Clinical and microbiological outcomes, by causative pathogen, in the ASPECT-NP randomized, controlled, Phase 3 trial comparing ceftolozane/tazobactam and meropenem for treatment of hospital-acquired/ventilator-associated bacterial pneumonia

Ignacio Martin-Loeches; Jean-François Timsit; Marin H Kollef; Richard G Wunderink; Nobuaki Shime; Martin Nováček; Ülo Kivistik; Álvaro Réa-Neto; Christopher J Bruno; Jennifer A Huntington; Gina Lin; Erin H Jensen; Mary Motyl; Brian Yu; Davis Gates; Joan R Butterton; Elizabeth G Rhee

doi:10.1093/jac/dkab494

. 2022 Jan 12;77(4):1166–1177. doi: 10.1093/jac/dkab494

Clinical and microbiological outcomes, by causative pathogen, in the ASPECT-NP randomized, controlled, Phase 3 trial comparing ceftolozane/tazobactam and meropenem for treatment of hospital-acquired/ventilator-associated bacterial pneumonia

Ignacio Martin-Loeches ^1,², Jean-François Timsit ³, Marin H Kollef ⁴, Richard G Wunderink ⁵, Nobuaki Shime ⁶, Martin Nováček ⁷, Ülo Kivistik ⁸, Álvaro Réa-Neto ⁹, Christopher J Bruno ¹⁰, Jennifer A Huntington ¹¹, Gina Lin ¹², Erin H Jensen ¹³, Mary Motyl ¹⁴, Brian Yu ¹⁵, Davis Gates ¹⁶, Joan R Butterton ¹⁷, Elizabeth G Rhee ^18,^✉

PMCID: PMC9432134 PMID: 35022730

Abstract

Objectives

In the ASPECT-NP trial, ceftolozane/tazobactam was non-inferior to meropenem for treating nosocomial pneumonia; efficacy outcomes by causative pathogen were to be evaluated.

Methods

Mechanically ventilated participants with hospital-acquired/ventilator-associated bacterial pneumonia were randomized to 3 g ceftolozane/tazobactam (2 g ceftolozane/1 g tazobactam) q8h or 1 g meropenem q8h. Lower respiratory tract (LRT) cultures were obtained ≤36 h before first dose; pathogen identification and susceptibility were confirmed at a central laboratory. Prospective secondary per-pathogen endpoints included 28 day all-cause mortality (ACM), and clinical and microbiological response at test of cure (7–14 days after the end of therapy) in the microbiological ITT (mITT) population.

Results

The mITT population comprised 511 participants (264 ceftolozane/tazobactam, 247 meropenem). Baseline LRT pathogens included Klebsiella pneumoniae (34.6%), Pseudomonas aeruginosa (25.0%) and Escherichia coli (18.2%). Among baseline Enterobacterales isolates, 171/456 (37.5%) were ESBL positive. For Gram-negative baseline LRT pathogens, susceptibility rates were 87.0% for ceftolozane/tazobactam and 93.3% for meropenem. For Gram-negative pathogens, 28 day ACM [52/259 (20.1%) and 62/240 (25.8%)], clinical cure rates [157/259 (60.6%) and 137/240 (57.1%)] and microbiological eradication rates [189/259 (73.0%) and 163/240 (67.9%)] were comparable with ceftolozane/tazobactam and meropenem, respectively. Per-pathogen microbiological eradication for Enterobacterales [145/195 (74.4%) and 129/185 (69.7%); 95% CI: −4.37 to 13.58], ESBL-producing Enterobacterales [56/84 (66.7%) and 52/73 (71.2%); 95% CI: −18.56 to 9.93] and P. aeruginosa [47/63 (74.6%) and 41/65 (63.1%); 95% CI: −4.51 to 19.38], respectively, were also comparable.

Conclusions

In mechanically ventilated participants with nosocomial pneumonia owing to Gram-negative pathogens, ceftolozane/tazobactam was comparable with meropenem for per-pathogen 28 day ACM and clinical and microbiological response.

Introduction

Hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP) are common, serious nosocomial infections.¹ Crude mortality rates associated with ventilated nosocomial pneumonia (NP) can reach 50%, with an attributable mortality of approximately 13%.^1–3 Gram-negative bacteria are frequently the causative pathogen for HABP/VABP, and the worldwide increase in antibacterial resistance among these pathogens adversely affects treatment outcomes in HABP/VABP, including patient survival and length of hospital stay.^4–7 Recent data demonstrate that HABP/VABP is most frequently caused by Enterobacterales and Pseudomonas aeruginosa (together approximately 60%), including notable amounts (i.e. ≥10%) of ESBL-producing Enterobacterales, third-generation cephalosporin-resistant Enterobacterales, MDR P. aeruginosa and/or carbapenem-non-susceptible P. aeruginosa.^8–14 The rising resistance among HABP/VABP pathogens, with substantial geographical variation, complicates the selection of appropriate antibacterial therapy, which requires rapid initiation to improve survival and other outcomes, especially in high-risk patients (e.g. those in the ICU, with septic shock and/or at high risk for MDR pathogens).^1,15–19

Ceftolozane/tazobactam, which is approved for HABP/VABP treatment as well as complicated intra-abdominal infections and complicated urinary tract infections, including pyelonephritis,²⁰ is a combination of the potent anti-pseudomonal cephalosporin ceftolozane and the established ESBL inhibitor tazobactam²⁰ and has in vitro activity against a wide range of Gram-negative pathogens that cause HABP, including MDR P. aeruginosa and ESBL-producing Enterobacterales.^8,21,22 Recent results demonstrated activity of ceftolozane/tazobactam against ESBL screen-positive lower respiratory tract (LRT) pathogens, with susceptibility of 67.1% and 86.5% in Klebsiella pneumoniae (n = 85) and Escherichia coli (n = 74) isolates, respectively;²³ another study found that 82.4% of ESBL screen-positive, carbapenemase-negative Enterobacterales isolates were susceptible to ceftolozane/tazobactam.²⁴ Furthermore, ceftolozane/tazobactam has shown substantial intrapulmonary penetration in both healthy volunteers and critically ill, ventilated participants with pneumonia.^25,26 The randomized, controlled ASPECT-NP trial demonstrated the non-inferiority of a 3 g ceftolozane/tazobactam dosing regimen to a 1 g meropenem dosing regimen, in both primary and key secondary endpoints, for the treatment of NP in mechanically ventilated participants.²⁷ This high-dose ceftolozane/tazobactam regimen was originally selected based on data from healthy volunteers and to account for the complex antibacterial pharmacokinetics/pharmacodynamics in critically ill patients, lower drug concentrations in the lung versus plasma, and the relatively high prevalence of resistant pathogens in NP.^8,28,29 A systematic literature review of real-world evidence showed that in 33 studies with 658 participants treated with ceftolozane/tazobactam, 92.8% had respiratory infections caused by P. aeruginosa and 87.6% were MDR, but they had similar clinical and microbiological success compared with clinical studies despite higher numbers of MDR infections.³⁰

To evaluate further the clinical utility of ceftolozane/tazobactam against specific HABP/VABP pathogens of interest, we compared per-pathogen clinical and microbiological outcomes of ceftolozane/tazobactam versus meropenem for the treatment of ventilated NP from ASPECT-NP. Key pathogens, including P. aeruginosa, ESBL-producing Enterobacterales and third-generation cephalosporin-resistant pathogens, underwent further analysis.

Participants and methods

Study design overview

Protocol MK-7625A-008 (ASPECT-NP) was a Phase 3, randomized, controlled, double-blind, multicentre, non-inferiority trial characterizing efficacy and safety of 3 g ceftolozane/tazobactam (2 g ceftolozane/1 g tazobactam) q8h versus 1 g meropenem q8h in adults with ventilated NP (ClinicalTrials.gov identifier: NCT02070757). Results for primary and key secondary endpoints and the full protocol have been published previously.²⁷ The study was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies.

Inclusion and exclusion criteria

The trial enrolled intubated and mechanically ventilated adults (≥18 years of age) diagnosed with VABP (onset ≥48 h after intubation) or ventilated HABP (onset ≥48 h after hospital admission or ≤ 7 days after hospital discharge). Diagnosis was based on the following clinical and radiographical criteria: purulent tracheal secretions with ≥1 other clinical criterion [fever (≥38°C) or hypothermia (≤35°C), WBC count ≥ 10 000 cells/mm³ or ≤ 4500 cells/mm³ or ≥ 15% immature neutrophils) and chest radiograph showing the presence of a new/progressive infiltrate ≤24 h before the first dose of study medication.

Exclusion criteria included baseline Gram stain with only Gram-positive pathogens, >24 h of active Gram-negative antibacterials for NP within 72 h before the first dose (exception: persistent/worsening or new NP despite ≥48 h of active Gram-negative antibacterial therapy), diagnoses/conditions potentially interfering with outcome assessment/interpretation, active immunosuppression, neutropenia, continuous renal replacement therapy or end-stage renal disease requiring haemodialysis. Detailed inclusion/exclusion criteria are listed in the protocol.

Study treatments

Eligible participants were stratified by diagnosis (VABP versus ventilated HABP) and age (< 65 versus ≥65 years) and randomized 1:1 to either 3 g ceftolozane/tazobactam or 1 g meropenem; both study drugs were dose-adjusted based on renal function, which was comparable across treatment arms, and administered as 1 h IV infusions q8h for 8–14 days.²⁰ Adjunctive linezolid 600 mg IV administered every 12 h (or a suitable alternative) was required for all participants until baseline LRT cultures confirmed absence of Staphylococcus aureus. Adjunctive empirical therapy with amikacin 15 mg/kg was permitted for the first 72 h at study sites with ≥15% meropenem-resistant P. aeruginosa, as deemed necessary by the investigator.

Microbiological assessments

A baseline LRT specimen for Gram stain and quantitative culture was required ≤36 h before receipt of the first dose of study drug. Specimens could be obtained by bronchoalveolar lavage (BAL), non-bronchoscopic BAL (mini-BAL), protected brush specimen (PBS) or endotracheal aspirate (ETA). The first three modalities were strongly recommended over ETA; ETA specimens with an average of ≥10 squamous epithelial cells or ≤25 polymorphonuclear cells per low-power field were considered inadequate and an adequate repeat specimen was required. Collection of post-baseline quantitative LRT cultures was required in intubated participants on Days 1, 2, 3 and 8; in extubated participants, post-baseline LRT cultures could optionally be collected via sputum samples. Post-baseline LRT specimens were also collected at the end of therapy (EOT) and at test of cure (TOC; 7–14 days post-EOT), if clinically indicated. LRT specimens at EOT and TOC could be obtained by any of the same sampling methods, at the discretion of the investigator, that were used for obtaining baseline LRT samples (i.e. BAL or mini-BAL, PBS or ETA) but it was not required to use the same sampling method as the baseline sample. In post-baseline samples only, sputum was also allowed in extubated participants. To account for the differing sensitivity of the allowed sampling methods, quantitative culturing was performed and cfu criteria based on the sampling method were used to assess microbiological response (e.g. <10⁴ cfu/mL for ETA/sputum, <10³ cfu/mL for BAL/mini-BAL or <10² cfu/mL for PBS).

Pathogen identification and susceptibility were confirmed at a central laboratory using standard broth microdilution methodology.³¹ Susceptibility to ceftolozane/tazobactam was determined using study-defined, provisional breakpoints, with an MIC of ≤4 mg/L for Enterobacterales and ≤8 mg/L for P. aeruginosa, Acinetobacter baumannii and Haemophilus influenzae (Table S1, available as Supplementary data at JAC Online). Meropenem susceptibility was interpreted using CLSI breakpoints, including ≤2 mg/L for P. aeruginosa and A. baumannii, ≤0.5 mg/L for H. influenzae and ≤1 mg/L for Enterobacterales (Table S1).³² Baseline resistant organisms were defined as those LRT pathogens that were resistant to both study drugs. Third-generation cephalosporin-resistant Enterobacterales were defined as those isolates resistant to ceftazidime; susceptibility to other third-generation cephalosporins was not assessed centrally. All Enterobacterales isolates with an MIC of ≥2 mg/L ceftriaxone, aztreonam, ceftazidime, imipenem and meropenem and/or with a ceftolozane/tazobactam MIC of ≥4 mg/L, as well as all P. aeruginosa isolates with a ceftazidime MIC of ≥16 mg/L, imipenem and/or meropenem MIC of ≥4 mg/L and/or ceftolozane/tazobactam MIC of ≥8 mg/L were evaluated for the presence of ESBL genes using WGS analysis, quantitative RT–PCR and western blot analysis, as described previously.³³

Outcomes

All microbiological data are presented in those analysis populations with confirmed eligible baseline LRT pathogens, i.e. the microbiological ITT (mITT) population (ITT participants who received ≥1 dose of study treatment and with ≥1 Gram-negative or streptococcal respiratory pathogen from baseline LRT cultures confirmed to be susceptible to ≥1 study drug) and the microbiologically evaluable (ME) population [mITT participants who received study drug, had a baseline LRT pathogen(s) count at the appropriate diagnostic threshold of ≥10⁵ cfu/mL for ETA, ≥10⁴ cfu/mL for BAL or ≥10³ cfu/mL for PBS specimens, adhered to the study protocol through TOC, and had evaluable clinical outcomes at TOC]. Secondary endpoints of this study included per-pathogen (i.e. according to baseline pathogen) 28 day all-cause mortality (ACM; mITT population), per-pathogen clinical response at TOC (mITT and ME populations) and per-pathogen microbiological response at TOC (mITT and ME populations).

Clinical response was categorized as cure (resolution of baseline HABP/VABP signs/symptoms, no new signs/symptoms and no additional antibacterial therapy administered for HABP/VABP), failure (progression/relapse/recurrence of HABP/VABP, insufficient resolution of baseline signs/symptoms, study drug discontinuation owing to resistant LRT pathogens, or participant death from HABP/VABP) or indeterminate (participant died owing to a cause other than HABP/VABP, discontinued treatment because no baseline Gram-negative or streptococcal isolates were identified, or data missing for any reason).

Microbiological response was categorized, based on LRT cultures obtained at TOC, as eradication (≥1 log reduction in baseline LRT pathogen bacterial burden, with a resulting per-pathogen count of ≤10⁴ cfu/mL for ETA or sputum, ≤10³ cfu/mL for BAL or ≤10² cfu/mL for PBS), presumed eradication (no microbiological culture available in participants with clinical cure), persistence [continued presence of the baseline pathogen(s), defined as <1 log reduction in baseline LRT pathogen burden; or >10⁴ cfu/mL for ETA or sputum, >10³ cfu/mL for BAL or >10² cfu/mL for PBS specimens; or baseline pathogen still present without quantitative culture count data available], presumed persistence (no microbiological culture available in participants without clinical cure), indeterminate (no microbiological culture available in participants with indeterminate clinical response) or recurrence [isolation of the baseline LRT pathogen(s) at the appropriate diagnostic threshold of ≥10⁵ cfu/mL for ETA or sputum, ≥10⁴ cfu/mL for BAL or ≥10³ cfu/mL for PBS specimens in participants with documented eradication at the EOT visit]. A superinfection was identified if a pathogen other than the baseline pathogen from a post-baseline LRT culture was isolated while the participant was still receiving study treatment. A new infection was identified if a pathogen was isolated other than the baseline pathogen from an LRT culture taken after completion of the study therapy.

Statistical analysis

Formal statistical testing for significant treatment differences was not performed for any of the secondary per-pathogen endpoints, as it was challenging to justify a fixed control rate and non-inferiority margin for various pathogens. For each treatment difference, 95% CIs were calculated as unstratified Newcombe CIs. Within-group 95% CIs were calculated as unstratified Wilson CIs. Participants with missing mortality data were considered deceased and those with indeterminate response data were considered to have clinical failure or microbiological persistence. All statistical analyses were performed using SAS software (versions 9.3 and 9.4; SAS Institute, Cary NC, USA).

Ethics

The final study protocol, including the final version of the informed consent form, was approved by Institutional Review Boards (Table S2). The study was performed in accordance with the protocol, ethical principles that have their origin in the Declaration of Helsinki and are consistent with the International Conference on Harmonization E6 Good Clinical Practice: Consolidated Guideline, and any applicable local regulations. The investigator or a designee explained the study and informed consent form to the participant or the participant’s legally authorized representative and answered any questions. The informed consent form was signed by the participant or the participant’s legally authorized representative before any study-related procedures were performed.

Results

Baseline pathogens

The mITT population comprised 511 participants—264 participants in the ceftolozane/tazobactam arm (72.9% of ITT participants) and 247 in the meropenem arm (67.9% of ITT participants; Table S3); the ME population included 115 and 118 participants, respectively. Among the 511 participants in the mITT population, the most frequently isolated baseline pathogens were K. pneumoniae (34.6%), P. aeruginosa (25.0%) and E. coli (18.2%; Table S4). The frequency of different baseline LRT specimen collection methods is reported in Figure S1. A total of 699 unique LRT isolates were obtained in the mITT population (Table 1). Overall, 171/457 (37.4%) of all Enterobacterales isolates, 105/176 (59.7%) of K. pneumoniae, 30/93 (32.3%) of E. coli and 21/43 (48.8%) of Proteus mirabilis isolates were ESBL producers. For all Gram-negative baseline LRT pathogens, susceptibility rates were 87.0% for ceftolozane/tazobactam and 93.3% for meropenem; 96.9% and 83.5%, respectively, for P. aeruginosa; 83.6% and 99.8%, respectively, for all Enterobacterales; and 62.0% and 100.0%, respectively, for ESBL-producing Enterobacterales (Table 1). Susceptibility to commonly used non-study agents (including amikacin, cefepime, ceftazidime, levofloxacin, piperacillin/tazobactam and polymyxin B) was similar between study arms (Table S5).

Table 1.

Most common (n ≥ 10) baseline LRT isolates (pooled across both treatment arms) in the mITT population (N = 511), with summary MIC values and susceptibility to both study drugs

Pathogen	Statistic	Ceftolozane/tazobactam	Meropenem
Gram-negative pathogens (overall)	N1	699	697
	MIC range	< 0.064 to ≥256	< 0.064 to ≥256
	MIC₅₀	0.5	< 0.064
	MIC₉₀	16	1
	Susceptible, n/N1 (%)	608/699 (87.0)	650/697 (93.3)
	Intermediate, n/N1 (%)	17/699 (2.4)	5/697 (0.7)
	Resistant, n/N1 (%)	74/699 (10.6)	42/697 (6.0)
P. aeruginosa	N1	127	127
	MIC range	0.125 to ≥256	< 0.064 to 128
	MIC₅₀	1	0.5
	MIC₉₀	2	8
	Susceptible, n/N1 (%)	123/127 (96.9)	106/127 (83.5)
	Intermediate, n/N1 (%)	0/127	5/127 (3.9)
	Resistant, n/N1 (%)	4/127 (3.1)	16/127 (12.6)
AmpC-overexpressing P. aeruginosa	N1	15	15
	MIC range	1–8	0.25–32
	MIC₅₀	2	8
	MIC₉₀	4	32
	Susceptible, n/N1 (%)	15/15 (100)	6/15 (40)
	Intermediate, n/N1 (%)	0/15	1/15 (6.7)
	Resistant, n/N1 (%)	0/15	8/15 (53.3)
Enterobacterales (overall)	N1	456	457
	MIC range	< 0.064 to ≥256	< 0.064 to 16
	MIC₅₀	0.5	< 0.064
	MIC₉₀	16	0.125
	Susceptible, n/N1 (%)	381/456 (83.6)	456/457 (99.8)
	Intermediate, n/N1 (%)	17/456 (3.7)	0/457
	Resistant, n/N (%)	58/456 (12.7)	1/457 (0.2)
ESBL-producing Enterobacterales	N1	171	171
	MIC range	0.25 to ≥256	< 0.064 to 1
	MIC₅₀	2	< 0.064
	MIC₉₀	128	1
	Susceptible, n/N1 (%)	106/171 (62.0)	171/171 (100)
	Intermediate, n/N1 (%)	11/171 (6.4)	0/171
	Resistant, n/N1 (%)	54/171 (31.6)	0/171
K. pneumoniae	N1	175	176
	MIC range	0.125 to ≥256	< 0.064 to 16
	MIC₅₀	2	< 0.064
	MIC₉₀	128	1
	Susceptible, n/N1 (%)	114/175 (65.1)	175/176 (99.4)
	Intermediate, n/N1 (%)	7/175 (4.0)	0/176
	Resistant, n/N1 (%)	54/175 (30.9)	1/176 (0.6)
ESBL-producing K. pneumoniae	N1	105	105
	MIC range	0.25 to ≥256	< 0.064 to 1
	MIC₅₀	8	< 0.064
	MIC₉₀	128	1
	Susceptible, n/N1 (%)	46/105 (43.8)	105/105 (100)
	Intermediate, n/N1 (%)	7/105 (6.7)	0/105
	Resistant, n/N1 (%)	52/105 (49.5)	0/105
E. coli	N1	93	93
	MIC range	0.125–64	< 0.064 to 0.125
	MIC₅₀	0.25	< 0.064
	MIC₉₀	1	< 0.064
	Susceptible, n/N1 (%)	92/93 (98.9)	93/93 (100)
	Intermediate, n/N1 (%)	0/93	0/93
	Resistant, n/N1 (%)	1/93 (1.1)	0/93
ESBL-producing E. coli	N1	30	30
	MIC range	0.25–64	< 0.064 to < 0.064
	MIC₅₀	0.5	< 0.064
	MIC₉₀	1	< 0.064
	Susceptible, n/N1 (%)	29/30 (96.7)	30/30 (100)
	Intermediate, n/N1 (%)	0/30	0/30
	Resistant, n/N1 (%)	1/30 (3.3)	0/30
P. mirabilis	N1	43	43
	MIC range	0.25–8	< 0.064 to 0.125
	MIC₅₀	0.5	< 0.064
	MIC₉₀	4	0.125
	Susceptible, n/N1 (%)	40/43 (93.0)	43/43 (100)
	Intermediate, n/N1 (%)	3/43 (7.0)	0/43
	Resistant, n/N1 (%)	0/43	0/43
ESBL-producing P. mirabilis	N1	21	21
	MIC range	0.5–8	< 0.064 to 0.125
	MIC₅₀	0.5	< 0.064
	MIC₉₀	4	0.125
	Susceptible, n/N1 (%)	19/21 (90.5)	21/21 (100)
	Intermediate, n/N1 (%)	2/21 (9.5)	0/21
	Resistant, n/N1 (%)	0/21	0/21
Enterobacter cloacae	N1	33	33
	MIC range	0.125–8	< 0.064 to 0.125
	MIC₅₀	0.5	< 0.064
	MIC₉₀	8	< 0.064
	Susceptible, n/N1 (%)	29/33 (87.9)	33/33 (100)
	Intermediate, n/N1 (%)	4/33 (12.1)	0/33
	Resistant, n/N1 (%)	0/33	0/33
ESBL-producing E. cloacae	N1	2	2
	MIC range	0.5–8	< 0.064 to < 0.064
	MIC₅₀	0.5	< 0.064
	MIC₉₀	8	< 0.064
	Susceptible, n/N1 (%)	1/2 (50)	2/2 (100)
	Intermediate, n/N1 (%)	1/2 (50.0)	0/2
	Resistant, n/N1 (%)	0/2	0/2
Serratia marcescens	N1	29	29
	MIC range	0.25–16	< 0.064 to 0.5
	MIC₅₀	1	< 0.064
	MIC₉₀	8	< 0.064
	Susceptible, n/N1 (%)	26/29 (89.7)	29/29 (100)
	Intermediate, n/N1 (%)	2/29 (6.9)	0/29
	Resistant, n/N1 (%)	1/29 (3.4)	0/29
ESBL-producing S. marcescens	N1	8	8
	MIC range	0.5–16	< 0.064 to 0.125
	MIC₅₀	4	< 0.064
	MIC₉₀	16	0.125
	Susceptible, n/N1 (%)	6/8 (75.0)	8/8 (100)
	Intermediate, n/N1 (%)	1/8 (12.5)	0/8
	Resistant, n/N1 (%)	1/8 (12.5)	0/8
Klebsiella oxytoca	N1	26	26
	MIC range	0.125–2	< 0.064 to < 0.064
	MIC₅₀	0.25	< 0.064
	MIC₉₀	0.5	< 0.064
	Susceptible, n/N1 (%)	26/26 (100)	26/26 (100)
	Intermediate, n/N1 (%)	0/26	0/26
	Resistant, n/N1 (%)	0/26	0/26
ESBL-producing K. oxytoca	N1	3	3
	MIC range	0.25–1	< 0.064 to < 0.064
	MIC₅₀	0.5	< 0.064
	MIC₉₀	1	< 0.064
	Susceptible, n/N1 (%)	3/3 (100)	3/3 (100)
	Intermediate, n/N1 (%)	0/3	0/3
	Resistant, n/N1 (%)	0/3	0/3
A. baumannii	N1	38	38
	MIC range	< 0.064 to ≥256	< 0.064 to ≥256
	MIC₅₀	4	1
	MIC₉₀	≥256	128
	Susceptible, n/N1 (%)	32/38 (84.2)	25/38 (65.8)
	Intermediate, n/N1 (%)	0/38	0/38
	Resistant, n/N1 (%)	6/38 (15.8)	13/38 (34.2)
H. influenzae	N1	37	35
	MIC range	< 0.064 to 8	< 0.064 to 0.25
	MIC₅₀	0.125	< 0.064
	MIC₉₀	0.5	0.125
	Susceptible, n/N1 (%)	37/37 (100)	35/35 (100)
	Intermediate, n/N1 (%)	0/37	0/35
	Resistant, n/N1 (%)	0/37	0/35

Open in a new tab

N, the number of participants in the mITT population; N1, the number of pathogens with baseline MIC data available.

Percentages are calculated as 100 × (n/N1). The MIC is expressed as mg/L. Each pathogen is counted once per participant and where there are multiple values, the pathogen with highest MIC was used for summaries. Susceptibility interpretation by broth microdilution testing for ceftolozane/tazobactam and meropenem was based on provisional, study-defined breakpoints.

28 day ACM

Per-pathogen 28 day ACM in the mITT population was generally comparable between ceftolozane/tazobactam and meropenem treatment groups [20.1% versus 25.8%; difference 5.8% (−1.62 to 13.2)] and this was consistent regardless of baseline pathogen identified. For the ceftolozane/tazobactam group, mortality rates were somewhat higher for P. aeruginosa [25.4% versus 18.5%; difference −6.9 (−21.08 to 7.42)] and lower for Enterobacterales [19.5% versus 26.5%; difference 7.0 (−1.46 to 15.40)] and H. influenzae [0% versus 12.5%; difference 12.5 (−4.88 to 36.02)] compared with meropenem (Table 2). Among participants in the mITT population with all baseline pathogens susceptible to randomized study drug, 28 day ACM was lower with ceftolozane/tazobactam versus meropenem [15.9% versus 25.6%; difference 9.7 (1.97–17.30)] and per-pathogen 28 day ACM was lower with ceftolozane/tazobactam versus meropenem for Enterobacterales [14.7% versus 25.7%; difference 11.1 (2.21–19.57)] and ESBL-producing Enterobacterales [13.0% versus 29.4%; difference 16.4 (0.57–29.96)], but higher for P. aeruginosa [24.5% versus 19.6%; difference −4.9 (−20.54 to 11.12); Table 3]. Per-participant 28 day ACM for other pathogens is reported in Table 3. Per-participant 28 day ACM in mITT participants with polymicrobial infections involving mixed susceptibility (i.e. ≥ 1 pathogen susceptible and ≥ 1 pathogen resistant) to randomized study drug was 11/48 (22.9%) for ceftolozane/tazobactam and 11/42 (26.2%) for meropenem [difference 3.3 (−14.17 to 20.99)].

Table 2.

Per-pathogen 28 day ACM rates for key baseline LRT pathogens (mITT population)

Pathogen	Ceftolozane/tazobactam	Meropenem	% Difference (95% CI)^a
Pathogen	n/N (%)	n/N (%)	% Difference (95% CI)^a
Gram-negative pathogens (overall)	52/259 (20.1)	62/240 (25.8)	5.8 (−1.62 to 13.12)
Enterobacterales	38/195 (19.5)	49/185 (26.5)	7.0 (−1.46 to 15.40)
ESBL-producing Enterobacterales	18/84 (21.4)	21/73 (28.8)	7.3 (−6.13 to 20.81)
Third-generation cephalosporin-resistant Enterobacterales	18/81 (22.2)	20/72 (27.8)	5.6 (−8.05 to 19.19)
ESBL-producing K. pneumoniae	13/53 (24.5)	12/52 (23.1)	−1.5 (−17.50 to 14.75)
ESBL-producing E. coli	5/20 (25.0)	5/10 (50.0)	25.0 (−9.24 to 54.74)
P. aeruginosa	16/63 (25.4)	12/65 (18.5)	−6.9 (−21.08 to 7.42)
MDR P. aeruginosa	5/24 (20.8)	1/11 (9.1)	−11.7 (−32.75 to 19.16)
XDR P. aeruginosa	2/10 (20.0)	0/5 (0.0)	−20.0 (−50.98 to 25.75)
H. influenzae	0/22 (0)	2/16 (12.5)	12.5 (−4.88 to 36.02)

Open in a new tab

N, number of participants in a specific population of pathogen or pathogen category; n, number of participants in a specific category who died by Day 28.

Unstratified Newcombe CIs. Positive differences are in favour of ceftolozane/tazobactam, while negative differences are in favour of meropenem.

Table 3.

Per-pathogen 28 day ACM, clinical cure and microbiological eradication rates for key baseline LRT pathogens in participants in the mITT population with all pathogens susceptible to study treatment

	Ceftolozane/tazobactam	Meropenem	% Difference (95% CI)^a
	n/N (%)	n/N (%)	% Difference (95% CI)^a
28-day ACM
Enterobacterales	22/150 (14.7)	44/171 (25.7)	11.1 (2.21–19.57)
ESBL-producing Enterobacterales	6/46 (13.0)	20/68 (29.4)	16.4 (0.57–29.96)
P. aeruginosa	13/53 (24.5)	10/51 (19.6)	−4.9 (−20.54 to 11.12)
Clinical cure at TOC
Enterobacterales	99/150 (66.0)	98/171 (57.3)	8.7 (−1.98 to 19.01)
ESBL-producing Enterobacterales	30/46 (65.2)	42/68 (61.8)	3.5 (−14.48 to 20.14)
P. aeruginosa	31/53 (58.5)	30/51 (58.8)	−0.3 (−18.60 to 18.01)
Microbiological eradication at TOC
Enterobacterales	118/150 (78.7)	118/171 (69.0)	9.7 (−0.03 to 18.97)
ESBL-producing Enterobacterales	33/46 (71.7)	48/68 (70.6)	1.2 (−16.00 to 17.16)
P. aeruginosa	41/53 (77.4)	31/51 (60.8)	16.6 (−1.16 to 33.07)

Open in a new tab

N, number of participants in a specific population of pathogen or pathogen category; n, number of participants who had died by Day 28 or with the corresponding clinical or microbiological outcome, depending on the specific category.

Unstratified Newcombe CIs. Positive differences are in favour of ceftolozane/tazobactam, while negative differences are in favour of meropenem.

Clinical response

Per-pathogen clinical cure rates at the TOC visit in the mITT population were high for both ceftolozane/tazobactam and meropenem treatment arms, respectively, against P. aeruginosa [57.1% versus 60.0%; difference −2.9 (−19.36 to 13.84)], Enterobacterales [61.5% versus 56.8%; difference 4.8 (−5.06 to 14.51)] and H. influenzae [86.4% versus 50.0%; difference 36.4 (6.83–60.09); Table 4]. In participants in the mITT population with all baseline pathogens susceptible to randomized study drug, per-pathogen clinical cure rates in the mITT population were also high and comparable between ceftolozane/tazobactam and meropenem for P. aeruginosa [58.5% versus 58.8%; difference −0.3 (−18.60 to 18.01)], Enterobacterales [66.0% versus 57.3%; difference 8.7 (−1.98 to 19.01)] and ESBL-producing Enterobacterales (65.2% versus 61.8%; difference 3.5 (−14.48 to 20.41); Table 3]. In the ME population, ceftolozane/tazobactam was associated with higher clinical cure rates for H. influenzae [91.7% versus 50%; difference 41.7 (2.39–70.96); Table 5]. Per-participant clinical cure rates in mITT participants with polymicrobial infections involving mixed susceptibility to randomized study drug were 25/48 (52.1%) for ceftolozane/tazobactam and 22/42 (52.4%) for meropenem [difference −0.3 (−20.11 to 19.59)].

Table 4.

Per-pathogen clinical cure rates and microbiological eradication rates at TOC for key baseline LRT pathogens (mITT population)

Pathogen	Clinical cure			Microbiological eradication
	Ceftolozane/tazobactam	Meropenem	% Difference	Ceftolozane/tazobactam	Meropenem	% Difference
	n/N (%)	n/N (%)	(95% CI)^a	n/N (%)	n/N (%)	(95% CI)^a
Gram-negative pathogens (overall)	157/259 (60.6)	137/240 (57.1)	3.5 (−5.07 to 12.08)	189/259 (73.0)	163/240 (67.9)	5.1 (−2.93 to 13.01)
Enterobacterales	120/195 (61.5)	105/185 (56.8)	4.8 (−5.06 to 14.51)	145/195 (74.4)	129/185 (69.7)	4.6 (−4.37 to 13.58)
ESBL-producing Enterobacterales	48/84 (57.1)	45/73 (61.6)	−4.5 (−19.33 to 10.74)	56/84 (66.7)	52/73 (71.2)	−4.6 (−8.56 to 9.93)
Ceftazidime-resistant Enterobacterales	46/81 (56.8)	44/72 (61.1)	−4.3 (−19.37 to 11.11)	52/81 (64.2)	52/72 (72.2)	−8.0 (−22.14 to 6.77)
ESBL-producing K. pneumoniae	31/53 (58.5)	34/52 (65.4)	−6.9 (−24.53 to 11.39)	33/53 (62.3)	38/52 (73.1)	−10.8 (−27.67 to 6.99)
ESBL-producing E. coli	11/20 (55.0)	5/10 (50.0)	5.0 (−28.56 to 37.58)	18/20 (90.0)	8/10 (80.0)	10.0 (−14.69 to 41.81)
P. aeruginosa	36/63 (57.1)	39/65 (60.0)	−2.9 (−19.36 to 13.84)	47/63 (74.6)	41/65 (63.1)	11.5 (−4.51 to 26.72)
MDR P. aeruginosa	13/24 (54.2)	6/11 (54.5)	−0.4 (31.19–31.65)	18/24 (75.0)	6/11 (54.5)	20.5 (−10.86 to 50.00)
XDR P. aeruginosa	4/10 (40.0)	2/5 (40.0)	0.0 (−43.60 to 40.29)	6/10 (60.0)	2/5 (40.0)	20.0 (−26.79 to 56.53)
H. influenzae	19/22 (86.4)	8/16 (50.0)	36.4 (6.83–60.09)	20/22 (90.9)	11/16 (68.8)	22.2 (−3.19 to 47.37)

Open in a new tab

N, number of participants in a specific population of pathogen or pathogen category; n, number of participants with the corresponding clinical or microbiological outcome.

Unstratified Newcombe CIs. Positive differences are in favour of ceftolozane/tazobactam, while negative differences are in favour of meropenem.

Table 5.

Per-pathogen clinical cure rates and microbiological eradication rates at TOC for key baseline LRT pathogens (ME population)

Pathogen	Clinical cure			Microbiologic eradication
	Ceftolozane/tazobactam	Meropenem	% Difference	Ceftolozane/tazobactam	Meropenem	% Difference
	n/N (%)	n/N (%)	(95% CI)^a	n/N (%)	n/N (%)	(95% CI)^a
Gram-negative pathogens (overall)	85/113 (75.2)	78/117 (66.7)	8.6 (−3.19 to 19.94)	79/113 (69.9)	73/117 (62.4)	7.5 (−4.69 to 19.38)
Enterobacterales	62/83 (74.7)	58/90 (64.4)	10.3 (−3.50 to 23.36)	57/83 (68.7)	59/90 (65.6)	3.1 (−10.80 to 16.75)
ESBL-producing Enterobacterales	33/45 (73.3)	27/39 (69.2)	4.1 (−14.75 to 23.06)	30/45 (66.7)	27/39 (69.2)	−2.6 (−21.59 to 17.14)
Ceftazidime-resistant Enterobacterales	31/45 (68.9)	26/38 (68.4)	0.5 (−18.71 to 20.12)	27/45 (60.0)	25/38 (65.8)	−5.8 (−25.30 to 14.73)
ESBL-producing K. pneumoniae	22/30 (73.3)	19/27 (70.4)	3.0 (−19.53 to 25.57)	20/30 (66.7)	18/27 (66.7)	0.0 (−23.15 to 23.54)
ESBL-producing E. coli	8/12 (66.7)	5/7 (71.4)	−4.8 (−39.06 to 35.78)	10/12 (83.3)	6/7 (85.7)	−2.4 (−32.86 to 36.53)
P. aeruginosa	23/29 (79.3)	28/38 (73.7)	5.6 (−15.40 to 24.70)	23/29 (79.3)	21/38 (55.3)	24.0 (1.11–43.01)
MDR P. aeruginosa	9/11 (81.8)	4/6 (66.7)	15.2 (−22.67 to 54.07)	9/11 (81.8)	3/6 (50.0)	31.8 (−11.16 to 65.67)
XDR P. aeruginosa	3/5 (60.0)	1/3 (33.3)	26.7 (−32.24 to 65.86)	3/5 (60.0)	1/3 (33.3)	26.7 (−32.24 to 65.86)
H. influenzae	11/12 (91.7)	4/8 (50.0)	41.7 (2.39–70.96)	11/12 (91.7)	4/8 (50.0)	41.7 (2.39–70.96)

Open in a new tab

N, number of participants in a specific population of pathogen or pathogen category; n, number of participants with the corresponding clinical or microbiological outcome.

Unstratified Newcombe CIs. Positive differences are in favour of ceftolozane/tazobactam, while negative differences are in favour of meropenem.

Microbiological response

Per-pathogen microbiological eradication rates at TOC in the mITT population were high against P. aeruginosa [74.6% versus 63.1%; difference 11.5 (−4.51 to 26.72)], Enterobacterales [74.4% versus 69.7%; difference 4.6 (−4.37 to 13.58)] and H. influenzae [90.9% versus 68.8%; difference 22.2 (−3.19 to 47.37)] for ceftolozane/tazobactam and meropenem, respectively (Table 4). Per-pathogen microbiological eradication rates at TOC in the mITT population with all baseline pathogens susceptible to randomized study drug were also high and comparable against P. aeruginosa [77.4% versus 60.8%; difference 16.6 (−1.16 to 33.07)], Enterobacterales [78.7% versus 69.0%; difference 9.7 (−0.03 to 18.97)] and ESBL-producing Enterobacterales (71.7% versus 70.6%; difference 1.2 (−16.00 to 17.16)] with ceftolozane/tazobactam and meropenem, respectively (Table 3). In the ME population, ceftolozane/tazobactam was associated with higher microbiological eradication rates for H. influenzae [91.7% versus 50%; difference 41.7 (2.39–70.96)] and P. aeruginosa [79.3% versus 55.3%; difference 24.0 (1.11–43.01); Table 5]. Per-participant microbiological eradication rates in mITT participants with polymicrobial infections involving mixed susceptibility to randomized study drug were 30/48 (62.5%) for ceftolozane/tazobactam and 28/42 (66.7%) for meropenem [difference −4.2 (−22.92 to 15.31)].

Concordance between clinical and microbiological response

When comparing the percentage of participants who had both a clinical cure and microbiological eradication at TOC, there was high concordance between these outcomes, especially for ceftolozane/tazobactam. In the mITT and ME populations, 92.5% and 90.8% of participants, respectively, had both a clinical cure and microbiological eradication at TOC, respectively, in the ceftolozane/tazobactam arm compared with 88.6% and 83.3% with meropenem (Figure S2). Concordance between participants with both clinical failure and microbiological persistence at TOC was generally much lower in the mITT population.

Other microbiological outcomes

New infections, defined as isolation of a pathogen other than the causative baseline pathogen from an LRT culture obtained after completion of study therapy through to the end-of-study follow-up, in a participant with signs and symptoms of infection,³⁴ were comparable between treatment groups. In the mITT population, 54/264 (20.5%) of ceftolozane/tazobactam-treated and 51/247 (20.6%) of meropenem-treated participants had a superinfection (Table S6), mostly owing to A. baumannii (in 44.4% of ceftolozane/tazobactam-treated and 54.9% of meropenem-treated participants with superinfections), K. pneumoniae (20.4% and 7.8%, respectively) and P. aeruginosa (13.0% and 17.6%, respectively). New infections were reported in 26/264 (9.8%) of ceftolozane/tazobactam-treated and 16/247 (6.5%) of meropenem-treated participants (Table S6), mostly owing to P. aeruginosa (30.8% of ceftolozane/tazobactam-treated and 31.3% of meropenem-treated participants with new infections), K. pneumoniae (26.9% and 18.8%, respectively) and A. baumannii (19.2% and 0%, respectively). There were no notable differences between treatment arms.

Discussion

In the ASPECT-NP Phase 3 trial, a 3 g ceftolozane/tazobactam dose administered q8h was non-inferior to meropenem for the primary endpoint of 28 day ACM and the key secondary endpoint of clinical cure at TOC.²⁷ Due to the potential for differential treatment outcomes according to causative LRT pathogen, such as P. aeruginosa or ESBL-producing Enterobacterales, the ASPECT-NP trial design also included several per-pathogen secondary endpoints, which are presented in this paper. Overall, the results of these analyses, which are based on data from ASPECT-NP, suggest that ceftolozane/tazobactam is an effective treatment for mechanically ventilated patients with HABP/VABP over a range of important causative pathogens. Per-pathogen outcomes with ceftolozane/tazobactam were comparable to those seen with meropenem, which is recommended as a first-line treatment for HABP/VABP according to multiple clinical guidelines.^1,19

The baseline susceptibility of causative pathogens was also as expected based on previous studies.^10,35,36 Susceptibility to commonly used non-study agents (including amikacin, cefepime, ceftazidime, levofloxacin, piperacillin/tazobactam and polymyxin B) was similar between study arms, suggesting that there were no imbalances in terms of more resistant pathogens in either treatment group. Overall susceptibility of baseline LRT isolates to both study drugs was approximately 90%. The baseline susceptibility of P. aeruginosa isolates to ceftolozane/tazobactam was higher than that to meropenem, while the opposite was true for Enterobacterales; in both pathogen groups, susceptibility to ceftolozane/tazobactam and meropenem was >80%. These baseline susceptibility data are consistent with global surveillance studies.^21,37,38 Across all Gram-negative baseline pathogens, the average 28 day ACM in the mITT population ranged from 20% to 30%. For participants with baseline ESBL-producing E. coli, the meropenem arm had a 28 day ACM of 50% compared with 25% for the ceftolozane/tazobactam arm. Mortality was lower in participants with baseline P. aeruginosa infections who received meropenem compared with those who received ceftolozane/tazobactam (18.5% versus 25.4%). In participants with all baseline pathogens susceptible to study drug, ACM was lower for Enterobacterales (11%) and ESBL-producing Enterobacterales (16%) with ceftolozane/tazobactam compared with meropenem. It is possible that mortality rates were due at least in part to death due to underlying comorbidities rather than to E. coli pneumonia. Clinical cure rates were generally comparable across treatment arms in the mITT population, ranging from 50% to 65% depending on the baseline LRT pathogen and treatment. The exceptions included participants with XDR P. aeruginosa, who achieved a clinical cure rate of 40%, regardless of treatment arm, and participants with H. influenzae, who achieved an 86% clinical cure rate with ceftolozane/tazobactam. However, the sample size in each treatment arm was small, with a range of 5–10 participants with XDR P. aeruginosa and 16–22 participants with H. influenzae, so this finding should be interpreted with caution. Similar patterns, but with somewhat higher clinical cure rates across baseline pathogens, were observed in the ME population. Microbiological eradication rates in the mITT and ME populations followed a similar pattern, with lower rates of eradication for XDR and MDR P. aeruginosa and some ESBL-producing Enterobacterales in both treatment arms and higher rates for H. influenzae in the ceftolozane/tazobactam arm. In the ME population, microbiological eradication rates for P. aeruginosa were higher with ceftolozane/tazobactam (approximately 80%) than with meropenem (approximately 55%), but this difference was not reflected in differential clinical response or mortality rates. Superinfections (approximately 20%) and new infections (approximately 10%) occurred with similar frequency in both treatment arms.

From a clinical practice perspective, an important outcome of this study is that ceftolozane/tazobactam yielded treatment outcomes similar to meropenem, in participants with ESBL-producing Enterobacterales, for clinical cure and microbiological eradication in both microbiological analysis populations. High response rates against ESBL-producing pathogens support previous efficacy data from other prospective, randomized, controlled clinical trials evaluating ceftolozane/tazobactam for complicated urinary tract and complicated intra-abdominal infections.^39–41 Previously it has been suggested that infections caused by ESBL-producing pathogens may be more effectively treated with a carbapenem compared with tazobactam-based combination antibacterial agents.⁴² This assumption was primarily based on results from the MERINO trial, which compared piperacillin/tazobactam versus meropenem for the treatment of ceftriaxone-resistant bloodstream infections.⁴³ In that trial, piperacillin/tazobactam was less effective than the carbapenem comparator for reducing mortality and improving clinical and microbiological outcomes. Although the MERINO trial did not evaluate outcomes in participants with HABP/VABP, the results raised concerns about the general use of tazobactam-based combination antibacterial agents for invasive ESBL infections. However, for the treatment of HABP/VABP including infections caused by ESBL-producing pathogens, results of the ASPECT-NP trial suggest that the use of ceftolozane/tazobactam may be appropriate, given that there were no treatment differences for any efficacy outcomes in participants with infections owing to ESBL-producing pathogens. The MERINO trial differed from ASPECT-NP in that it included a more heterogeneous patient population at higher risk for mortality (i.e. immunosuppressed patients and patients with various sources of bacteraemia) compared with ASPECT-NP, which excluded immunosuppressed patients and enrolled only participants with mechanically ventilated NP. A Phase 3 clinical study (NCT04238390) is underway to assess whether ceftolozane/tazobactam is as effective as meropenem with respect to 30 day mortality in the treatment of bloodstream infection caused by third-generation non-susceptible Enterobacterales or a known chromosomal AmpC-producing Enterobacterales.

Certain limitations should be considered when evaluating the results of this analysis. The study was not specifically designed to evaluate per-pathogen outcomes. The participant sample sizes across baseline pathogen subgroups varied, and in subgroups with small denominators, such as XDR P. aeruginosa, the differences between treatment arms should be interpreted with caution. Also notable is that all participants in ASPECT-NP were mechanically ventilated and therefore had a high risk of adverse treatment outcomes, which could contribute to generally lower response rates than would have been expected from a population with less severe illness.

In summary, ceftolozane/tazobactam was an effective treatment for HABP/VABP in the high-risk population of mechanically ventilated adults, regardless of the pathogen identified. Ceftolozane/tazobactam demonstrated 28 day ACM, clinical cure and microbiological eradication rates comparable to meropenem in participants with infections owing to a variety of Gram-negative LRT pathogens, mainly P. aeruginosa, including MDR and XDR strains, and Enterobacterales, including ESBL producers. For P. aeruginosa and H. influenzae, microbiological eradication was significantly improved with ceftolozane/tazobactam versus meropenem, although the populations were small. Based on these results, ceftolozane/tazobactam appears to be an effective treatment option for HABP/VABP, including infections caused by P. aeruginosa or ESBL-producing Enterobacterales.

Supplementary Material

dkab494_Supplementary_Data

Click here for additional data file.^{(170KB, docx)}

Acknowledgements

We thank the participants and their families and caregivers for participating in this study, along with all investigators and site personnel. We would also like to thank Carisa D. De Anda, PharmD, for critically reviewing the study report. A subset of the data in this manuscript was presented at the 29^th ECCMID Congress in Amsterdam, The Netherlands, 13–16 April 2019, Abstract O0302.

Contributor Information

Ignacio Martin-Loeches, St James’s Hospital, Trinity College Dublin, James Street, Dublin 8, Ireland; Universitat de Barcelona, IDIBAPS, CIBERes, Barcelona, Spain.

Jean-François Timsit, UMR 1137, IAME, Université Paris Diderot, F75018, Paris, France.

Marin H. Kollef, Washington University School of Medicine, 4523 Clayton Ave, Campus Box 8052, St. Louis, MO 63110, USA

Richard G. Wunderink, Northwestern University Feinberg School of Medicine, 303 East Superior St, Simpson Querrey 5th Floor, Suite 5-301, Chicago, IL 60611, USA

Nobuaki Shime, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.

Martin Nováček, General Hospital of Kolin, Zizkova 146, Kolin 3, 280 00, Czech Republic.

Ülo Kivistik, North Estonia Medical Centre Foundation, Sütiste tee 19, Tallinn, Harjumaa 13419, Estonia.

Álvaro Réa-Neto, Universidade Federal do Paraná, Rua XV de Novembro, 1299 – Centro, Curitiba – PR, 80060-000, Brazil.

Christopher J. Bruno, Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA

Jennifer A. Huntington, Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA

Gina Lin, Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.

Erin H. Jensen, Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA

Mary Motyl, Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.

Brian Yu, Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.

Davis Gates, Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA.

Joan R. Butterton, Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA

Elizabeth G. Rhee, Merck & Co., Inc., 2000 Galloping Hill Rd, Kenilworth, NJ 07033, USA

Funding

Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD). Medical writing assistance was provided by Dominik Wolf, MSc, of MSD, and Susan E. DeRocco, PhD, of The Lockwood Group, Stamford, CT, USA. This assistance was funded by MSD.

Transparency declarations

Employees of the funder, including several of the co-authors, were involved in the design, execution, analysis or reporting of the research. All authors had full access to the study data and take joint responsibility for this article. I.M.-L. has received institutional research funding from MSD and has also received personal fees from MSD, Pfizer, bioMérieux and Gilead, and grants from Grifols. J.-F.T. has received institutional research funding from MSD and has also received grants from MSD, bioMérieux and Brahms, and personal fees from MSD, Pfizer, Gilead, Becton, Dickinson and Company, Shionogi and Nabriva. M.H.K. has received institutional research funding from MSD and has also received advisory board and speaker’s bureau fees from MSD. R.G.W. has received institutional research funding from MSD and has also received grants and personal fees from MSD, Shionogi, Polyphor, Melinta, The Medicines Company and Arsanis, and personal fees from Microbiotix, KBP Biosciences and Meiji Seika. N.S. has received institutional research funding from MSD and has also received lecture fees from MSD. M.N., Ü.K. and Á.R.-N have received investigator fees and institutional research funding from MSD. C.J.B., J.A.H., G.L., E.H.J., M.M., B.Y., D.G., J.R.B. and E.G.R. are employees of MSD and may hold stock and/or stock options in Merck & Co., Inc., Kenilworth, NJ, USA. None of the authors received any reimbursement for preparing this article.

Author contributions

Contributions to data collection: I.M.-L, R.G.W., N.S., M.N., Á.R.-N., J.A.H. and B.Y. Contributions to data analysis: I.M.-L., J.-F.T., M.H.K., R.G.W., C.J.B., J.A.H., G.L., E.H.J., J.B. and D.G. Contributions to data interpretation: I.M.-L, J.-F.T., M.H.K., R.G.W., Ü.K., C.J.B., J.A.H., G.L., E.H.J., M.M., B.Y., D.G., J.R.B. and E.G.R. Contributions to manuscript writing: all authors. All authors were involved in critically reviewing manuscript drafts and approving the final version for submission.

All authors are responsible for the work described in this paper. All authors were involved in at least one of the following: (i) conception, design of work or acquisition, analysis, interpretation of data; and (ii) drafting the manuscript and/or revising/reviewing the manuscript for important intellectual content. All authors provided the final approval of the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Supplementary data

Tables S1 to S6 are available as Supplementary data at JAC Online.

References

1. Kalil AC, Metersky ML, Klompas M et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016; 63: e61–111. [DOI] [PMC free article] [PubMed] [Google Scholar]
2. Melsen WG, Rovers MM, Groenwold RHH et al. Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis 2013; 13: 665–71. [DOI] [PubMed] [Google Scholar]
3. Talbot GH, Das A, Cush S et al. Evidence-based study design for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. J Infect Dis 2019; 10: 1536–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
4. Borgatta B, Gattarello S, Mazo CA et al. The clinical significance of pneumonia in patients with respiratory specimens harbouring multidrug-resistant Pseudomonas aeruginosa: a 5-year retrospective study following 5667 patients in four general ICUs. Eur J Clin Microbiol Infect Dis 2017; 36: 2155–63. [DOI] [PubMed] [Google Scholar]
5. Tedja R, Nowacki A, Fraser T et al. The impact of multidrug resistance on outcomes in ventilator-associated pneumonia. Am J Infect Control 2014; 42: 542–5. [DOI] [PubMed] [Google Scholar]
6. Timsit J-F, Pilmis B, Zahar J-R. How should we treat hospital-acquired and ventilator-associated pneumonia caused by extended-spectrum β-lactamase-producing Enterobacteriaceae? Semin Respir Crit Care Med 2017; 38: 287–300. [DOI] [PubMed] [Google Scholar]
7. Kaye KS, Pogue JM. Infections caused by resistant Gram-negative bacteria: epidemiology and management. Pharmacotherapy 2015; 35: 949–62. [DOI] [PubMed] [Google Scholar]
8. Carvalhaes CG, Castanheira M, Sader HS et al. Antimicrobial activity of ceftolozane-tazobactam tested against gram-negative contemporary (2015-2017) isolates from hospitalized patients with pneumonia in US medical centers. Diagn Microbiol Infect Dis 2019; 94: 93–102. [DOI] [PubMed] [Google Scholar]
9. Sader HS, Castanheira M, Mendes RE et al. Frequency and antimicrobial susceptibility of Gram-negative bacteria isolated from patients with pneumonia hospitalized in ICUs of US medical centres (2015–17). J Antimicrob Chemother 2018; 73: 3053–9. [DOI] [PubMed] [Google Scholar]
10. Sader HS, Castanheira M, Flamm RK. Antimicrobial activity of ceftazidime-avibactam against Gram-negative bacteria isolated from patients hospitalized with pneumonia in U.S. medical centers, 2011 to 2015. Antimicrob Agents Chemother 2017; 61: e02083-16. [DOI] [PMC free article] [PubMed] [Google Scholar]
11. Rosenthal VD, Al-Abdely HM, El-Kholy AA et al. International Nosocomial Infection Control Consortium report, data summary of 50 countries for 2010-2015: device-associated module. Am J Infect Control 2016; 44: 1495–504. [DOI] [PubMed] [Google Scholar]
12. Rosenthal VD, Maki DG, Mehta Y et al. International Nosocomial Infection Control Consortium (INICC) report, data summary of 43 countries for 2007-2012. Device-associated module. Am J Infect Control 2014; 42: 942–56. [DOI] [PubMed] [Google Scholar]
13. Sader HS, Farrell DJ, Flamm RK et al. Antimicrobial susceptibility of Gram-negative organisms isolated from patients hospitalised with pneumonia in US and European hospitals: results from the SENTRY Antimicrobial Surveillance Program, 2009-2012. Int J Antimicrob Agents 2014; 43: 328–34. [DOI] [PubMed] [Google Scholar]
14. Vincent J-L, Sakr Y, Singer M et al. Prevalence and outcomes of infection among patients in intensive care units in 2017. JAMA 2020; 323: 1478–87. [DOI] [PMC free article] [PubMed] [Google Scholar]
15. Kumar A, Ellis P, Arabi Y et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009; 136: 1237–48. [DOI] [PubMed] [Google Scholar]
16. Funk DJ, Kumar A. Antimicrobial therapy for life-threatening infections: speed is life. Crit Care Clin 2011; 27: 53–76. [DOI] [PubMed] [Google Scholar]
17. Kethireddy S, Bilgili B, Sees A et al. Culture-negative septic shock compared with culture-positive septic shock: a retrospective cohort study. Crit Care Med 2018; 46: 506–12. [DOI] [PubMed] [Google Scholar]
18. Kelly DN, Martin-Loeches I. Comparing current US and European guidelines for nosocomial pneumonia. Curr Opin Pulm Med 2019; 25: 263–70. [DOI] [PubMed] [Google Scholar]
19. Torres A, Niederman MS, Chastre J et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociacion Latinoamericana del Torax (ALAT). Eur Respir J 2017; 50: 1700582. [DOI] [PubMed] [Google Scholar]
20. ZERBAXA® (ceftolozane and tazobactam) for injection, for intravenous use . Prescribing Information. Merck Sharp & Dohme Corp, 2020. https://www.merck.com/product/usa/pi_circulars/z/zerbaxa/zerbaxa_pi.pdf. [Google Scholar]
21. Castanheira M, Duncan LR, Mendes RE et al. Activity of ceftolozane-tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae isolates collected from respiratory tract specimens of hospitalized patients in the United States during 2013 to 2015. Antimicrob Agents Chemother 2018; 62: e02125-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
22. Shortridge D, Pfaller MA, Castanheira M et al. Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa collected from patients with bloodstream infections isolated in United States hospitals (2013-2015) as part of the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) surveillance program. Diagn Microbiol Infect Dis 2018; 92: 158–63. [DOI] [PubMed] [Google Scholar]
23. Karlowsky JA, Lob SH, Young K et al. Activity of ceftolozane/tazobactam against Gram-negative isolates from patients with lower respiratory tract infections - SMART United States 2018-2019. BMC Microbiol 2021; 21: 74. [DOI] [PMC free article] [PubMed] [Google Scholar]
24. Karlowsky JA, Kazmierczak KM, Young K et al. In vitro activity of ceftolozane/tazobactam against phenotypically defined extended-spectrum β-lactamase (ESBL)-positive isolates of Escherichia coli and Klebsiella pneumoniae isolated from hospitalized patients (SMART 2016). Diagn Microbiol Infect Dis 2020; 96: 114925. [DOI] [PubMed] [Google Scholar]
25. Chandorkar G, Huntington JA, Gotfried MH et al. Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects. J Antimicrob Chemother 2012; 67: 2463–9. [DOI] [PubMed] [Google Scholar]
26. Caro L, Nicolau DP, De Waele JJ et al. Lung penetration, bronchopulmonary pharmacokinetic/pharmacodynamic profile and safety of 3 g of ceftolozane/tazobactam administered to ventilated, critically ill patients with pneumonia. J Antimicrob Chemother 2020; 75: 1546–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
27. Kollef MH, Novacek M, Kivistik U et al. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2019; 19: 1299–311. [DOI] [PubMed] [Google Scholar]
28. Xiao AJ, Miller BW, Huntington JA et al. Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. J Clin Pharmacol 2016; 56: 56–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Rodvold KA, Hope WW, Boyd SE. Considerations for effect site pharmacokinetics to estimate drug exposure: concentrations of antibiotics in the lung. Curr Opin Pharmacol 2017; 36: 114–23. [DOI] [PubMed] [Google Scholar]
30. Puzniak L, Dillon R, Palmer T et al. Systematic literature review of real-world evidence of ceftolozane/tazobactam for the treatment of respiratory infections. Infect Dis Ther 2021; 10: 1227–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
31. CLSI . Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Eleventh Edition: M07. 2018. [Google Scholar]
32. CLSI . Performance Standards for Antimicrobial Susceptibility Testing—Twenty-Eighth Edition: M100. 2018. [Google Scholar]
33. Castanheira M, Johnson MG, Yu B et al. Molecular characterization of baseline Enterobacterales and Pseudomonas aeruginosa isolates from a phase 3 nosocomial pneumonia (ASPECT-NP) clinical trial. Antimicrob Agents Chemother 2021; 65: e02461-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Johnson MG, Bruno C, Castanheira M et al. Evaluating the emergence of nonsusceptibility among Pseudomonas aeruginosa respiratory isolates from a phase-3 clinical trial for treatment of nosocomial pneumonia (ASPECT-NP). Int J Antimicrob Agents 2021; 57: 106278. [DOI] [PubMed] [Google Scholar]
35. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis 2010; 51 Suppl 1: S81–7. [DOI] [PubMed] [Google Scholar]
36. Weiner LM, Webb AK, Limbago B et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011-2014. Infect Control Hosp Epidemiol 2016; 37: 1288–301. [DOI] [PMC free article] [PubMed] [Google Scholar]
37. Shortridge D, Pfaller MA, Arends SJR et al. Comparison of the in vitro susceptibility of ceftolozane-tazobactam with the cumulative susceptibility rates of standard antibiotic combinations when tested against Pseudomonas aeruginosa from ICU patients with bloodstream infections or pneumonia. Open Forum Infect Dis 2019; 6: ofz240. [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Shortridge D, Pfaller MA, Streit JM et al. Antimicrobial activity of ceftolozane/tazobactam tested against contemporary (2015-2017) Pseudomonas aeruginosa isolates from a global surveillance programme. J Glob Antimicrob Resist 2020; 21: 60–4. [DOI] [PubMed] [Google Scholar]
39. Mikamo H, Monden K, Miyasaka Y et al. The efficacy and safety of tazobactam/ceftolozane in combination with metronidazole in Japanese patients with complicated intra-abdominal infections. J Infect Chemother 2019; 25: 111–6. [DOI] [PubMed] [Google Scholar]
40. Solomkin J, Hershberger E, Miller B et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis 2015; 60: 1462–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
41. Wagenlehner FM, Umeh O, Steenbergen J et al. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet 2015; 385: 1949–56. [DOI] [PubMed] [Google Scholar]
42. Pogue JM, Heil EL. Laces out Dan! The role of tazobactam based combinations for invasive ESBL infections in a post-MERINO world. Expert Opin Pharmacother 2019; 20: 2053–57. [DOI] [PubMed] [Google Scholar]
43. Harris PNA, Tambyah PA, Lye DC et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA 2018; 320: 984–94. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

dkab494_Supplementary_Data

Click here for additional data file.^{(170KB, docx)}

[dkab494-B1] 1. Kalil AC, Metersky ML, Klompas M et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis 2016; 63: e61–111. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B2] 2. Melsen WG, Rovers MM, Groenwold RHH et al. Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis 2013; 13: 665–71. [DOI] [PubMed] [Google Scholar]

[dkab494-B3] 3. Talbot GH, Das A, Cush S et al. Evidence-based study design for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. J Infect Dis 2019; 10: 1536–44. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B4] 4. Borgatta B, Gattarello S, Mazo CA et al. The clinical significance of pneumonia in patients with respiratory specimens harbouring multidrug-resistant Pseudomonas aeruginosa: a 5-year retrospective study following 5667 patients in four general ICUs. Eur J Clin Microbiol Infect Dis 2017; 36: 2155–63. [DOI] [PubMed] [Google Scholar]

[dkab494-B5] 5. Tedja R, Nowacki A, Fraser T et al. The impact of multidrug resistance on outcomes in ventilator-associated pneumonia. Am J Infect Control 2014; 42: 542–5. [DOI] [PubMed] [Google Scholar]

[dkab494-B6] 6. Timsit J-F, Pilmis B, Zahar J-R. How should we treat hospital-acquired and ventilator-associated pneumonia caused by extended-spectrum β-lactamase-producing Enterobacteriaceae? Semin Respir Crit Care Med 2017; 38: 287–300. [DOI] [PubMed] [Google Scholar]

[dkab494-B7] 7. Kaye KS, Pogue JM. Infections caused by resistant Gram-negative bacteria: epidemiology and management. Pharmacotherapy 2015; 35: 949–62. [DOI] [PubMed] [Google Scholar]

[dkab494-B8] 8. Carvalhaes CG, Castanheira M, Sader HS et al. Antimicrobial activity of ceftolozane-tazobactam tested against gram-negative contemporary (2015-2017) isolates from hospitalized patients with pneumonia in US medical centers. Diagn Microbiol Infect Dis 2019; 94: 93–102. [DOI] [PubMed] [Google Scholar]

[dkab494-B9] 9. Sader HS, Castanheira M, Mendes RE et al. Frequency and antimicrobial susceptibility of Gram-negative bacteria isolated from patients with pneumonia hospitalized in ICUs of US medical centres (2015–17). J Antimicrob Chemother 2018; 73: 3053–9. [DOI] [PubMed] [Google Scholar]

[dkab494-B10] 10. Sader HS, Castanheira M, Flamm RK. Antimicrobial activity of ceftazidime-avibactam against Gram-negative bacteria isolated from patients hospitalized with pneumonia in U.S. medical centers, 2011 to 2015. Antimicrob Agents Chemother 2017; 61: e02083-16. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B11] 11. Rosenthal VD, Al-Abdely HM, El-Kholy AA et al. International Nosocomial Infection Control Consortium report, data summary of 50 countries for 2010-2015: device-associated module. Am J Infect Control 2016; 44: 1495–504. [DOI] [PubMed] [Google Scholar]

[dkab494-B12] 12. Rosenthal VD, Maki DG, Mehta Y et al. International Nosocomial Infection Control Consortium (INICC) report, data summary of 43 countries for 2007-2012. Device-associated module. Am J Infect Control 2014; 42: 942–56. [DOI] [PubMed] [Google Scholar]

[dkab494-B13] 13. Sader HS, Farrell DJ, Flamm RK et al. Antimicrobial susceptibility of Gram-negative organisms isolated from patients hospitalised with pneumonia in US and European hospitals: results from the SENTRY Antimicrobial Surveillance Program, 2009-2012. Int J Antimicrob Agents 2014; 43: 328–34. [DOI] [PubMed] [Google Scholar]

[dkab494-B14] 14. Vincent J-L, Sakr Y, Singer M et al. Prevalence and outcomes of infection among patients in intensive care units in 2017. JAMA 2020; 323: 1478–87. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B15] 15. Kumar A, Ellis P, Arabi Y et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest 2009; 136: 1237–48. [DOI] [PubMed] [Google Scholar]

[dkab494-B16] 16. Funk DJ, Kumar A. Antimicrobial therapy for life-threatening infections: speed is life. Crit Care Clin 2011; 27: 53–76. [DOI] [PubMed] [Google Scholar]

[dkab494-B17] 17. Kethireddy S, Bilgili B, Sees A et al. Culture-negative septic shock compared with culture-positive septic shock: a retrospective cohort study. Crit Care Med 2018; 46: 506–12. [DOI] [PubMed] [Google Scholar]

[dkab494-B18] 18. Kelly DN, Martin-Loeches I. Comparing current US and European guidelines for nosocomial pneumonia. Curr Opin Pulm Med 2019; 25: 263–70. [DOI] [PubMed] [Google Scholar]

[dkab494-B19] 19. Torres A, Niederman MS, Chastre J et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociacion Latinoamericana del Torax (ALAT). Eur Respir J 2017; 50: 1700582. [DOI] [PubMed] [Google Scholar]

[dkab494-B20] 20. ZERBAXA® (ceftolozane and tazobactam) for injection, for intravenous use . Prescribing Information. Merck Sharp & Dohme Corp, 2020. https://www.merck.com/product/usa/pi_circulars/z/zerbaxa/zerbaxa_pi.pdf. [Google Scholar]

[dkab494-B21] 21. Castanheira M, Duncan LR, Mendes RE et al. Activity of ceftolozane-tazobactam against Pseudomonas aeruginosa and Enterobacteriaceae isolates collected from respiratory tract specimens of hospitalized patients in the United States during 2013 to 2015. Antimicrob Agents Chemother 2018; 62: e02125-17. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B22] 22. Shortridge D, Pfaller MA, Castanheira M et al. Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa collected from patients with bloodstream infections isolated in United States hospitals (2013-2015) as part of the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS) surveillance program. Diagn Microbiol Infect Dis 2018; 92: 158–63. [DOI] [PubMed] [Google Scholar]

[dkab494-B23] 23. Karlowsky JA, Lob SH, Young K et al. Activity of ceftolozane/tazobactam against Gram-negative isolates from patients with lower respiratory tract infections - SMART United States 2018-2019. BMC Microbiol 2021; 21: 74. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B24] 24. Karlowsky JA, Kazmierczak KM, Young K et al. In vitro activity of ceftolozane/tazobactam against phenotypically defined extended-spectrum β-lactamase (ESBL)-positive isolates of Escherichia coli and Klebsiella pneumoniae isolated from hospitalized patients (SMART 2016). Diagn Microbiol Infect Dis 2020; 96: 114925. [DOI] [PubMed] [Google Scholar]

[dkab494-B25] 25. Chandorkar G, Huntington JA, Gotfried MH et al. Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects. J Antimicrob Chemother 2012; 67: 2463–9. [DOI] [PubMed] [Google Scholar]

[dkab494-B26] 26. Caro L, Nicolau DP, De Waele JJ et al. Lung penetration, bronchopulmonary pharmacokinetic/pharmacodynamic profile and safety of 3 g of ceftolozane/tazobactam administered to ventilated, critically ill patients with pneumonia. J Antimicrob Chemother 2020; 75: 1546–53. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B27] 27. Kollef MH, Novacek M, Kivistik U et al. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis 2019; 19: 1299–311. [DOI] [PubMed] [Google Scholar]

[dkab494-B28] 28. Xiao AJ, Miller BW, Huntington JA et al. Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia. J Clin Pharmacol 2016; 56: 56–66. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B29] 29. Rodvold KA, Hope WW, Boyd SE. Considerations for effect site pharmacokinetics to estimate drug exposure: concentrations of antibiotics in the lung. Curr Opin Pharmacol 2017; 36: 114–23. [DOI] [PubMed] [Google Scholar]

[dkab494-B30] 30. Puzniak L, Dillon R, Palmer T et al. Systematic literature review of real-world evidence of ceftolozane/tazobactam for the treatment of respiratory infections. Infect Dis Ther 2021; 10: 1227–52. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B31] 31. CLSI . Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically—Eleventh Edition: M07. 2018. [Google Scholar]

[dkab494-B32] 32. CLSI . Performance Standards for Antimicrobial Susceptibility Testing—Twenty-Eighth Edition: M100. 2018. [Google Scholar]

[dkab494-B33] 33. Castanheira M, Johnson MG, Yu B et al. Molecular characterization of baseline Enterobacterales and Pseudomonas aeruginosa isolates from a phase 3 nosocomial pneumonia (ASPECT-NP) clinical trial. Antimicrob Agents Chemother 2021; 65: e02461-20. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B34] 34. Johnson MG, Bruno C, Castanheira M et al. Evaluating the emergence of nonsusceptibility among Pseudomonas aeruginosa respiratory isolates from a phase-3 clinical trial for treatment of nosocomial pneumonia (ASPECT-NP). Int J Antimicrob Agents 2021; 57: 106278. [DOI] [PubMed] [Google Scholar]

[dkab494-B35] 35. Jones RN. Microbial etiologies of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Clin Infect Dis 2010; 51 Suppl 1: S81–7. [DOI] [PubMed] [Google Scholar]

[dkab494-B36] 36. Weiner LM, Webb AK, Limbago B et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2011-2014. Infect Control Hosp Epidemiol 2016; 37: 1288–301. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B37] 37. Shortridge D, Pfaller MA, Arends SJR et al. Comparison of the in vitro susceptibility of ceftolozane-tazobactam with the cumulative susceptibility rates of standard antibiotic combinations when tested against Pseudomonas aeruginosa from ICU patients with bloodstream infections or pneumonia. Open Forum Infect Dis 2019; 6: ofz240. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B38] 38. Shortridge D, Pfaller MA, Streit JM et al. Antimicrobial activity of ceftolozane/tazobactam tested against contemporary (2015-2017) Pseudomonas aeruginosa isolates from a global surveillance programme. J Glob Antimicrob Resist 2020; 21: 60–4. [DOI] [PubMed] [Google Scholar]

[dkab494-B39] 39. Mikamo H, Monden K, Miyasaka Y et al. The efficacy and safety of tazobactam/ceftolozane in combination with metronidazole in Japanese patients with complicated intra-abdominal infections. J Infect Chemother 2019; 25: 111–6. [DOI] [PubMed] [Google Scholar]

[dkab494-B40] 40. Solomkin J, Hershberger E, Miller B et al. Ceftolozane/tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis 2015; 60: 1462–71. [DOI] [PMC free article] [PubMed] [Google Scholar]

[dkab494-B41] 41. Wagenlehner FM, Umeh O, Steenbergen J et al. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind, phase 3 trial (ASPECT-cUTI). Lancet 2015; 385: 1949–56. [DOI] [PubMed] [Google Scholar]

[dkab494-B42] 42. Pogue JM, Heil EL. Laces out Dan! The role of tazobactam based combinations for invasive ESBL infections in a post-MERINO world. Expert Opin Pharmacother 2019; 20: 2053–57. [DOI] [PubMed] [Google Scholar]

[dkab494-B43] 43. Harris PNA, Tambyah PA, Lye DC et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA 2018; 320: 984–94. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Clinical and microbiological outcomes, by causative pathogen, in the ASPECT-NP randomized, controlled, Phase 3 trial comparing ceftolozane/tazobactam and meropenem for treatment of hospital-acquired/ventilator-associated bacterial pneumonia

Ignacio Martin-Loeches

Jean-François Timsit

Marin H Kollef

Richard G Wunderink

Nobuaki Shime

Martin Nováček

Ülo Kivistik

Álvaro Réa-Neto

Christopher J Bruno

Jennifer A Huntington

Gina Lin

Erin H Jensen

Mary Motyl

Brian Yu

Davis Gates

Joan R Butterton

Elizabeth G Rhee

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Participants and methods

Study design overview

Inclusion and exclusion criteria

Study treatments

Microbiological assessments

Outcomes

Statistical analysis

Ethics

Results

Baseline pathogens

Table 1.

28 day ACM

Table 2.

Table 3.

Clinical response

Table 4.

Table 5.

Microbiological response

Concordance between clinical and microbiological response

Other microbiological outcomes

Discussion

Supplementary Material

Acknowledgements

Contributor Information

Funding

Transparency declarations

Author contributions

Supplementary data

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases