes	Yes	No repeat MIC testing	NA
18	65/F	97	28/4	IAI	•\tKlebsiella pneumoniae •\tEnterococcus avium	I-R (days 68–80)	1250mg q6 hours	•\tNo other active agent for infection	Yes	No	No	No
19	39/M	37	30/1	PNA + BSI CDI	•\tEnterobacter cloacae •\tKlebsiella pneumoniae	MEM (days 0–2) CZA (day 2) I-R (days 7–23)	1250mg q6 hours	•\tConsolidation of regimen •\tNo other active agent for infection	No	Yes	No repeat MIC testing	NA
20	52/M	69	20/5	PNA + BSI Candidemia MRSA IE	•\tBurkholderia cepacia •\tEnterobacter cloacae	AMK (day 47) FDC (days 47–68) CZA (days 68–73) FDC (days 74–80) I-R (days 74–89)	500mg q6 hours	•\tDouble-coverage for CRE/C-R Pseudomonas	No	Yes	No	NA
21	80/M	67	NA/9	UTI + BSI	•\tEscherichia coli	MEM (days –23 to 14) I-R (days –15 to 2)	1000mg q6 hours	•\tOther: worsening on meropenem	No	Yes	No	NA

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Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation II scoring system; BSI, bloodstream infection (bacteremia); CCI, Charlson Comorbidity Index; CDI, Clostridiodes difficile infection; CrCl, creatinine clearance; CRRT, continuous renal replacement therapy; CVVHD, continuous veno-venous hemodiafiltration; I-R, imipenem-cilastatin-relebactam; IAI, intraabdominal infection; IE, infective endocarditis; IPD, invasive prosthetic device; MIC, minimum inhibitory concentration; MRSA, methicillin-resistant Staphylococcus aureus; NA, not available; PNA, pneumonia or lower respiratory tract infection; S/SX, signs and symptoms; SCr, serum creatinine; SSTI, skin and soft tissue infection; UTI, urinary tract infection.

Antibacterial agents: AMK, amikacin; ATM, aztreonam; C/T, ceftolozane-tazobactam; CIP, ciprofloxacin; CRO, ceftriaxone; CST, colistin; CZA, ceftazidime-avibactam; FDC, cefiderocol; FEP, cefepime; MEM, meropenem; MEV, meropenem-vaborbactam; MIN, minocycline; MZ, metronidazole; SXT, trimethoprim-sulfamethoxazole; TOB, tobramycin; TZP, piperacillin-tazobactam; VAN, vancomycin.

Days starting from index infection culture draw date, or date of empiric antibiotic initiation leading to I-R use.

The most common infections were respiratory tract infections, including HAP and VAP (PNA; 11/21, 52%), urinary tract infections (UTIs; 3/21, 14%), and invasive prosthetic device (IPD) infections (3/21, 14%). Bacteremia occurred in 29% of patients. I-R was utilized for the following bacteria: Pseudomonas aeruginosa (16/21, 76%), Klebsiella pneumoniae (3/21, 14%), and Proteus mirabilis (3/21, 14%), among other gram-negative pathogens. Resistance was common, with 3/8 patients with Enterobacterales having a CRE infection, and nearly all (15/16, 94%) P. aeruginosa cases were MDR (drug nonsusceptibility present in at least 3 antimicrobial classes), as shown in Table 2 [26, 27]. I-R was used for polymicrobial bacterial infection 29% of the time. Only 52% of cases had I-R MICs performed, which were done primarily by Etest, with an MIC range of 0.125/4 to ≥32/4, where 8/11 or 73% were susceptible.

Table 2.

MIC Resistance Profile of Infections Treated With Imipenem-Cilastatin-Relebactam

ID #	Index Organism(S)	MIC Resistance Profile^a
1	•\tProteus mirabilis •\tPseudomonas aeruginosa •\tStaphylococcus aureus (MRSA)	Pseudomonas: Aztreonam-R Cefepime-I	Ceftazidime-R Ceftaz-Avi-S Cipro/Levo-R	Gent/Tobra-S Meropenem-I Pip-tazo-I(64)
2	•\tProteus mirabilis •\tPseudomonas aeruginosa •\tEnterococcus faecalis	Pseudomonas: Cefepime-S Ceftazidime-S Ceftaz-Avi(Etest)-S	Ceftolo-tazo(Etest)-S Cipro/Levo-R Gent/Tobra-S	Imi-Rel-I(3)^b^,^c Meropenem-R Pip-tazo-S
3	•\tAchromobacter spp. •\tPseudomonas aeruginosa	Pseudomonas: Amikacin-S Aztreonam-R Cefepime-R Cefiderocol(DD)-R Ceftazidime-R	Ceftaz-Avi-R Ceftolo-tazo-R Ceftriaxone-R Cipro/Levo-R Colistin-S Gent/Tobra-S	Imipenem-S Imi-Rel(Etest)-S^2,3 Meropenem-R Mero-Vabor-S Pip-tazo-I
4	•\tPseudomonas aeruginosa	Pseudomonas: Amikacin-S Cefepime-R	Ceftazidime-I Ceftriaxone-R Cipro/Levo-R	Meropenem-R
5	•\tPseudomonas aeruginosa	Pseudomonas: Amikacin-S Cefepime-I Ceftazidime-I	Ceftaz-Avi-S Ceftriaxone-R Gent/Tobra-S Imi-Rel-S^2,3	Meropenem-I Pip-tazo-I Polymyxin B-S
6	•\tPseudomonas aeruginosa	Pseudomonas: Amikacin-S Cefepime-I	Ceftazidime-I Ceftaz-Avi(Etest)-R Ceftriaxone-R	Cipro/Levo-R Gent/Tobra-S Meropenem-R
7	•\tPseudomonas aeruginosa	Pseudomonas: Amikacin(DD)-S Aztreonam(Etest)-R Cefepime(DD)-R	Ceftazidime(DD)-R Ceftaz-Avi(Etest)-R Cipro/Levo(DD)-R Colistin(Etest)-S	Gent/Tobra(DD)-R Imi-Rel(Etest)-S^2,3 Meropenem(DD)-R Pip-tazo(DD)-S
8	•\tPseudomonas aeruginosa	Pseudomonas: Amikacin-S Aztreonam-R Cefepime-R Ceftazidime-R Ceftaz-Avi-R	Ceftolo-tazo-R Ceftriaxone-R Cipro/Levo-R Colistin-S Gent/Tobra-S	1. Imipenem-S 2. Imipenem(Etest)-R Imi-Rel(Etest)-R^2,3 Meropenem-R Mero-Vabor-R Pip-tazo-I
9	•\tPseudomonas aeruginosa	Pseudomonas: Ceftazidime-I	Cipro/Levo-R Gent/Tobra-S	Imipenem-R
10	•\tPseudomonas aeruginosa	Pseudomonas: Cefepime-R	Ceftazidime-R Cipro/Levo-R	Gent/Tobra-S Imipenem-R
11	•\tPseudomonas aeruginosa	Pseudomonas: Cefepime-R Ceftazidime-R	Cipro/Levo-R Gent/Tobra-S	Imipenem-R Pip-tazo-R
12	•\tPseudomonas aeruginosa	Pseudomonas: Amikacin-S(16) Cefepime-R Ceftazidime-R	Ceftaz-Avi(Etest)-R Ceftriaxone-R Cipro/Levo-R Gent/Tobra-S	Imipenem-R Meropenem-R Mero-Vabor(Etest)-SDD Pip-tazo-R
13	•\tPseudomonas aeruginosa	Pseudomonas: Amikacin-I Aztreonam-R Cefepime-R	Cefiderocol-S Cipro/Levo-I Colistin(BMD)-I Gent-I/Tobra-S	Imi-Rel(BMD)-S^2,3 Meropenem-R Pip-tazo-R
14	•\tPseudomonas aeruginosa •\tStenotrophomonas maltophilia	Pseudomonas: Amikacin-S Cefepime-S(8)	Ceftazidime-R Ceftaz-Avi(Etest)-R Ceftriaxone-R	Cipro/Levo-R Gent/Tobra-S Meropenem-R
15	•\tPseudomonas aeruginosa •\tSerratia marcescens •\tAcinetobacter baumanii	Pseudomonas: Amikacin-S Aztreonam(DD)-R Ceftazidime-R Cefepime(DD)-R	Cefiderocol(BMD)-S Cipro/Levo-R Ceftolo-tazo-S Gent-I/Tobra-S	Imipenem-R Imi-Rel(Etest)-R^2,3 Meropenem-R Pip-tazo(DD)-R
16	•\tKlebsiella oxytoca •\tPseudomonas aeruginosa •\tEnterococcus faecalis •\tGroup B Streptococcus	Klebsiella (ESBL+): Aztreonam-R Ceftriaxone-R Cipro/Levo-S Gent/Tobra-S Meropenem-S Pip-tazo-R	Pseudomonas: Aztreonam-I Cefepime-S(8) Ceftazidime-S	Cipro/Levo-R Gent/Tobra-S Meropenem-I Pip-tazo-S
17	•\tKlebsiella pneumoniae •\tAcinetobacter baumanii •\tProteus mirabilis •\tStenotrophomonas maltophilia	Klebsiella: Amikacin-R Cefazolin-R Cefepime-SDD Cefiderocol(DD)-S Ceftazidime-I	Ceftriaxone-R Cipro/Levo-R Gent-S/Tobra-R Imipenem(Etest)-S Imi-Rel(Etest)-S^2,3	Meropenem(Etest)-S Minocycline(Etest)-I Pip-tazo-R Tetracycline-R
18	•\tKlebsiella pneumoniae •\tEnterococcus avium	Klebsiella: Amikacin-S(16) Cefazolin-R Cefepime-R Ceftazidime-R Ceftriaxone-R	Ceftaz-Avi-S Cipro/Levo-R Colistin-S Eravacycline-2 Ertapenem-R Gent-S/Tobra-R Imi-Rel-S^2,3	Meropenem-R Mero-Vabor-S Pip-tazo-R Tetracycline-R TMP/SMX-R
19	•\tEnterobacter cloacae •\tKlebsiella pneumoniae	Enterobacter: Amikacin-S Aztreonam(DD)-R Cefepime(DD)-R Ceftazidime-R	Ceftaz-Avi(Etest)-R Ceftriaxone-R Cipro/Levo-R Colistin(BMD)-S Gent/Tobra-S	Imi-Rel(Etest)-S^2,3 Meropenem-R Mero-Vabor(Etest)-S Tigecycline(DD)-R TMP/SMX-R
20	•\tBurkholderia cepacia complex •\tEnterobacter cloacae	Burkholderia: Cefiderocol(BMD)-0.25 Ceftazidime-S Ceftaz-Avi(BMD)-3 Cipro/Levo-R Imi-Rel(Etest)-2^2,3 Meropenem-I Minocycline-I TMP/SMX-R	Enterobacter: Amikacin-S Aztreonam-R Cefazolin-R Cefepime-I Cefiderocol(BMD)-S Cefpodoxime-R Ceftazidime-R	Ceftaz-Avi-S Cipro/Levo-S Gent/Tobra-S Imi-Rel(BMD)-S^2,3 Meropenem-S Pip-tazo-R TMP/SMX-R
21	•\tEscherichia coli	Escherichia: Amikacin-S Cefepime-S Cefoxitin-R	Ceftazidime-S Ceftriaxone-S Cipro/Levo-R	Gent/Tobra-S Meropenem-S TMP/SMX-R

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Abbreviations: BMD, Broth Microdilution; CLSI, Clinical and Laboratory Standards Institute; DD, Disk Diffusion; ESBL, extended-spectrum β-lactamase; EUCAST, European Committee on Antimicrobial Susceptibility Testing; IMI/REL, imipenem-cilastatin-relebactam; MIC, minimum inhibitory concentration; R, resistant; S, susceptible; SDD, susceptible dose-dependent; TMP/SMX, trimethoprim/sulfamethoxazole.

CLSI breakpoints used for determinations of S, SDD, I, and R. Where I or SDD has multiple MIC breakpoints or MICs are significantly discrepant between CLSI and EUCAST, the specific MIC is listed in parentheses after the CLSI classification [31]. Parentheses after the antibiotic specify susceptibility method if not automated (ie, Disk Diffusion, Etest, or Broth Microdilution).

CLSI susceptibility breakpoints for IMI/REL are ≤1/4mg/L for Enterobacterales and ≤2/4 for P. aeruginosa. EUCAST breakpoints are ≤2/4 for P. aeruginosa and Enterobacterales.

For susceptibility testing purposes, the concentration of relebactam is fixed at 4mg/L.

I-R was used as combination therapy 29% (6/21) of the time, with tobramycin as the most common concomitant antibiotic (4/6,67%). The median duration of I-R therapy (IQR) was 8 (4.5–14) days. Clinical reasoning for I-R was primarily due to “no other active agent for infection” (14/21, 67%), followed by “double coverage for suspected CRE/carbapenem-resistant P. aeruginosa” (5/21, 24%). Inhaled antibiotics were used in 14% (3/21) of patients. I-R was switched in only 3/21 patients to a different agent; 2 patients were switched to meropenem-vaborbactam (MEV) and 1 patient to ceftazidime-avibactam (CZA).

Mortality occurred in 7/21 (33%) patients. Clinical cure occurred in 13/21 (62%) patients treated with I-R. Nonsusceptibility to I-R developed on treatment in only 1 case (1/21, 5%) or in only 11% (1/9) of those isolates with subsequent MIC testing post–index culture. Microbiological recurrence occurred in 5/21 (24%) patients. Subsequent cultures were obtained in 5/21 patients within 90 days post–I-R initiation. Two of the cultures grew isolates that demonstrated increased I-R MICs relative to the index culture from 1.5/4mg/L and 2/4mg/L (susceptible) to 12/4mg/L and 8/4mg/L (resistant), respectively. Two adverse events occurred, 1 gastrointestinal (nausea, vomiting, diarrhea) and 1 encephalopathic (altered mental status, somnolence, new-onset seizures). Neither of the adverse events led to drug discontinuation.

DISCUSSION

We report early, real-world observations of I-R use among patients at 8 medical centers. Our findings suggest that I-R is used for MDR P. aeruginosa, in some cases for CRE, and that I-R seems to lead to clinical cure in the majority of cases. In addition, we observed a mortality rate of 33%. However, it is worth noting that the patients receiving I-R often have high APACHE II scores associated with mortality rates around 40% [28]. The patients here have higher APACHE-II scores than the RESTORE-IMI 1 trial did, with slightly lower clinical cure rates and higher mortality, as expected [15].

In our experience, I-R was utilized for a variety of infections including PNA, UTI, and IAI caused by MDR gram-negative bacteria. However, the treatment niche for I-R seems to be in MDR P. aeruginosa due to relebactam’s activity against AmpC hyperproduction, resistance to efflux, and porin channel–mediated resistance in P. aeruginosa [9, 16, 18]. This place in therapy may have been further emphasized with an ongoing drug shortage and recall of ceftolozane/tazobactam (C/T), a principal agent used against MDR P. aeruginosa, since January 4, 2021 [29]. I-R also seems to have a place in polymicrobial-resistant infections with Enterococcus faecalis given that CZA and C/T have no activity against this bacterium.

The most common clinical reasoning for I-R selection was “no other active agent for infection” and may explain its relatively infrequent current use. Of note, I-R requires renal dosage adjustment below a CrCl of 90mL/min. This is a higher threshold than other antibiotics; yet, appropriate dose adjustments for I-R were often implemented (14/21, 67%), with some departure from listed adjustments likely due to age or clinical status. A significant limitation of this report is its observational nature, which limits controlled experimental analyses. There are many antimicrobials, patient statuses, durations of therapy, and infection types that may impact the results and effectiveness of the antibiotic. MICs for I-R were only acquired in just over half of cases making it difficult to assess I-R activity in the unreported cases. Also, while adverse effects were reported, it is difficult to link them directly to I-R use as Naranjo Adverse Drug Reaction Probability scores were not calculated [30]. However, I-R seems to be utilized effectively in these patients with limited available antibiotic options and with limited adverse effects. Given its spectrum of activity, I-R may remain a viable option for infections caused by MDR P. aeruginosa, other nonlactose fermenters, and CRE, in addition to potential use in polymicrobial infections with Enterococcus faecalis. Therefore, I-R provides another useful tool to the antibiotic repertoire in the fight against antimicrobial resistance.

Acknowledgments

Author contributions. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Patient consent. This study does not include factors necessitating patient consent. Furthermore, the design and reporting of this study have been approved by local institutional review boards.

Financial support. This work was supported by an investigator-initiated grant from Merck & Co.

Potential conflicts of interest. N.R., T.M., S.A., A.M.L., K.B., K.A., T.J.C., J.F., M.B., W.J.M, N.M., and B.J.R. have no conflicts of interest to disclose. J.J. served on an advisory board for Merck & Co and served on the Speaker’s Bureau for bioMérieux and the Therapeutic Research Center. W.D.K. received research grant funding from Merck and Melinta Therapeutics. M.J.R. has received funds for research and consulting or participated in speaking bureaus for Allergan, Contrafect, Melinta, Merck, Paratek Pharmaceuticals, Shionogi, Sunovian, and Tetraphase and is partially supported by National Institute of Allergy and Infectious Diseases R01 AI121400. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

References

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[CIT0001] 1. Centers for Disease Control and Prevention. Antibiotic Resistance Threats in the United States, 2019. Centers for Disease Control and Prevention; 2019. [Google Scholar]

[CIT0002] 2. Thaden JT, Lewis SS, Hazen KC, et al. . Rising rates of carbapenem-resistant Enterobacteriaceae in community hospitals: a mixed-methods review of epidemiology and microbiology practices in a network of community hospitals in the Southeastern United States. Infect Control Hosp Epidemiol 2014; 35:978–83. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0003] 3. Neuner EA, Gallagher JC.. Pharmacodynamic and pharmacokinetic considerations in the treatment of critically Ill patients infected with carbapenem-resistant Enterobacteriaceae. Virulence 2017; 8:440–52. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0004] 4. Nakamura I, Yamaguchi T, Tsukimori A, et al. . New options of antibiotic combination therapy for multidrug-resistant Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis 2015; 34:83–7. [DOI] [PubMed] [Google Scholar]

[CIT0005] 5. van Duin D, Bonomo RA.. Ceftazidime/avibactam and ceftolozane/tazobactam: second-generation β-lactam/β-lactamase inhibitor combinations. Clin Infect Dis 2016; 63:234–41. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0006] 6. Zasowski EJ, Rybak JM, Rybak MJ.. The β-lactams strike back: ceftazidime-avibactam. Pharmacotherapy 2015; 35:755–70. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0007] 7. Jorgensen SCJ, Rybak MJ.. Meropenem and vaborbactam: stepping up the battle against carbapenem-resistant Enterobacteriaceae. Pharmacotherapy 2018; 38:444–61. [DOI] [PubMed] [Google Scholar]

[CIT0008] 8. Zhanel GG, Lawrence CK, Adam H, et al. . Imipenem-relebactam and meropenem-vaborbactam: two novel carbapenem-β-lactamase inhibitor combinations. Drugs 2018; 78:65–98. [DOI] [PubMed] [Google Scholar]

[CIT0009] 9. Young K, Painter RE, Raghoobar SL, et al. . In vitro studies evaluating the activity of imipenem in combination with relebactam against Pseudomonas aeruginosa. BMC Microbiol 2019; 19:150. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0010] 10. Tamma PD, Aitken SL, Bonomo RA, et al. . Infectious Diseases Society of America guidance on the treatment of extended-spectrum β-lactamase producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE), and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa). Clin Infect Dis 2021; 72:1109–16. [DOI] [PubMed] [Google Scholar]

[CIT0011] 11. Food and Drug Administration. FDA approves new treatment for complicated urinary tract and complicated intra-abdominal infections. Published 24 March 2020. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-complicated-urinary-tract-and-complicated-intra-abdominal-infections. Accessed 28 January 2021.

[CIT0012] 12. Merck Sharp & Dohme. Recarbrio^TM (imipenem, cilastatin, and relebactam): US prescribing information. 2021. https://www.fda.gov. Accessed 26 July 2021.

[CIT0013] 13. Titov I, Wunderink RG, Roquilly A, et al. . A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 Study). Clin Infect Dis. In press. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0014] 14. Livermore DM, Warner M, Mushtaq S.. Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J Antimicrob Chemother 2013; 68:2286–90. [DOI] [PubMed] [Google Scholar]

[CIT0015] 15. Motsch J, Murta de Oliveira C, Stus V, et al. . RESTORE-IMI 1: a multicenter, randomized, double-blind trial comparing efficacy and safety of imipenem/relebactam vs colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections. Clin Infect Dis 2020; 70:1799–808. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0016] 16. Kohno S, Bando H, Yoneyama F, et al. . The safety and efficacy of relebactam/imipenem/cilastatin in Japanese patients with complicated intra-abdominal infection or complicated urinary tract infection: a multicenter, open-label, noncomparative phase 3 study. J Infect Chemother 2021; 27:262–70. [DOI] [PubMed] [Google Scholar]

[CIT0017] 17. Lapuebla A, Abdallah M, Olafisoye O, et al. . Activity of imipenem with relebactam against gram-negative pathogens from New York City. Antimicrob Agents Chemother 2015; 59:5029–31. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0018] 18. Papp-Wallace KM, Barnes MD, Alsop J, et al. . Relebactam is a potent inhibitor of the KPC-2 β-lactamase and restores imipenem susceptibility in KPC-producing Enterobacteriaceae. Antimicrob Agents Chemother 2018; 62:e00174-18. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0019] 19. Alexander EL, Loutit J, Tumbarello M, et al. . Carbapenem-resistant Enterobacteriaceae infections: results from a retrospective series and implications for the design of prospective clinical trials. Open Forum Infect Dis 2017; 4:XXX–XX. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0020] 20. Clinical and Laboratory Standards Institute. M100: Performance Standards for Antimicrobial Susceptibility Testing. 29th ed. CLSI; 2019. [Google Scholar]

[CIT0021] 21. Food and Drug Administration. Antibacterial susceptibility test interpretive criteria. 2020. Available at: https://www.fda.gov/drugs/development-resources/antibacterial-susceptibility-test-interpretive-criteria. Accessed 7 June 2021. [Google Scholar]

[CIT0022] 22. Cockcroft DW, Gault MH.. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31–41. [DOI] [PubMed] [Google Scholar]

[CIT0023] 23. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl 2012; 2:1–138. [Google Scholar]

[CIT0024] 24. Gross AE, Van Schooneveld TC, Olsen KM, et al. . Epidemiology and predictors of multidrug-resistant community-acquired and health care-associated pneumonia. Antimicrob Agents Chemother 2014; 58:5262–8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0025] 25. Harris PA, Taylor R, Thielke R, et al. . Research Electronic Data Capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42:377–81. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CIT0026] 26.Centers for Disease Control and Prevention. Antimicrobial Resistant Phenotype Definitions. Centers for Disease Control and Prevention; 2021. [Google Scholar]

[CIT0027] 27. Magiorakos AP, Srinivasan A, Carey RB, et al. . Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18:268–81. [DOI] [PubMed] [Google Scholar]

[CIT0028] 28. Knaus WA, Draper EA, Wagner DP, Zimmerman JE.. APACHE II: a severity of disease classification system. Crit Care Med 1985; 13:818–29. [PubMed] [Google Scholar]

[CIT0029] 29. Drug shortage detail: ceftolozane and tazobactam injection. Available at: https://www.ashp.org:443/Drug-Shortages/Current-Shortages/Drug-Shortage-Detail.aspx?id=705. Accessed 27 July 2021.

[CIT0030] 30. Naranjo CA, Busto U, Sellers EM, et al. . A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981; 30:239–45. [DOI] [PubMed] [Google Scholar]

[CIT0031] 31. The European Committee on Antimicrobial Susceptibility Testing (EUCAST). Breakpoint tables for interpretation of MICs and zone diameters. 2021. Available at: http://www.eucast.org. Accessed 26 July 2021.

PERMALINK

Early Multicenter Experience With Imipenem-Cilastatin-Relebactam for Multidrug-Resistant Gram-Negative Infections

Nicholas Rebold

Taylor Morrisette

Abdalhamid M Lagnf

Sara Alosaimy

Dana Holger

Katie Barber

Julie Ann Justo

Kayla Antosz

Travis J Carlson

Jeremy J Frens

Mark Biagi

Wesley D Kufel

William J Moore

Nicholas Mercuro

Brian R Raux

Michael J Rybak

Abstract

METHODS

RESULTS

Table 1.

Table 2.

DISCUSSION

Acknowledgments

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Early Multicenter Experience With Imipenem-Cilastatin-Relebactam for Multidrug-Resistant Gram-Negative Infections

Nicholas Rebold

Taylor Morrisette

Abdalhamid M Lagnf

Sara Alosaimy

Dana Holger

Katie Barber

Julie Ann Justo

Kayla Antosz

Travis J Carlson

Jeremy J Frens

Mark Biagi

Wesley D Kufel

William J Moore

Nicholas Mercuro

Brian R Raux

Michael J Rybak

Abstract

METHODS

RESULTS

Table 1.

Table 2.

DISCUSSION

Acknowledgments

References

ACTIONS

PERMALINK

RESOURCES

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