In vitro synergy of the combination of sulbactam-durlobactam and cefepime at clinically relevant concentrations against A. baumannii, P. aeruginosa and Enterobacterales

Aliaa Fouad; David P Nicolau; Christian M Gill

doi:10.1093/jac/dkad244

. 2023 Oct 16;78(12):2801–2809. doi: 10.1093/jac/dkad244

In vitro synergy of the combination of sulbactam-durlobactam and cefepime at clinically relevant concentrations against A. baumannii, P. aeruginosa and Enterobacterales

Aliaa Fouad ¹, David P Nicolau ^2,³, Christian M Gill ^4,^✉

PMCID: PMC10689914 PMID: 37839896

Abstract

Background

Sulbactam-durlobactam is a potent combination active against Acinetobacter baumannii; however, it lacks activity against other nosocomial pathogens. Cefepime is a common first-line therapy for hospital/ventilator-associated pneumonia caused by Gram-negative pathogens including Pseudomonas aeruginosa and Enterobacterales. With increasing resistance to cefepime, and the significant proportion of polymicrobial nosocomial infections, effective therapy for infections caused by Acinetobacter baumannii, P. aeruginosa and Enterobacterales is needed. This study investigated the in vitro synergy of sulbactam-durlobactam plus cefepime against relevant pathogens.

Methods

Static time–kills assays were performed in duplicate against 14 cefepime-resistant isolates (A. baumannii, n = 4; P. aeruginosa, n = 4; Escherichia coli, n = 3; Klebsiella pneumoniae, n = 3). One WT K. pneumoniae isolate was included. Antibiotic concentrations simulated the free-steady state average concentration of clinically administered doses in patients.

Results

Sulbactam-durlobactam alone showed significant activity against A. baumannii consistent with the MIC values. Sulbactam-durlobactam plus cefepime showed synergy against one A. baumannii isolate with an elevated MIC to sulbactam-durlobactam (32 mg/L). Against all P. aeruginosa isolates, synergy was observed with sulbactam-durlobactam plus cefepime. For the Enterobacterales, one E. coli isolate demonstrated synergy while the others were indifferent due to significant kill from sulbactam-durlobactam alone. The combination of sulbactam-durlobactam plus cefepime showed synergy against one of the K. pneumoniae and additive effects against the other two K. pneumoniae tested. No antagonism was observed in any isolates including the WT strain.

Conclusions

Synergy and no antagonism was observed with a combination of sulbactam-durlobactam and cefepime; further in vivo pharmacokinetic/pharmacodynamics data and clinical correlation are necessary to support our findings.

Introduction

Acinetobacter baumannii has emerged in recent years as a difficult-to-treat, drug-resistant organism responsible for nosocomial infections.^1,2 Carbapenem-resistant A. baumannii (CRAB) is listed by WHO as a ‘priority status’ pathogen due to its association with significant morbidity and mortality.^3,4 Due to the expression of multiple mechanisms of resistance, CRAB has limited therapeutic options.²

Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are widespread nosocomial infections in critically ill patients and are associated with high morbidity and mortality.⁵ HABP/VABP due to carbapenem-resistant and MDR Gram-negative organisms including A. baumannii, Pseudomonas aeruginosa and Enterobacterales are even more challenging due to limited treatment options.^6,7 In addition, polymicrobial infections are increasing in healthcare facilities, where patients’ infections can be caused by multiple bacteria including CRAB, Enterobacterales and P. aeruginosa.⁸ This clinical challenge necessitates novel agents and combinations to optimize treatment for critically ill patients at risk for carbapenem-resistant organisms.

Sulbactam-durlobactam is a novel combination designed specifically for CRAB due to the potent PBP3 inhibition by sulbactam, and durlobactam’s ability to inhibit class A, C and most notably class D β-lactamases common to this pathogen.⁹ Sulbactam-durlobactam demonstrates significant in vitro activity against A. baumannii, including carbapenem-resistant isolates, representing a significant advance in the treatment of infections caused by this organism.^10,11

CRAB nosocomial infections are often polymicrobial, requiring the use of effective combination therapy at the onset of treatment. Sulbactam-durlobactam lacks activity against P. aeruginosa and Enterobacterales, which represent a significant portion of organisms responsible for nosocomial infections.⁵ In the pivotal Phase III clinical trial, sulbactam-durlobactam was co-administered with imipenem to treat coinfecting, non-Acinetobacter pathogens; however, evaluation of other agents as an empirical partner with sulbactam-durlobactam are warranted.¹² Cefepime is a common first-line therapy for HABP/VABP caused by Gram-negative, nosocomial pathogens including P. aeruginosa and Enterobacterales,¹³ for which sulbactam-durlobactam has limited activity.

It is well described that appropriate selection of initial therapeutic agents improves clinical outcomes for patients with Gram-negative infections.¹⁴ Co-administration of cefepime with sulbactam-durlobactam may expand coverage of cefepime against P. aeruginosa and Enterobacterales due to protection of cefepime from Class A β-lactamases by durlobactam.⁹ Another potential benefit of this combination is the complementary PBP interactions. Although durlobactam lacks significant antibacterial activity against P. aeruginosa, synergy may be possible between cefepime (PBP1 and 3 inhibition) and durlobactam (PBP2 inhibition), which has been observed with other diazabicyclooctane (DBO) agents with PBP2 activity.^9,15,16

In the current study, we used time–kill assays to investigate the synergistic effect of clinical concentrations of sulbactam-durlobactam in combination with cefepime against difficult-to-treat bacteria, including CRAB, with sulbactam-durlobactam MICs at or around the preliminary breakpoint of 4 mg/L. Other relevant nosocomial pathogens including P. aeruginosa and Enterobacterales isolates were chosen due to their elevated MICs of both agents and were assessed for synergy to further evaluate the potential utility of this combination.

Materials and methods

Antimicrobial agents and broth

Sulbactam (lot number 990085-00195) and durlobactam (lot number 134693) were provided by Entasis Therapeutics (Waltham, MA, USA) and used for the in vitro experiments. Cefepime (lot number LRAB8503) analytical powder was purchased from Sigma–Aldrich (St. Louis, MO, USA). CAMHB (Becton, Dickinson and Company, Sparks, MD, USA) was used in the time–kill assays.

Isolates

Four A. baumannii clinical isolates were obtained from Entasis Therapeutics and selected because these isolates had a range of sulbactam-durlobactam MIC values, including isolates at the high end of the MIC distribution to assess potential synergy with cefepime. The remaining eight isolates were selected from the Center for Anti-Infective Research and Development (CAIRD) isolate repository. Genotypic data for the Enterobacterales and P. aeruginosa isolates were available either from the CDC AR Bank or as previously described.¹⁷ All isolates were maintained in skimmed milk (BD Biosciences, Sparks, MD, USA) at −80°C. Each isolate was subcultured twice on Trypticase soy agar with 5% sheep blood (BD Biosciences) and grown for 18 to 20 h at 37°C under 5% CO₂ prior to use in the experiments.

In vitro MICs of sulbactam-durlobactam and cefepime

In vitro MICs were measured for sulbactam-durlobactam and cefepime per CLSI standards in triplicate by broth microdilution (BMD), and modal results were reported. Sulbactam-durlobactam was measured as a dilution of sulbactam with a fixed concentration of durlobactam (4 mg/L) based on CLSI guidance.¹⁸ Routine quality control was conducted per CLSI standards.¹⁸

Time–kill studies

Time–kill experiments were conducted in Mueller–Hinton broth (Becton, Dickinson and Company) with a starting bacterial burden of ∼10⁶ cfu/mL.¹⁹ The 15 isolates were tested in four groups (untreated growth control, sulbactam-durlobactam alone, cefepime alone, and sulbactam-durlobactam plus cefepime). All isolate and drug combinations were assessed in duplicate time–kill experiments. The final volume of the broth, bacterium and drug suspensions was adjusted to be 10 mL, then was incubated in a shaking water bath at 37°C. Samples were taken at 0 (baseline bacterial burden), 3, 6 and 24 h. Samples were serially diluted, plated onto blood agar plates with 5% sheep’s blood, and incubated for 18–24 h to quantify the mean bacterial densities (log₁₀ cfu/mL). All time–kill experiments were conducted with the final antibiotic concentrations simulating the free-steady state average plasma concentration for sulbactam-durlobactam (1 g/1 g IV q6h 3 h infusion) and cefepime (2 g IV q8h 0.5 h infusion). Free steady-state average concentration (fC_ssavg) for each drug was 12.04 mg/L for sulbactam, 17.10 mg/L for durlobactam²⁰ and 26.3 mg/L for cefepime.²¹ The minimal accurately countable bacterial burden was 50 cfu/mL.

Data analysis

Bactericidal activity of single antibiotics or combinations was defined as a ≥3 log₁₀ reduction in cfu/mL after 24 h of incubation relative to baseline bacterial burden. Synergy was defined as a ≥2 log₁₀ decrease in cfu/mL between the antibiotic combination and the most active single agent after 24 h. Additivity was defined as a 1 to <2 log₁₀ decrease in cfu/mL between the antibiotic combination and its most active constituent after 24 h, while indifference was defined by a <1 log₁₀ cfu/mL change between the antibiotic combination and its most active constituent. Antagonism was defined as a ≥2 log₁₀ increase in cfu/mL at 24 h with the combination compared with that of the most active agent alone.¹⁹

Results

BMD

The modal MICs and available genotypic data for the tested isolates are presented in Table 1. The four A. baumannii isolates were cefepime resistant and displayed varying sulbactam-durlobactam MICs at and above the potential susceptibility breakpoint of 4 mg/L. One WT Klebsiella pneumoniae isolate with low MICs to both drugs was also tested. The remaining 11 isolates were cefepime resistant with MIC values ranging from 16 to >256 mg/L. All P. aeruginosa isolates tested had elevated MICs of both cefepime and sulbactam-durlobactam (range 64 to >256 mg/L, and >128 mg/L, respectively). Interestingly, the sulbactam-durlobactam MICs of the tested Enterobacterales ranged from ≤0.125 to >128 mg/L.

Table 1.

MIC values of sulbactam-durlobactam and cefepime against isolates used in this study

Isolate	MIC (mg/L)		Species	Genotype
Isolate	Sulbactam-durlobactam^a	Cefepime	Species	Genotype
ACB 341	2	256	A. baumannii	ADC-25; PER-1; TEM-1; OXA-23; OXA-66
ACB 342	4	128	A. baumannii	ADC-162; OXA-23; OXA-66
ACB 343	8	64	A. baumannii	TEM-1; OXA-23; OXA-66; ADC-82; PBP3 (P508A; A515T)
ACB 344	32	16	A. baumannii	ADC-91-like; OXA-23; OXA-68; Partial AdeA; AdeRS not present; PBP3 (T526S)
PSA 1868	>128	256	P. aeruginosa	GES-19, GES-26
PSA 1602	>128	256	P. aeruginosa	aac(6′)-33, aadB, aatB7, KPC-5, mph(E), msr(E), OXA-50, PAO, sul1
PSA US-2-21	>128	64	P. aeruginosa	aph(3′)-IIb, bla_OXA-488, bla_PDC-40, catB7, crpP, fosA
PSA US-4-16	>128	>256	P. aeruginosa	aph(3′)-IIb, bla_OXA-846, bla_PDC-138, catB7, crpP, fosA
EC 722	≤0.125	16	E. coli	KPC-3, OXA-9, QnrS1, TEM-1A
EC 541	>128	256	E. coli	CMY-42, NDM-7
EC 766	≤0.125	32	E. coli	TEM-OSBL, CTX-M-15, CMY-4, OXA-48
KP 834	128	>256	K. pneumoniae	aph(3′′)-Ib, aph(6)-Id, catB4, CTX-M-15, dfrA14, Omp35, OmpK35, QnrB1, SHV-1, TEM-1B, tet(A), tet(R)
KP 836	≤0.125	>256	K. pneumoniae	CTX-M-15, dfrA14, fosA, KPC-3, oqxA, QnrS1, strA, strB, sul2, TEM-1B
KP 824	≤0.125	256	K. pneumoniae	aph(3′)-Ib, aph(6)-Id, catB4, CTX-M-15, dfrA14, NDM-1, OXA-1, QnrB1, sul2, TEM-1B, tet(A), tet(R)
KP JJ 7-44	≤0.125	≤0.125	K. pneumoniae	ND

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ND, not determined.

^aDurlobactam concentration fixed at 4 mg/L.

Time–kill studies

Time–kill curves for sulbactam-durlobactam, cefepime and the combination of both agents are shown in Figures 1–4. The mean bacterial density of the starting bacterial burden was 6.03 ± 0.18 log₁₀ cfu/mL across all isolates examined. Drug-free control experiments resulted in cfu increases of 2.75 ± 0.37 log₁₀ cfu/mL after 24 h.

Figure 1. — Time–kill experiments displaying the activity of sulbactam-durlobactam or cefepime alone and in combination against *A. baumannii* isolates. This figure appears in colour in the online version of *JAC* and in black and white in the print version of *JAC*.

Figure 4. — Time–kill experiments displaying the activity of sulbactam-durlobactam or cefepime alone and in combination against *K. pneumoniae* isolates. This figure appears in colour in the online version of *JAC* and in black and white in the print version of *JAC*.

Considering the CRAB isolates tested, as predicted by the MIC, sulbactam-durlobactam produced bacterial reductions against all isolates with MICs of ≤8 mg/L (Figure 1), while cefepime alone showed bacterial growth. For these isolates, synergy was not observed as the combination was no better than sulbactam-durlobactam alone but, importantly, antagonism was not observed. The combination therapy did show synergy against the one A. baumannii isolate with the highest sulbactam-durlobactam MIC of 32 mg/L, where each agent alone had limited activity.

As predicted by the MICs, sulbactam-durlobactam and cefepime alone resulted in bacterial growth against P. aeruginosa. All P. aeruginosa isolates showed synergy to sulbactam-durlobactam plus cefepime although regrowth was noted at 24 h for each isolate (Figure 2).

Figure 2. — Time–kill experiments displaying the activity of sulbactam-durlobactam or cefepime alone and in combination against *P. aeruginosa* isolates. This figure appears in colour in the online version of *JAC* and in black and white in the print version of *JAC*.

Sulbactam-durlobactam alone also showed significant activity against two of the Escherichia coli isolates that had low MICs for the agent with around 4.5 log₁₀ reduction in cfu/mL relative to 0 h control. Synergy was observed after addition of cefepime to sulbactam-durlobactam against the E. coli isolate that had an elevated MIC to sulbactam-durlobactam alone (Figure 3).

Figure 3. — Time–kill experiments displaying the activity of sulbactam-durlobactam or cefepime alone and in combination against *E. coli* isolates. This figure appears in colour in the online version of *JAC* and in black and white in the print version of *JAC*.

The combination therapy also exhibited synergy against one of the K. pneumoniae, with additive effect against the other two K. pneumoniae tested isolates. The final WT K. pneumoniae isolate tested exhibited no significant difference between sulbactam-durlobactam alone, cefepime alone, or sulbactam-durlobactam plus cefepime due to the bactericidal activity observed in all three treatment groups, as expected by the low MIC of each agent (Figure 4).

The antimicrobial interactions (i.e. synergy, additivity and indifference) observed with sulbactam-durlobactam in combination with cefepime against all evaluated isolates are summarized in Table 2.

Table 2.

Antimicrobial interactions and change in log₁₀ cfu/mL observed with sulbactam-durlobactam in combination with cefepime against 15 isolates at 24 h

Isolate	Interaction for combination of SUL-DUR plus FEP
Isolate	Change in log₁₀ cfu/mL at 24 h relative to 0 h	Change from most active single agent after 24 h	SUL-DUR plus FEP
ACB 341	−2.58	−0.45^a	Indifference
ACB 342	−2.30	−0.35^a	Indifference
ACB 343	−1.57	−0.66^a	Indifference
ACB 344	−3.50	−2.96^a	Synergy
PSA 1868	−0.85	−3.07^a	Synergy
PSA 1602	−1.18	−3.20^a	Synergy
PSA US-2-21	−0.86	−3.27^b	Synergy
PSA US-4-16	−0.75	−2.93^b	Synergy
EC 722	−4.14	0^a	Indifference
EC 541	−4.46	−5.82^a	Synergy
EC 766	−4.25	0^a	Indifference
KP 834	−4.45	−2.97^a	Synergy
KP 836	−4.11	−1.94^a	Additivity
KP 824	−1.24	−1.82^a	Additivity
KP JJ 7-44	−4.15	0^a	Indifference

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SUL-DUR, sulbactam-durlobactam; FEP, cefepime.

^aSulbactam-durlobactam was the most active agent.

^bCefepime was the most active agent.

Discussion

In the current study, we tested the activity of sulbactam-durlobactam in combination with cefepime against a variety of challenging clinical isolates including CRAB and MDR non-Acinetobacter organisms such as P. aeruginosa and Enterobacterales. These data confirm the in vitro activity of sulbactam-durlobactam against A. baumannii isolates with MICs at and near the proposed susceptibility breakpoint (4 mg/L). Due to the kill observed for sulbactam-durlobactam alone, the addition of cefepime did not enhance bacterial kill against A. baumannii, except for the isolate with the highest sulbactam-durlobactam MIC where synergy with cefepime was observed. For all four P. aeruginosa isolates, even though regrowth was common, sulbactam-durlobactam plus cefepime resulted in synergy. Activity of sulbactam-durlobactam against Enterobacterales was more variable, resulting in bactericidal activity against some isolates with or without cefepime coadministration. These data provide clinicians characterization of the in vitro activity of sulbactam-durlobactam with cefepime, which may be useful for the selection of antimicrobial agents and where polymicrobial infection is suspected.

Cefepime is one of the most commonly prescribed antimicrobials for nosocomial infections including HABP/VABP due to its activity against Gram-negative pathogens including P. aeruginosa and Enterobacterales.^5,13,22 Antimicrobial in vitro susceptibility studies using clinical isolates from nosocomial pneumonia patients in US medical centres between 2017 and 2018 showed adequate overall susceptibility to cefepime among common Gram-negative species. It was shown that 79.5%, 82.6% and 76.5% of P. aeruginosa, K. pneumoniae and E. coli isolates were susceptible to cefepime.²³ On the other hand, the same study found that cefepime susceptibility decreased against ESBL-producing isolates with MIC₅₀ and MIC₉₀ values of >16 mg/L, and 71.2% of isolates were resistant to cefepime.²³ Similarly, using clinical isolates of P. aeruginosa from ICU patients with respiratory tract infections in the USA between 2017 and 2019, cefepime showed activity against 76% of isolates; however, cefepime susceptibility decreased to 46% against meropenem-non-susceptible isolates.²⁴ The increasing resistance to cefepime has been attributed in part to serine-β-lactamases, therefore there is a rationale to combine cefepime with β-lactamase inhibitors to compensate for these resistance mechanisms and to protect the cephalosporin from these β-lactamases.²⁵ This was supported by the present study as enhanced bacterial kill was observed for all four P. aeruginosa isolates assessed, including β-lactamase-harbouring strains, in the presence of sulbactam-durlobactam. Indeed, cefepime-durlobactam MICs were not conducted in the present study as they will not be available in the clinic. However, practical synergy testing has been described for combinations of antimicrobials (e.g. zone of hope²⁶ and disc stacking²⁷), which future studies should assess as sulbactam-durlobactam test strips and discs become commercially available.

It should be noted that cefepime has relatively poor activity against CRAB. In an in vitro study, only ∼45% of A. baumannii clinical isolates were susceptible to cefepime.¹¹ Thus, empirical therapy in patients at high risk for CRAB infection requires novel treatment options. Sulbactam-durlobactam is a combination designed specifically for A. baumannii.⁹ Sulbactam-durlobactam demonstrated potent in vitro antibacterial activity against a collection of geographically diverse clinical A. baumannii isolates, including carbapenem-resistant isolates. The sulbactam-durlobactam MIC₅₀ and MIC₉₀ values were found to be 1 and 2 mg/L.¹⁰ Sulbactam-durlobactam MIC values were ≤4 mg/L (the preliminary susceptible breakpoint) for 98.3% of the 5032 clinical A. baumannii isolates from a global surveillance programme.¹¹

A potential mechanistic explanation for the synergy observed between sulbactam-durlobactam and cefepime in the present study is the complementary PBP interactions when coadminstered.^15,16 In addition to durlobactam’s inhibition of serine-β-lactamases, it also binds and inhibits PBP2.⁹ Although this inhibition is insufficient to exert clinically relevant antibacterial activity against species such as A. baumannii and P. aeruginosa, synergy may be possible when coadministered with cefepime’s PBP1 and 3 inhibition via complementary PBP saturation.^9,16 This phenomenon has been described with the novel combination cefepime-zidebactam.¹⁶ Indeed, although zidebactam does not inhibit MBLs, increased kill was observed when cefepime was combined with zidebactam, suggesting enhanced bacterial killing due to inhibition of multiple PBPs.¹⁶ This is not dissimilar to the present study where synergy and additivity was observed against MBL-producing EC541 and KP824, respectively. In the case of cefepime-zidebactam, the enhanced in vitro activity translated to significant in vivo activity. In the presence of human-simulated zidebactam exposures, cefepime human-simulated exposures produced profound kill despite less than 50%–70%fT_>MIC cefepime exposure traditionally associated with bactericidal activity.^28–30 In vivo validation of enhanced cefepime activity in the presence of durlobactam will provide clinicians with further evidence of the utility of this combination for MDR non-Acinetobacter organisms.

A notable finding of the present study was the significant in vitro activity of sulbactam-durlobactam against Enterobacterales, likely due to PBP2 inhibition.⁹ For the organisms where bactericidal activity was observed, the sulbactam-durlobactam MICs were relatively low bearing in mind that the durlobactam concentration was fixed at 4 mg/L, which is the proposed clinical testing methodology for the clinic. Similar MICs have been described in a cohort of carbapenem-resistant Enterobacterales (CRE), where MIC₉₀ values of ≤0.06 and 0.12 mg/L for sulbactam-durlobactam (durlobactam fixed at 4 mg/L) were observed for E. coli and K. pneumoniae, respectively.³¹ When assessed alone, the durlobactam MIC₉₀ was 1 and 8 mg/L for each species, respectively.³¹ Nonetheless, the free steady-state average durlobactam concentration, ∼17 mg/L, surpasses the 4 mg/L used in MIC testing and thus may indicate activity against such organisms. Previous PBP2 active agents have been developed and used clinically, such as mecillinam.³² Mecillinam and other PBP2-selective agents have the theoretical caveat that in laboratory-based assessments a high frequency of resistance has been observed that is thought to be due to the singular inhibition of PBP2.^32,33 Since sulbactam-durlobactam was specifically designed for the treatment of A. baumannii, the proposed breakpoints are limited to this organism. There are insufficient data to define the clinical utility of durlobactam against non-Acinetobacter coinfecting species. With this said, the present study indicates there may be a role of coadministration of sulbactam-durlobactam with other agents such as cefepime, which may be beneficial in polymicrobial infections.

HABP and VABP are widespread nosocomial infections associated with high morbidity and mortality.⁵ Polymicrobial infections are common within VABP, where nearly half of patients have an infection with multiple organisms.^34,35 Similarly, patients with CRE infection may often be infected with other Gram-negative MDR organisms such as carbapenem-resistant P. aeruginosa and CRAB. In a retrospective cohort study of 92 patients’ clinical isolates, about 40% of patients infected with CRE were found to be co-colonized with either P. aeruginosa and/or CRAB.^36,37 This can lead to inappropriate therapy for highly resistant isolates, which is associated with poor clinical outcomes.^38,39 It is clear there is a need to establish combinations that can provide activity against MDR polymicrobial infections for critically ill patients. The present study adds an important initial step in addressing MDR, polymicrobial infections that involve CRAB and other nosocomial pathogens as combination of sulbactam-durlobactam with cefepime was not associated with antagonism and in fact exhibited synergy against 4/4 P. aeruginosa isolates and synergy or additivity against 4/6 MDR Enterobacterales. Furthermore, this study provides a translational assessment as the observed antimicrobial activity was seen at clinically relevant antibiotic exposures since the drug concentrations in the experiments were similar to the fC_ssavg in patients receiving the clinical dose of each agent. Confirmatory in vivo and clinical studies evaluating the combination of sulbactam-durlobactam and cefepime for polymicrobial infections are warranted.

In summary, clinically relevant concentrations of sulbactam-durlobactam in combination with cefepime showed in vitro activity against cefepime-resistant P. aeruginosa, Enterobacterales and CRAB isolates. These data demonstrate the synergistic antimicrobial effects of sulbactam-durlobactam when administered with cefepime with no evidence of antagonism. Further in vitro and in vivo pharmacokinetic/pharmacodynamic analyses using clinical exposures of this combination against polymicrobial infections would be useful to provide translational data for these challenging infections.

Acknowledgements

We would like to recognize the staff at the Center for Anti-infective Research & Development for their vital assistance in this study.

Contributor Information

Aliaa Fouad, Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.

David P Nicolau, Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA; Division of Infectious Diseases, Hartford Hospital, Hartford, CT, USA.

Christian M Gill, Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, CT, USA.

Funding

This study was funded by Entasis Therapeutics, Waltham, MA, USA.

Transparency declarations

C.M.G. has received research funding from Cepheid, Shionogi, Everest Medicines and Entasis. D.P.N. served as a consultant, speaker’s bureau member or has received research funding from: Allergan, Cepheid, Merck, Pfizer, Wockhardt, Shionogi, Tetraphase, Venatorx. A.F. has none to declare.

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13. Nicasio AM, Eagye KJ, Nicolau DP et al. Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia. J Crit Care 2010; 25: 69–77. 10.1016/j.jcrc.2009.02.014 [DOI] [PubMed] [Google Scholar]
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15. Bhagwat S, Periasamy H, Takalkar S et al. The novel β-lactam enhancer zidebactam augments the in vivo pharmacodynamic activity of cefepime in a neutropenic mouse lung Acinetobacter baumannii infection model. Antimicrob Agents Chemother 2019; 63: e02146-18. 10.1128/AAC.02146-18 [DOI] [PMC free article] [PubMed] [Google Scholar]
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17. Gill CM, Aktaþ E, Alfouzan W et al. The ERACE-PA Global Surveillance Program: ceftolozane/tazobactam and ceftazidime/avibactam in vitro activity against a global collection of carbapenem-resistant Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis 2021; 40: 2533–41. 10.1007/s10096-021-04308-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
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21. Nicasio AM, Ariano RE, Zelenitsky SA et al. Population pharmacokinetics of high-dose, prolonged-infusion cefepime in adult critically ill patients with ventilator-associated pneumonia. Antimicrob Agents Chemother 2009; 53: 1476–81. 10.1128/AAC.01141-08 [DOI] [PMC free article] [PubMed] [Google Scholar]
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23. Sader HS, Flamm RK, Carvalhaes CG et al. Comparison of ceftazidime-avibactam and ceftolozane-tazobactam in vitro activities when tested against gram-negative bacteria isolated from patients hospitalized with pneumonia in United States medical centers (2017–2018). Diagn Microbiol Infect Dis 2020; 96: 114833. 10.1016/j.diagmicrobio.2019.05.005 [DOI] [PubMed] [Google Scholar]
24. Lob SH, DePestel DD, DeRyke CA et al. Ceftolozane/tazobactam and imipenem/relebactam cross-susceptibility among clinical isolates of Pseudomonas aeruginosa from patients with respiratory tract infections in ICU and non-ICU wards—SMART United States 2017–2019. Open Forum Infect Dis 2021; 8: ofab320. [DOI] [PMC free article] [PubMed] [Google Scholar]
25. Isler B, Harris P, Stewart AG et al. An update on cefepime and its future role in combination with novel β-lactamase inhibitors for MDR Enterobacterales and Pseudomonas aeruginosa. J Antimicrob Chemother 2021; 76: 550–60. 10.1093/jac/dkaa511 [DOI] [PubMed] [Google Scholar]
26. Avery LM, Nicolau DP. Assessing the in vitro activity of ceftazidime/avibactam and aztreonam among carbapenemase-producing Enterobacteriaceae: defining the zone of hope. Int J Antimicrob Agents 2018; 52: 688–91. 10.1016/j.ijantimicag.2018.07.011 [DOI] [PubMed] [Google Scholar]
27. Liu Z, Hang X, Yan T et al. A simple disk stacking plus micro-elution method for rapid detection of the synergistic effect of aztreonam and ceftazidime/avibactam against metallo-β-lactamase producing Enterobacterales. Infect Drug Resist 2023; 16: 1537–43. 10.2147/IDR.S402275 [DOI] [PMC free article] [PubMed] [Google Scholar]
28. Avery LM, Abdelraouf K, Nicolau DP. Assessment of the in vivo efficacy of WCK 5222 (cefepime-zidebactam) against carbapenem-resistant Acinetobacter baumannii in the neutropenic murine lung infection model. Antimicrob Agents Chemother 2018; 62: e00948-18. 10.1128/AAC.00948-18 [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Abuhussain SSA, Avery LM, Abdelraouf K et al. In vivo efficacy of humanized WCK 5222 (cefepime-zidebactam) exposures against carbapenem-resistant Acinetobacter baumannii in the neutropenic thigh model. Antimicrob Agents Chemother 2019; 63: e01931-18. 10.1128/AAC.01931-18 [DOI] [PMC free article] [PubMed] [Google Scholar]
30. Kidd JM, Abdelraouf K, Nicolau DP. Efficacy of human-simulated bronchopulmonary exposures of cefepime, zidebactam and the combination (WCK 5222) against MDR Pseudomonas aeruginosa in a neutropenic murine pneumonia model. J Antimicrob Chemother 2020; 75: 149–55. 10.1093/jac/dkz414 [DOI] [PubMed] [Google Scholar]
31. Shapiro A, Guler S, Carter N et al. ETX2514, a novel, rationally designed inhibitor of class A, C and D β-lactamases, for the treatment of Gram-negative infections. ASM Microbe, Boston, USA, 2016. Abstract LB-024.
32. Thulin E, Sundqvist M, Andersson DI. Amdinocillin (mecillinam) resistance mutations in clinical isolates and laboratory-selected mutants of Escherichia coli. Antimicrob Agents Chemother 2015; 59: 1718–27. 10.1128/AAC.04819-14 [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Doumith M, Mushtaq S, Livermore DM et al. New insights into the regulatory pathways associated with the activation of the stringent response in bacterial resistance to the PBP2-targeted antibiotics, mecillinam and OP0595/RG6080. J Antimicrob Chemother 2016; 71: 2810–4. 10.1093/jac/dkw230 [DOI] [PubMed] [Google Scholar]
34. Ferrer M, Difrancesco LF, Liapikou A et al. Polymicrobial intensive care unit-acquired pneumonia: prevalence, microbiology and outcome. J Crit Care 2015; 19: 450. 10.1186/s13054-015-1165-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
35. Combes A, Figliolini C, Trouillet J-L et al. Incidence and outcome of polymicrobial ventilator-associated pneumonia. Chest 2002; 121: 1618–23. 10.1378/chest.121.5.1618 [DOI] [PubMed] [Google Scholar]
36. Marchaim D, Perez F, Lee J et al. “Swimming in resistance”: co-colonization with carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii or Pseudomonas aeruginosa. Am J Infect Control 2012; 40: 830–5. 10.1016/j.ajic.2011.10.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Tadese BK, DeSantis SM, Mgbere O et al. Clinical outcomes associated with co-infection of carbapenem-resistant Enterobacterales and other multidrug-resistant organisms. Infection Prevention in Practice 2022; 4: 100255. 10.1016/j.infpip.2022.100255 [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Zilberberg MD, Nathanson BH, Puzniak LA et al. The risk of inappropriate empiric treatment and its outcomes based on pathogens in non-ventilated (nvHABP), ventilated (vHABP) hospital-acquired and ventilator-associated (VABP) bacterial pneumonia in the US, 2012–2019. BMC Infect Dis 2022; 22: 775. 10.1186/s12879-022-07755-y [DOI] [PMC free article] [PubMed] [Google Scholar]
39. Zilberberg MD, Nathanson BH, Puzniak LA et al. Inappropriate empiric therapy impacts complications and hospital resource utilization differentially among different types of bacterial nosocomial pneumonia: a cohort study, United States, 2014–2019. Crit Care Explor 2022; 4: e0667. 10.1097/CCE.0000000000000667 [DOI] [PMC free article] [PubMed] [Google Scholar]

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[dkad244-B11] 11. Karlowsky JA, Hackel MA, McLeod SM et al. In vitro activity of sulbactam-durlobactam against global isolates of Acinetobacter baumannii-calcoaceticus complex collected from 2016 to 2021. Antimicrob Agents Chemother 2022; 66: e00781-22. 10.1128/aac.00781-22 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B12] 12. Miller AA, Shapiro A, McLeod SM et al. Efficacy and safety of sulbactam-durlobactam are consistent across regions in the global ATTACK Phase 3 trial in the treatment of carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (CRABC) infections. ID Week 2022, Washington, DC, USA. Poster 225.

[dkad244-B13] 13. Nicasio AM, Eagye KJ, Nicolau DP et al. Pharmacodynamic-based clinical pathway for empiric antibiotic choice in patients with ventilator-associated pneumonia. J Crit Care 2010; 25: 69–77. 10.1016/j.jcrc.2009.02.014 [DOI] [PubMed] [Google Scholar]

[dkad244-B14] 14. Zasowski EJ, Bassetti M, Blasi F et al. A systematic review of the effect of delayed appropriate antibiotic treatment on the outcomes of patients with severe bacterial infections. Chest 2020; 158: 929–38. 10.1016/j.chest.2020.03.087 [DOI] [PubMed] [Google Scholar]

[dkad244-B15] 15. Bhagwat S, Periasamy H, Takalkar S et al. The novel β-lactam enhancer zidebactam augments the in vivo pharmacodynamic activity of cefepime in a neutropenic mouse lung Acinetobacter baumannii infection model. Antimicrob Agents Chemother 2019; 63: e02146-18. 10.1128/AAC.02146-18 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B16] 16. Moya B, Bhagwat S, Cabot G et al. Effective inhibition of PBPs by cefepime and zidebactam in the presence of VIM-1 drives potent bactericidal activity against MBL-expressing Pseudomonas aeruginosa. J Antimicrob Chemother 2020; 75: 1474–8. 10.1093/jac/dkaa036 [DOI] [PubMed] [Google Scholar]

[dkad244-B17] 17. Gill CM, Aktaþ E, Alfouzan W et al. The ERACE-PA Global Surveillance Program: ceftolozane/tazobactam and ceftazidime/avibactam in vitro activity against a global collection of carbapenem-resistant Pseudomonas aeruginosa. Eur J Clin Microbiol Infect Dis 2021; 40: 2533–41. 10.1007/s10096-021-04308-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B18] 18. CLSI . Performance Standards for Antimicrobial Susceptibility Testing—Thirty-Second Edition: M100. 2022. [Google Scholar]

[dkad244-B19] 19. Asempa TE, Nicolau DP, Kuti JL. In vitro activity of imipenem-relebactam alone or in combination with amikacin or colistin against Pseudomonas aeruginosa. Antimicrob Agents Chemother 2019; 63: e00997-19. 10.1128/AAC.00997-19 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B20] 20. Bhavnani S, Rubino C, Hammel J et al. Population pharmacokinetic (PPK), pharmacokinetic/pharmacodynamic attainment (PTA), clinical pharmacokinetic/pharmacodynamic (PK/PD) analyses for sulbactam-durlobactam (SUL-DUR) to support dose selection for the treatment of Acinetobacter baumannii–calcoaceticus complex (ABC) infections. ID Week 2022, Washington, DC, USA. Abstract ofac492.1896.

[dkad244-B21] 21. Nicasio AM, Ariano RE, Zelenitsky SA et al. Population pharmacokinetics of high-dose, prolonged-infusion cefepime in adult critically ill patients with ventilator-associated pneumonia. Antimicrob Agents Chemother 2009; 53: 1476–81. 10.1128/AAC.01141-08 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B22] 22. Claeys KC, Zasowski EJ, Trinh TD et al. Antimicrobial stewardship opportunities in critically ill patients with Gram-negative lower respiratory tract infections: a multicenter cross-sectional analysis. Infect Dis Ther 2018; 7: 135–46. 10.1007/s40121-017-0179-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B23] 23. Sader HS, Flamm RK, Carvalhaes CG et al. Comparison of ceftazidime-avibactam and ceftolozane-tazobactam in vitro activities when tested against gram-negative bacteria isolated from patients hospitalized with pneumonia in United States medical centers (2017–2018). Diagn Microbiol Infect Dis 2020; 96: 114833. 10.1016/j.diagmicrobio.2019.05.005 [DOI] [PubMed] [Google Scholar]

[dkad244-B24] 24. Lob SH, DePestel DD, DeRyke CA et al. Ceftolozane/tazobactam and imipenem/relebactam cross-susceptibility among clinical isolates of Pseudomonas aeruginosa from patients with respiratory tract infections in ICU and non-ICU wards—SMART United States 2017–2019. Open Forum Infect Dis 2021; 8: ofab320. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B25] 25. Isler B, Harris P, Stewart AG et al. An update on cefepime and its future role in combination with novel β-lactamase inhibitors for MDR Enterobacterales and Pseudomonas aeruginosa. J Antimicrob Chemother 2021; 76: 550–60. 10.1093/jac/dkaa511 [DOI] [PubMed] [Google Scholar]

[dkad244-B26] 26. Avery LM, Nicolau DP. Assessing the in vitro activity of ceftazidime/avibactam and aztreonam among carbapenemase-producing Enterobacteriaceae: defining the zone of hope. Int J Antimicrob Agents 2018; 52: 688–91. 10.1016/j.ijantimicag.2018.07.011 [DOI] [PubMed] [Google Scholar]

[dkad244-B27] 27. Liu Z, Hang X, Yan T et al. A simple disk stacking plus micro-elution method for rapid detection of the synergistic effect of aztreonam and ceftazidime/avibactam against metallo-β-lactamase producing Enterobacterales. Infect Drug Resist 2023; 16: 1537–43. 10.2147/IDR.S402275 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B28] 28. Avery LM, Abdelraouf K, Nicolau DP. Assessment of the in vivo efficacy of WCK 5222 (cefepime-zidebactam) against carbapenem-resistant Acinetobacter baumannii in the neutropenic murine lung infection model. Antimicrob Agents Chemother 2018; 62: e00948-18. 10.1128/AAC.00948-18 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B29] 29. Abuhussain SSA, Avery LM, Abdelraouf K et al. In vivo efficacy of humanized WCK 5222 (cefepime-zidebactam) exposures against carbapenem-resistant Acinetobacter baumannii in the neutropenic thigh model. Antimicrob Agents Chemother 2019; 63: e01931-18. 10.1128/AAC.01931-18 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B30] 30. Kidd JM, Abdelraouf K, Nicolau DP. Efficacy of human-simulated bronchopulmonary exposures of cefepime, zidebactam and the combination (WCK 5222) against MDR Pseudomonas aeruginosa in a neutropenic murine pneumonia model. J Antimicrob Chemother 2020; 75: 149–55. 10.1093/jac/dkz414 [DOI] [PubMed] [Google Scholar]

[dkad244-B31] 31. Shapiro A, Guler S, Carter N et al. ETX2514, a novel, rationally designed inhibitor of class A, C and D β-lactamases, for the treatment of Gram-negative infections. ASM Microbe, Boston, USA, 2016. Abstract LB-024.

[dkad244-B32] 32. Thulin E, Sundqvist M, Andersson DI. Amdinocillin (mecillinam) resistance mutations in clinical isolates and laboratory-selected mutants of Escherichia coli. Antimicrob Agents Chemother 2015; 59: 1718–27. 10.1128/AAC.04819-14 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B33] 33. Doumith M, Mushtaq S, Livermore DM et al. New insights into the regulatory pathways associated with the activation of the stringent response in bacterial resistance to the PBP2-targeted antibiotics, mecillinam and OP0595/RG6080. J Antimicrob Chemother 2016; 71: 2810–4. 10.1093/jac/dkw230 [DOI] [PubMed] [Google Scholar]

[dkad244-B34] 34. Ferrer M, Difrancesco LF, Liapikou A et al. Polymicrobial intensive care unit-acquired pneumonia: prevalence, microbiology and outcome. J Crit Care 2015; 19: 450. 10.1186/s13054-015-1165-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B35] 35. Combes A, Figliolini C, Trouillet J-L et al. Incidence and outcome of polymicrobial ventilator-associated pneumonia. Chest 2002; 121: 1618–23. 10.1378/chest.121.5.1618 [DOI] [PubMed] [Google Scholar]

[dkad244-B36] 36. Marchaim D, Perez F, Lee J et al. “Swimming in resistance”: co-colonization with carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii or Pseudomonas aeruginosa. Am J Infect Control 2012; 40: 830–5. 10.1016/j.ajic.2011.10.013 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B37] 37. Tadese BK, DeSantis SM, Mgbere O et al. Clinical outcomes associated with co-infection of carbapenem-resistant Enterobacterales and other multidrug-resistant organisms. Infection Prevention in Practice 2022; 4: 100255. 10.1016/j.infpip.2022.100255 [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B38] 38. Zilberberg MD, Nathanson BH, Puzniak LA et al. The risk of inappropriate empiric treatment and its outcomes based on pathogens in non-ventilated (nvHABP), ventilated (vHABP) hospital-acquired and ventilator-associated (VABP) bacterial pneumonia in the US, 2012–2019. BMC Infect Dis 2022; 22: 775. 10.1186/s12879-022-07755-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkad244-B39] 39. Zilberberg MD, Nathanson BH, Puzniak LA et al. Inappropriate empiric therapy impacts complications and hospital resource utilization differentially among different types of bacterial nosocomial pneumonia: a cohort study, United States, 2014–2019. Crit Care Explor 2022; 4: e0667. 10.1097/CCE.0000000000000667 [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

In vitro synergy of the combination of sulbactam-durlobactam and cefepime at clinically relevant concentrations against A. baumannii, P. aeruginosa and Enterobacterales

Aliaa Fouad

David P Nicolau

Christian M Gill