Frequency and antimicrobial susceptibility of Gram-negative bacteria isolated from patients with pneumonia hospitalized in ICUs of US medical centres (2015–17)

Abstract

Background

Treatment of infections in the ICU represents a great challenge, especially infections caused by Gram-negative organisms. Rapid introduction of appropriate antimicrobial therapy is crucial to reduce mortality, and resistance rates in the ICU can be elevated due to antimicrobial selection pressure.

Objectives

To evaluate the frequency and antimicrobial susceptibility of Gram-negative bacteria isolated from patients with pneumonia hospitalized in ICUs.

Methods

A total of 6091 bacterial isolates were consecutively collected from 75 US medical centres in 2015–17 as part of the International Network for Optimal Resistance Monitoring (INFORM) programme and tested for susceptibility to multiple antimicrobial agents at a central laboratory by reference broth microdilution methods.

Results

The most common organisms were Staphylococcus aureus (30.0%), Pseudomonas aeruginosa (20.7%), Klebsiella spp. (11.8%), Enterobacter spp. (8.3%), Escherichia coli (7.1%) and Stenotrophomonas maltophilia (5.1%). Colistin (99.8% susceptible), ceftazidime/avibactam (96.8% susceptible in 2015–17 and 96.2% in 2017) and ceftolozane/tazobactam (96.5% susceptible in 2017) were the most active compounds against P. aeruginosa. Ceftazidime/avibactam (100.0% susceptible), amikacin (99.4% susceptible) and meropenem (97.6% susceptible) were the most active compounds against Enterobacteriaceae. S. maltophilia and Acinetobacter baumannii exhibited high resistance rates to most antimicrobials tested.

Conclusions

Gram-negative bacteria were isolated from 67.1% of the patients and P. aeruginosa and Enterobacteriaceae represented >80% of these organisms. Ceftazidime/avibactam and amikacin provided the best coverage against Gram-negative organisms overall.

Introduction

Pneumonia is the second most common infection in hospitalized patients and it is associated with significant morbidity and mortality. The initial antimicrobial management of patients with pneumonia is determined mostly by the understanding of causative pathogens and there is very little current information regarding the frequency and antimicrobial susceptibility of organisms causing healthcare-associated pneumonia.^1,2 Although Staphylococcus aureus is a significant cause of pneumonia in hospitalized patients, the importance of Gram-negative organisms such as Pseudomonas aeruginosa and Enterobacteriaceae species, mainly Klebsiella pneumoniae, Enterobacter spp. and Escherichia coli, has increased substantially in recent years.^3–5

The choice of antimicrobial treatment of pneumonia is based on various factors, including recommendations from guidelines and evidence-based reviews,^2,6 as well as local and/or regional data on frequency of occurrence and antimicrobial susceptibility.^3–5 For decades, the foundation for the antimicrobial treatment of pneumonia has been drugs from the β-lactam class;⁷ however, the emergence and wide spread of ESBLs and carbapenemases, such as KPC, have limited the clinical utility of β-lactams in recent years.^8,9

Infections caused by MDR Gram-negative bacteria represent the most difficult challenges faced by physicians. Most of these organisms harbour various β-lactamase genes and resistance determinants for other antimicrobial classes. Although a variety of non-β-lactam agents are being developed, numerous investigational approaches involve both established and new β-lactamase inhibitors in novel combinations and a few of these compounds have been recently approved for clinical use in the USA. In the present study, we evaluated the frequency and antimicrobial susceptibility of Gram-negative bacteria isolated from patients hospitalized with pneumonia in ICUs of US medical centres. We assessed the activity and spectrum of two recently approved β-lactamase inhibitor combinations, ceftazidime/avibactam and ceftolozane/tazobactam,^10,11 and many other antimicrobial agents currently used to treat pneumonia.

Materials and methods

Bacterial isolates

A total of 6091 bacterial isolates were collected from 75 US medical centres in 36 states from all nine US census divisions in 2015–17 as part of the International Network for Optimal Resistance Monitoring (INFORM) programme. The INFORM programme monitors the in vitro activity of ceftazidime/avibactam and numerous antimicrobial agents against Enterobacteriaceae and P. aeruginosa isolates worldwide. In the USA, bacterial isolates are consecutively collected (one per infection episode) according to the infection type and sent to a monitoring laboratory (JMI Laboratories, North Liberty, IA, USA) where they are tested for susceptibility by reference broth microdilution methods to most antimicrobial agents currently used to treat systemic Gram-negative infections.¹² The isolates evaluated in this investigation were collected from patients with pneumonia hospitalized in an ICU. Each participating centre was requested to collect consecutive bacterial isolates from lower respiratory tract sites determined to be significant by local criteria as the reported probable cause of pneumonia. Only isolates from invasive sampling (transtracheal aspiration, bronchoalveolar lavage, protected brush samples, qualified sputum samples etc.) were accepted. Although all bacterial species were collected, the INFORM programme only evaluates the antimicrobial susceptibility of Gram-negative organisms. Species identification was confirmed by standard biochemical tests and using the MALDI-TOF Biotyper (Bruker Daltonics, Billerica, MA, USA) according to the manufacturer instructions, where necessary.

Resistant subsets

Isolates were categorized as MDR and XDR according to criteria published by Magiorakos et al.,¹³ which define MDR as non-susceptible to ≥1 agent in ≥3 antimicrobial classes and XDR as non-susceptible to ≥1 agent in all but ≤2 antimicrobial classes. Isolates were categorized as non-susceptible as per CLSI (document M100)¹⁴ or FDA criteria where CLSI breakpoints were not available. The antimicrobial classes and drug representatives used in the analysis for Enterobacteriaceae were: broad-spectrum cephalosporins (ceftriaxone, ceftazidime and cefepime), carbapenems (imipenem, meropenem and doripenem), broad-spectrum penicillins combined with a β-lactamase inhibitor (piperacillin/tazobactam), fluoroquinolones (ciprofloxacin and levofloxacin), aminoglycosides (gentamicin, tobramycin and amikacin), glycylcyclines (tigecycline) and the polymyxins (colistin; EUCAST criteria). The antimicrobial classes and drug representatives used in the analysis for P. aeruginosa were: antipseudomonal cephalosporins (ceftazidime and cefepime), carbapenems (imipenem, meropenem and doripenem), broad-spectrum penicillins combined with a β-lactamase inhibitor (piperacillin/tazobactam), fluoroquinolones (ciprofloxacin and levofloxacin), aminoglycosides (gentamicin, tobramycin and amikacin) and the polymyxins (colistin). Additionally, the definition of carbapenem-resistant Enterobacteriaceae (CRE) was resistant [MIC ≥4 mg/L (CLSI)] to imipenem (imipenem was not applied to Proteus mirabilis or to indole-positive Proteeae), meropenem or doripenem.

Susceptibility testing

Antimicrobial susceptibility was evaluated by reference broth microdilution methods conducted according to CLSI procedures (document M07).¹⁵ Avibactam was provided by Allergan (Irvine, CA, USA) and combined with ceftazidime (avibactam at fixed concentration of 4 mg/L) for susceptibility testing. Ceftolozane stock solution was obtained from Thermo Fisher Scientific (Cleveland, OH, USA) and combined with tazobactam [acquired from United States Pharmacopeia (USP)] at a fixed concentration of 4 mg/L for susceptibility testing. Ceftolozane/tazobactam was only tested against isolates collected in 2017, whereas all other compounds were tested against isolates from 2015 to 2017. All other compounds were obtained from USP or Sigma–Aldrich (St Louis, MO, USA). Concurrent quality control (QC) testing was performed to ensure proper test conditions and procedures. QC strains included E. coli ATCC 25922 and NCTC 13353, K. pneumoniae ATCC 700603 and ATCC BAA 1705, P. aeruginosa ATCC 27853 and Haemophilus influenzae ATCC 49247. CLSI¹⁴ and EUCAST¹⁶ susceptibility interpretive criteria were used to determine susceptibility/resistance rates for comparator agents.

Screening for carbapenemases

All CRE isolates were tested for carbapenemase-encoding genes using next-generation sequencing (NGS). Total genomic DNA was extracted using the fully automated Thermo Scientific™ KingFisher™ Flex Magnetic Particle Processor (Cleveland, OH, USA). To perform NGS, DNA extracts were quantified using the Qubit™ High Sensitivity dsDNA assay (Invitrogen, Thermo Fisher Inc.) and normalized to 0.2 ng/μL. A total of 1 ng of high-quality genomic DNA was used as input material for library construction using the Nextera XT™ DNA Library Preparation Kit (Illumina, San Diego, CA, USA). Libraries were normalized using the bead-based normalization procedure (Illumina) and sequenced on MiSeq. Fastq files generated were assembled using SPAdes Assembler and subjected to a proprietary software (JMI Laboratories) for screening of β-lactamase genes.

Results

The most common organisms isolated from patients with pneumonia hospitalized in an ICU were S. aureus (30.0%), P. aeruginosa (20.7%), Klebsiella spp. (11.8%), Enterobacter spp. (8.3%), E. coli (7.1%), Stenotrophomonas maltophilia (5.1%), Serratia marcescens (4.6%), H. influenzae (2.8%), Acinetobacter baumannii (2.8%) and Streptococcus pneumoniae (1.5%; Figure 1). Overall, 67.1% of the organisms were Gram-negative and 32.9% were Gram-positive.

Figure 1.

Frequency of organisms isolated from patients with pneumonia hospitalized in ICUs of US medical centres (2015–17).

The most active compounds against P. aeruginosa were colistin (MIC_50/90, ≤0.5/1 mg/L; 99.8% susceptible), ceftolozane/tazobactam [MIC_50/90, 0.5/2 mg/L (data not shown); 96.5% susceptible (tested in 2017 only)], ceftazidime/avibactam [MIC_50/90, 2/8 mg/L; 96.8% susceptible overall (96.2% susceptible in 2017)], amikacin (MIC_50/90, 4/16 mg/L; 96.2% susceptible as per CLSI) and tobramycin (MIC_50/90, 0.5/4 mg/L; 91.8% susceptible). These agents were the only compounds active against >90% of isolates (Tables 1 and 2 and Figure 2).

Table 1.

Antimicrobial susceptibility of P. aeruginosa and Enterobacteriaceae isolates from patients with pneumonia hospitalized in ICUs of US medical centres (2015–17)

Antimicrobial agent	MIC50 (mg/L)	MIC90 (mg/L)	CLSIa		EUCASTa
			percentage susceptible	percentage resistant	percentage susceptible	percentage resistant
P. aeruginosa (1259)
ceftazidime/avibactam	2	8	96.8	3.2	96.8	3.2
ceftazidime	2	32	81.3	13.1	81.3	18.7
cefepime	4	16	82.5	5.8	82.5	17.5
piperacillin/tazobactam	8	>64	74.7	11.6	74.7	25.3
meropenem	0.5	16	73.9	17.7	73.9	11.5
levofloxacin	0.5	>4	73.4	18.7	63.1	36.9
amikacin	4	16	96.2	1.4	89.9	3.8
gentamicin	2	>8	83.2	10.2	83.2	16.8
tobramycin	0.5	4	91.8	6.7	91.8	8.2
colistin	≤0.5	1	99.8	0.2	99.8	0.2
MDR P. aeruginosa (327)
ceftazidime/avibactam	4	16	88.1	11.9	88.1	11.9
ceftazidime	16	>32	49.8	36.1	49.8	50.2
cefepime	16	>16	44.6	19.9	44.6	55.4
piperacillin/tazobactam	32	>64	32.1	32.1	32.1	67.9
meropenem	8	32	16.8	61.5	16.8	42.2
levofloxacin	>4	>4	22.7	58.6	10.1	89.9
amikacin	8	32	88.4	4.3	71.3	11.6
gentamicin	4	>8	51.1	31.5	51.1	48.9
tobramycin	1	>8	74.4	22.3	74.4	25.6
colistin	1	1	99.4	0.6	99.4	0.6
XDR P. aeruginosa (145)
ceftazidime/avibactam	4	16	78.6	21.4	78.6	21.4
ceftazidime	32	>32	25.5	51.7	25.5	74.5
cefepime	16	>16	18.6	35.2	18.6	81.4
piperacillin/tazobactam	64	>64	4.1	48.3	4.1	95.9
meropenem	16	32	1.4	84.1	1.4	62.8
levofloxacin	>4	>4	9.7	75.7	2.1	97.9
gentamicin	8	>8	31.7	47.6	31.7	68.3
amikacin	8	32	81.4	6.9	57.9	18.6
tobramycin	2	>8	60.7	35.7	60.7	39.3
colistin	1	1	98.6	1.4	98.6	1.4
P. aeruginosa non-susceptible to ceftazidime, meropenem and piperacillin/tazobactam (130)
ceftazidime/avibactam	8	32	72.3	27.7	72.3	27.7
cefepime	16	>16	16.2	40.8	16.2	83.8
levofloxacin	>4	>4	27.9	62.0	14.0	86.0
amikacin	8	32	83.1	6.9	63.8	32.0
gentamicin	8	>8	49.2	34.6	49.2	50.8
tobramycin	2	>8	68.0	29.1	68.0	32.0
colistin	1	1	99.2	0.8	99.2	0.8
Enterobacteriaceae (2151)
ceftazidime/avibactam	0.12	0.25	100.0	0.0	100.0	0.0
ceftazidime	0.25	32	83.7	15.0	81.3	16.3
ceftriaxone	0.12	>8	79.5	18.7	79.5	18.7
cefepime	≤0.12	4	89.5	7.8	87.4	9.0
piperacillin/tazobactam	2	32	87.4	6.7	82.6	12.6
meropenem	0.03	0.06	97.6	2.0	98.0	0.9
levofloxacin	0.06	>4	87.2	11.8	83.1	14.3
gentamicin	0.5	2	92.5	6.4	91.8	7.5
amikacin	2	4	99.4	<0.1	98.5	0.6
tigecycline	0.25	1	97.2b	0.2b	91.2	2.8
colistin	0.12	>8			78.2	21.8
MDR Enterobacteriaceae (190)c
ceftazidime/avibactam	0.25	1	100.0	0.0	100.0	0.0
ceftazidime	>32	>32	18.9	77.4	15.3	81.1
ceftriaxone	>8	>8	12.1	84.7	12.1	84.7
cefepime	16	>16	32.1	56.8	25.8	62.6
piperacillin/tazobactam	32	>64	43.2	37.9	34.2	56.8
meropenem	0.06	8	73.7	21.6	78.4	10.0
levofloxacin	>4	>4	36.8	56.3	22.6	73.2
gentamicin	8	>8	40.0	48.9	37.4	60.0
amikacin	2	16	94.7	0.5	88.4	5.3
tigecycline	0.5	4	88.4b	2.6b	77.2	11.6
colistin	0.25	>8			67.4	32.6
CRE (50)d
ceftazidime/avibactam	1	2	100.0	0.0	100.0	0.0
levofloxacin	>4	>4	42.0	56.0	24.0	70.0
gentamicin	8	>8	48.0	28.0	44.0	52.0
amikacin	4	16	90.0	0.0	78.0	10.0
tigecycline	0.5	2	96.0b	2.0b	82.0	4.0
colistin	0.12	0.5			92.0	8.0

a

Criteria as published by CLSI¹⁴ and EUCAST.¹⁶ The percentage susceptible and percentage resistance values do not add up to 100.0% for some antimicrobials due to the intermediate category.

b

Breakpoints from US FDA Package Insert.²⁰

c

Organisms include Citrobacter freundii species complex (2), Enterobacter aerogenes (6), Enterobacter cloacae species complex (34), E. coli (40), Hafnia alvei (1), Klebsiella oxytoca (7), K. pneumoniae (56), Morganella morganii (2), P. mirabilis (21), Providencia stuartii (7), Raoultella ornithinolytica (1), S. marcescens (12) and Raoultella sp. (1).

d

Organisms include C. freundii species complex (1), E. aerogenes (3), E. cloacae species complex (13), E. coli (3), K. oxytoca (3), K. pneumoniae (23), R. ornithinolytica (1), S. marcescens (2) and Raoultella sp. (1).

Table 2.

Antimicrobial activity of broad-spectrum β-lactams when tested against P. aeruginosa and the most common Enterobacteriaceae species/genus isolated from patients with pneumonia hospitalized in ICUs of US medical centres in 2017

Organism (no. tested)a	Percentage susceptible
	ceftazidime/avibactam	ceftolozane/tazobactam	meropenem	piperacillin/tazobactam
P. aeruginosa (423)	96.2	96.5	71.9	71.4
MDR (121)	86.2	87.6	18.2	31.4
XDR (54)	77.8	79.6	0.0	5.6
BLM-NS (47)	70.2	72.3	0.0	0.0
Enterobacteriaceae (694)	100.0	92.0	98.3	86.7
Klebsiella spp. (223)	100.0	96.0	98.7	89.7
Enterobacter spp. (163)	100.0	78.4	96.3	70.6
E. coli (144)	100.0	95.8	99.3	93.1
S. marcescens (85)	100.0	98.8	98.8	92.9
MDR isolates (56)	100.0	60.0	78.6	42.9

BLM-NS, β-lactam non-susceptible; i.e. non-susceptible to ceftazidime, meropenem and piperacillin/tazobactam.

a

Number of isolates collected in 2017.

Figure 2.

Antimicrobial susceptibility of P. aeruginosa and Enterobacteriaceae isolates from 2017 to ceftazidime/avibactam (dark grey bars) and ceftolozane/tazobactam (light grey bars). BLM-NS, β-lactam non-susceptible; i.e. non-susceptible to ceftazidime, meropenem and piperacillin/tazobactam; CRO-NS, ceftriaxone non-susceptible.

MDR and XDR phenotypes¹³ were observed in 327 (26.0%) and 145 (11.5%) P. aeruginosa isolates, respectively (Table 1). Colistin retained in vitro activity against >98% of MDR and XDR isolates. Amikacin was active against 88.4% and 81.4% of MDR and XDR isolates, respectively, at the CLSI susceptible breakpoint (71.3% and 57.9% at the EUCAST susceptible breakpoint, respectively) and ceftazidime/avibactam inhibited 88.1% and 78.6% of isolates, respectively, at the susceptible breakpoint (Table 1 and Figure 2). Ceftolozane/tazobactam, which was tested only against the isolates collected in 2017, was active against 87.6% of MDR and 79.6% of XDR P. aeruginosa (Table 2 and Figure 2). All other compounds exhibited very limited activity against these organism subsets (Table 1).

Although ceftazidime, meropenem and piperacillin/tazobactam demonstrated high rates of cross-resistance, ceftazidime/avibactam and ceftolozane/tazobactam retained good activity against P. aeruginosa isolates that were non-susceptible to other β-lactam compounds. Susceptibility to ceftazidime/avibactam and ceftolozane/tazobactam among P. aeruginosa isolates from 2017 that were non-susceptible to ceftazidime, meropenem and piperacillin/tazobactam (n = 47) were 70.2% and 72.3%, respectively (Table 2 and Figure 2).

Ceftazidime/avibactam was the most active agent against Enterobacteriaceae (MIC_50/90, 0.12/0.25 mg/L; 100.0% susceptible) and retained potent activity against MDR (MIC_50/90, 0.25/1 mg/L; 100.0% susceptible) and CRE (MIC_50/90, 1/2 mg/L; 100.0% susceptible; Table 1 and Figure 2) isolates. Among other β-lactam compounds, meropenem [MIC_50/90, 0.03/0.06 mg/L; 97.6% susceptible overall (98.3% in 2017); Table 1] and ceftolozane/tazobactam [MIC_50/90, 0.25/2 mg/L; 92.0% susceptible (2017); Table 2] exhibited good activity against Enterobacteriaceae overall, but these two compounds showed limited activity against the MDR Enterobacteriaceae (78.6% and 60.0% susceptibility in 2017, respectively) and ceftriaxone-non-susceptible Klebsiella spp. (75.2% and 73.5% susceptible, respectively) subsets and were inactive against CRE isolates [Table 2, Table S1 (available as Supplementary data at JAC Online) and Figure 2]. Furthermore, ceftolozane/tazobactam exhibited more limited activity against Enterobacter spp. (78.4% susceptible in 2017) when compared with meropenem (96.3% susceptible in 2017) and ceftazidime/avibactam (100.0% susceptible in 2017; Table 2).

The most common carbapenemase genes observed among CRE isolates were bla_KPC-3 (32 isolates; 64.0% of CRE isolates), bla_KPC-2 (12 isolates; 24.0%), bla_SME-4 (1 isolate; 2.0%) and bla_NMC-A [1 isolate (2.0%), which also had a bla_KPC-3]. No carbapenemase genes were observed in five CRE isolates (10.0%) and no MBL genes were observed in any CRE isolate.

Among non-β-lactam compounds, the most active agents against Enterobacteriaceae were amikacin (MIC_50/90, 2/4 mg/L; 99.4%/98.5% susceptible as per CLSI/EUCAST), tigecycline (MIC_50/90, 0.25/1 mg/L; 97.2%/91.2% susceptible as per FDA/EUCAST) and gentamicin (MIC_50/90, 0.5/2 mg/L; 92.5%/91.8% susceptible as per CLSI/EUCAST). Amikacin and tigecycline retained good activity against MDR Enterobacteriaceae [94.7% and 88.4% susceptible, respectively (CLSI and/or FDA)] and CRE [90.0% and 96.0% susceptible, respectively (CLSI and/or FDA)], whereas gentamicin exhibited limited activity against these resistant subsets (40.0% and 48.0% susceptible, respectively; Table 1).

The most active agents against S. maltophilia were minocycline (MIC_50/90, 0.5/2 mg/L; 100.0% susceptible as per CLSI) and trimethoprim/sulfamethoxazole (MIC_50/90, ≤0.5/≤0.5 mg/L; 95.5%/98.1% susceptible as per CLSI/EUCAST), and the most active agents against A. baumannii were colistin (MIC_50/90, ≤0.5/2 mg/L; 91.7% susceptible as per CLSI and EUCAST) and minocycline (MIC_50/90, 0.25/8 mg/L; 86.9% susceptible as per CLSI; Table S1). H. influenzae showed high rates of susceptibility to most antimicrobial agents tested (Table S1).

Discussion

Very scarce data are available on the frequency and antimicrobial susceptibility of bacteria isolated from ICU patients with pneumonia. The frequency of organisms observed in the present study for patients hospitalized with pneumonia in an ICU is comparable to those previously reported for patients hospitalized with pneumonia in all hospital units combined or for ventilator-associated pneumonia (VAP).^4,5 Overall, approximately two-thirds of the organisms were Gram-negative and one-third were Gram-positive. Among the Gram-negative organisms, 83.1% were represented by P. aeruginosa (30.7%) and Enterobacteriaceae species (52.4%), whereas 11.7% of Gram-negative organisms were represented by highly resistant non-fermentative Gram-negative bacilli for which there are very few treatment options, i.e. S. maltophilia (7.5% of Gram-negative organisms and 5.1% of total) and Acinetobacter spp. (4.1% of Gram-negative organisms and 2.8% of total).

As reported by other investigators,^3,5,P. aeruginosa was the most common Gram-negative organism and showed low susceptibility rates to many antimicrobial agents, with 26.0% (327/1259) and 11.5% (145/1259) of isolates showing MDR and XDR phenotypes, respectively. The most active β-lactam compounds against these organisms were ceftazidime/avibactam and ceftolozane/tazobactam.¹¹ These two compounds exhibited a very similar anti-P. aeruginosa spectrum (96.2%–96.5% susceptibility in 2017) and retained good activity against MDR (86.2%–87.6% susceptibility in 2017) and XDR (77.8%–79.6% susceptibility in 2017) isolates. Besides these two recently approved β-lactamase inhibitor combinations, only colistin and amikacin exhibited good in vitro activity against MDR and XDR P. aeruginosa isolates.

The Enterobacteriaceae family represents the group of bacteria most frequently isolated from hospital-acquired infections and the antimicrobial susceptibility of these organisms may vary substantially among different geographical regions or even among hospitals within a region.^8,17,18 In the present investigation, Enterobacteriaceae species were isolated from 35.3% of the patients and the activities of the β-lactams against these organisms varied substantially, especially against the MDR and the ceftriaxone-non-susceptible subsets. It is important to note that MBL-producing Enterobacteriaceae isolates are still uncommon in US medical centres and were not observed in the present study.

The elevated frequency of S. maltophilia and A. baumannii is of great concern since very few agents are active against these organisms.¹⁹ These two organisms represented 7.9% of the organisms (11.7% of Gram-negative organisms), which is similar to the data reported by Magill et al.³ from a US multistate point-prevalence survey (5.5% for S. maltophilia and 3.6% for A. baumannii).³

In the present investigation, we evaluated the frequency and antimicrobial susceptibility of bacterial isolates collected from >6000 patients hospitalized with pneumonia in ICUs of US medical centres. Our results corroborate reports from other investigators by showing the predominance of Gram-negative bacteria and high occurrence of MDR organisms.^1–9 The results of the present study also indicate that the two cephalosporin/β-lactamase inhibitor combinations recently approved by the FDA, ceftazidime/avibactam and ceftolozane/tazobactam, represent a valuable addition to the anti-P. aeruginosa armamentarium.^10,11 Furthermore, ceftazidime/avibactam provided complete coverage against Enterobacteriaceae and may represent a valuable option for empirical therapy for patients hospitalized with pneumonia in US medical centres.

Funding

This study was performed by JMI Laboratories and supported by Allergan, which included funding for services related to preparing this manuscript.

Transparency declarations

JMI Laboratories was contracted to perform services in 2017 for Achaogen, Actelion, Allecra Therapeutics, AmpliPhi Biosciences, API, Astellas Pharma, AstraZeneca, Basilea Pharmaceutica, Bayer AG, BD, Biomodels, Cardeas Pharma Corp., CEM-102 Pharma, Cempra, Cidara Therapeutics, Inc., CorMedix, CSA Biotech, Cutanea Life Sciences, Inc., Debiopharm Group, Dipexium Pharmaceuticals, Inc., Entasis Therapeutics, Inc., Fortress Biotech, Fox Chase Chemical Diversity Center, Inc., Geom Therapeutics, Inc., GSK, Laboratory Specialists, Inc., Medpace, Melinta Therapeutics, Inc., Merck & Co., Inc., Micromyx, MicuRx Pharmaceuticals, Inc., Motif Bio, N8 Medical, Inc., Nabriva Therapeutics, Inc., Nexcida Therapeutics, Inc., Novartis, Paratek Pharmaceuticals, Inc., Pfizer, Polyphor, Rempex, Scynexis, Shionogi, Spero Therapeutics, Symbal Therapeutics, Synlogic, TenNor Therapeutics, TGV Therapeutics, The Medicines Company, Theravance Biopharma, Thermo Fisher Scientific, VenatoRx Pharmaceuticals, Inc., Wockhardt and Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare.

Supplementary data

Table S1 is available as Supplementary data at JAC Online.