Ceftolozane/tazobactam activity tested against Gram-negative bacterial isolates from hospitalised patients with pneumonia in US and European medical centres (2012)

During 2012, a total of 2968 isolates were consecutively collected from 59 medical centres in the USA and 15 European countries from hospitalised patients with pneumonia. Ceftolozane/tazobactam (tazobactam at a fixed concentration of 4 mg/L) and comparator agents were tested by reference methods, and MIC endpoints were interpreted by CLSI (2013) and EUCAST (2013) breakpoint criteria. Pseudomonas aeruginosa was the most common isolated pathogen (1019 strains; 34.3%), and ceftolozane/tazobactam was the most active β-lactam tested against P. aeruginosa (MIC_50/90, 0.5/4 mg/L; 94.1% inhibited at ≤8 mg/L). P. aeruginosa exhibited moderate susceptibility to meropenem (MIC_50/90, 0.5/>8 mg/L; 73.7% susceptible), ceftazidime (MIC_50/90, 2/>32 mg/L; 73.6% susceptible), cefepime (MIC_50/90, 4/>16 mg/L; 76.5% susceptible), piperacillin/tazobactam (MIC_50/90, 8/>64 mg/L; 69.5% susceptible), levofloxacin [MIC_50/90, 0.5/>4 mg/L; 69.9/61.0% susceptible (CLSI/EUCAST criteria)] and gentamicin (MIC_50/90, 2/>8 mg/L; 80.7% susceptible). Ceftolozane/tazobactam exhibited activity against many ceftazidime-non-susceptible, meropenem-non-susceptible and piperacillin/tazobactam-non-susceptible, multidrug-resistant (MDR) and extensively drug-resistant (XDR) P. aeruginosa isolates. Ceftolozane/tazobactam was active (MIC_50/90, 0.25/4 mg/L; 94.6% inhibited at ≤8 mg/L) against 1530 Enterobacteriaceae, including activity against many MDR and XDR strains. MDR and XDR prevalence varied widely between countries both for P. aeruginosa (24.1% MDR and 17.1% XDR overall) and Enterobacteriaceae (15.4% MDR and 2.7% XDR overall). All β-lactams had limited activity against Acinetobacter spp. and Stenotrophomonas maltophilia. Ceftolozane/tazobactam demonstrated greater in vitro activity than currently available cephalosporins, carbapenems and piperacillin/tazobactam when tested against P. aeruginosa. In addition, ceftolozane/tazobactam demonstrated greater activity than contemporary cephalosporins and piperacillin/tazobactam when tested against most Enterobacteriaceae.     

Ceftolozane/tazobactam activity against drug-resistant Enterobacteriaceae and Pseudomonas aeruginosa causing healthcare-associated infections in the Asia-Pacific region (minus China,Australia and New Zealand): report from an Antimicrobial Surveillance Programme (2013–2015)

The aim of this study was to evaluate the in vitro activity of ceftolozane/tazobactam and comparator agents tested against Enterobacteriaceae and Pseudomonas aeruginosa isolates from patients in the Asia-Pacific (APAC) region with healthcare-associated infections. Ceftolozane/tazobactam is an antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor. A total of 1963 Gram-negative organisms (489 P. aeruginosa and 1474 Enterobacteriaceae) were consecutively collected using a prevalence-based approach from 14 medical centres in the APAC region. Antimicrobial susceptibility testing was performed by broth microdilution method as described by the CLSI and the results were interpreted according to EUCAST and CLSI breakpoint criteria. Ceftolozane/tazobactam [MIC_50/90, 0.25/4?µg/mL; 89.2/85.8% susceptible (CLSI/EUCAST)] and meropenem [MIC_50/90, ≤0.06/≤0.06?µg/mL; 96.3/96.5% susceptible (CLSI/EUCAST)] were the most active compounds tested against Enterobacteriaceae. Isolates displayed susceptibility rates to other β-lactam agents ranging from 85.8/81.0% for piperacillin/tazobactam to 74.4/72.7% for cefepime and 72.8/68.1% for ceftazidime using CLSI/EUCAST breakpoints. Among the Enterobacteriaceae isolates, 3.6% were carbapenem-resistant Enterobacteriaceae (CRE) and 25.6% exhibited an extended-spectrum β-lactamase (ESBL) non-CRE phenotype. Ceftolozane/tazobactam showed good activity against ESBL non-CRE phenotype strains of Enterobacteriaceae (MIC_50/90, 0.5/16?µg/mL), but not against isolates with a CRE phenotype (MIC_50/90, >32/>32?µg/mL). Ceftolozane/tazobactam was the most potent (MIC_50/90, 0.5/4?µg/mL) β-lactam agent tested against P. aeruginosa isolates, inhibiting 90.8% at an MIC of ≤4?µg/mL. Pseudomonas aeruginosa exhibited high rates of susceptibility to amikacin [91.2/89.4% (CLSI/EUCAST)] and colistin [98.4/100.0% (CLSI/EUCAST)]. Ceftolozane/tazobactam was the most active β-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than available cephalosporins when tested against Enterobacteriaceae.     

Activity of ceftolozane-tazobactam against Gram-negative pathogens isolated from lower respiratory tract infections in the Asia-Pacific region: SMART 2015-2016

The aim of this study was to investigate the susceptibility of respiratory Gram-negative bacteria to ceftolozane/tazobactam and other antibiotics in the Asia-Pacific region during 2015-2016. MICs were determined using the CLSI standard broth microdilution method and interpreted accordingly. Pseudomonas aeruginosa (1574 isolates), Klebsiella pneumoniae (1226), Acinetobacter baumannii (627) and Escherichia coli (476) accounted for 73.1% of 5342 Gram-negative respiratory pathogens. Susceptibility to ceftolozane/tazobactam of individual Enterobacteriaceae was >80%, except for Enterobacter cloacae (76.6%). Ceftolozane/tazobactam inhibited 81.9% of K. pneumoniae and 91.9% of E. coli, with respective MIC₅₀/MIC₉₀ values of 0.5/>32 and 0.25/2 mg/L. For carbapenem-susceptible, ESBL-producing K. pneumoniae and E. coli, susceptibility was 65.5% and 93.3%, respectively, and respective MIC₅₀/MIC₉₀ values were 2/>32 and 0.5/2 mg/L. Bla_{CTX-M-1 group} was most prevalent in selected ESBL-producing K. pneumoniae (40 of 54 isolates) and E. coli (15 of 22 isolates), with ceftolozane/tazobactam susceptibility rates of 50% and 80%, respectively. Bla_SHV-ESBL was the second most prevalent, and ceftolozane/tazobactam inhibited 20% of 20 K. pneumoniae isolates with bla_SHV-ESBL. The only effective antibiotics for carbapenem-non-susceptible K. pneumoniae (111 isolates) and E. coli (24 isolates) were amikacin and colistin. Ceftolozane/tazobactam was effective against almost all tested P. aeruginosa and carbapenem-non-susceptible strains, with susceptibility of 92.3% and 72.8%, respectively; the respective MIC₅₀/MIC₉₀ values were 1/4 and 2/>32 mg/L. The high susceptibility of ceftolozane/tazobactam remained in different age groups, patient locations, recovery times and countries, except Vietnam. In conclusion, ceftolozane/tazobactam was effective against most respiratory Gram-negative pathogens in the Asia-Pacific region; however, the emergence of carbapenem resistance mandates ongoing surveillance.     

Efficacy of ceftolozane/tazobactam,alone and in combination with colistin,against multidrug-resistant Pseudomonas aeruginosa in an in vitro biofilm pharmacodynamic model

Objectives

Ceftolozane/tazobactam is a potential tool for infections caused by multidrug-resistant (MDR) Pseudomonas aeruginosa (P. aeruginosa), but its efficacy against some difficult-to-treat infections has not been well defined.

In-vitro activity of ceftolozane/tazobactam against Pseudomonas aeruginosa collected in the Study for Monitoring Antimicrobial Resistance Trends (SMART) between 2016 and 2019 in China

Ceftolozane/tazobactam (an antipseudomonal cephalosporin) in combination with a well-established β-lactamase inhibitor has not been approved to date in clinical practice in China. The aim of this study was to evaluate the in-vitro activity of ceftolozane/tazobactam and comparator agents against Pseudomonas aeruginosa with various resistance patterns. P. aeruginosa (n=2178) specimens were collected from multiple sources in seven geographic regions of China between 2016 and 2019. All isolates were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, and minimum inhibitory concentrations of various antimicrobial agents (ceftolozane/tazobactam, amikacin, tobramycin, ceftazidime, cefepime, colistin, levofloxacin, aztreonam, meropenem, imipenem and piperacillin/tazobactam) were determined using the Clinical and Laboratory Standards Institute's broth microdilution method. P. aeruginosa demonstrated considerably high rates of multi-drug resistance (MDR, 57.3%), extensive drug resistance (XDR, 43.5%) and difficult-to-treat resistance (DTR, 16.8%). The overall susceptibility of P. aeruginosa to ceftolozane/tazobactam was 81.9%, and ceftolozane/tazobactam showed diverse activity against the three resistant subsets, ranging from 28.5% against DTR P. aeruginosa to 68.9% against MDR P. aeruginosa. P. aeruginosa, MDR P. aeruginosa, XDR P. aeruginosa and DTR P. aeruginosa derived from the East (Jiangzhe area) region maintained significantly lower susceptibility to ceftolozane/tazobactam compared with P. aeruginosa, MDR P. aeruginosa, XDR P. aeruginosa and DTR P. aeruginosa from other regions. The susceptibility rates of P. aeruginosa isolated from diverse sources to ceftolozane/tazobactam were similar to isolates from bloodstream infections, with the highest being 88.6%. Compared with other antimicrobial agents, ceftolozane/tazobactam was more active than the β-lactams tested but was slightly less active than amikacin. Amikacin demonstrated the best activity against P. aeruginosa and the three resistant subsets. Ceftolozane/tazobactam demonstrated considerable in-vitro activity against P. aeruginosa, MDR P. aeruginosa, XDR P. aeruginosa and DTR P. aeruginosa, indicating that it could be an optional therapeutic agent against P. aeruginosa.     

Evaluating the emergence of nonsusceptibility among Pseudomonas aeruginosa respiratory isolates from a phase-3 clinical trial for treatment of nosocomial pneumonia (ASPECT-NP)

Objectives: The emergence of nonsusceptibility to ceftolozane/tazobactam and meropenem was evaluated among Pseudomonas aeruginosa (P. aeruginosa) lower respiratory tract isolates obtained from participants in the ASPECT-NP clinical trial.Methods: ASPECT-NP was a phase-3, randomised, double-blind, multicentre trial that demonstrated noninferiority of 3 g ceftolozane/tazobactam q8h versus 1 g meropenem q8h for treatment of ventilated hospital-acquired/ventilator-associated bacterial pneumonia. Molecular resistance mechanisms among postbaseline nonsusceptible P. aeruginosa isolates and clinical outcomes associated with participants with emergence of nonsusceptibility were examined. Baseline susceptible and postbaseline nonsusceptible P. aeruginosa isolate pairs from the same participant underwent molecular typing.Results: Emergence of nonsusceptibility was not observed among the 59 participants with baseline susceptible P. aeruginosa isolates in the ceftolozane/tazobactam arm. Among 58 participants with baseline susceptible P. aeruginosa isolates in the meropenem arm, emergence of nonsusceptibility was observed in 13 (22.4%). Among participants who received ceftolozane/tazobactam and meropenem, 5.1% and 3.4% had a new infection with a nonsusceptible strain, respectively. None of the isolates with emergence of nonsusceptibility to meropenem developed co-resistance to ceftolozane/tazobactam. The molecular mechanisms associated with emergence of nonsusceptibility to meropenem were decreased expression or loss of OprD and overexpression of MexXY.Conclusions: Among participants with emergence of nonsusceptibility to meropenem, clinical outcomes were similar to overall clinical outcomes in the ASPECT-NP meropenem arm. Ceftolozane/tazobactam was more stable to emergence of nonsusceptibility versus meropenem; emergence of nonsusceptibility was not observed in any participants with baseline susceptible P. aeruginosa who received ceftolozane/tazobactam in ASPECT-NP.     

In vitro activity of parenteral Beta-lactams, levofloxacin and tobramycin alone or in combination against extended-spectrum Beta-lactamase producing Klebsiella pneumoniae

MICs and time-kill studies were performed for four clinical isolates of extended-spectrum Beta-lactamase (ESBL)-producing Klebsiella pneumoniae. MICs (mg/L) were: piperacillin/tazobactam 8, cefepime 1-2, meropenem 0.03-0.06, levofloxacin 0.5-8 and tobramycin 0.25-32. For monotherapy, only meropenem maintained bactericidal activity over the 24 h for all isolates. Levofloxacin and tobramycin maintained bactericidal activity against the isolate susceptible to each drug. Piperacillin/tazobactam and cefepime did not maintain bactericidal activity against any isolate. Combination therapy with piperacillin/tazobactam or cefepime combined with levofloxacin or tobramycin were able to provide dramatic killing against ESBL K. pneumoniae, but did not always maintain bactericidal activity. Future studies should evaluate different antimicrobial combinations against pathogens producing specific ESBL enzymes to define their utility as an alternative to carbapenems.     

Cefepime/tazobactam compared with other tazobactam combinations against problem Gram-negative bacteria

ObjectivesPiperacillin/tazobactam has long been a broad-spectrum ‘workhorse’ antibiotic; however, it is compromised by resistance. One response is to re-partner tazobactam with cefepime, which is easier to protect, being less β-lactamase labile, and to use a high-dose and prolonged infusion. On this basis, Wockhardt are developing cefepime/tazobactam (WCK 4282) as a 2+2 g q8h combination with a 90-min infusion.MethodsThe activity of cc cefepime/tazobactam was assessed, with other tazobactam combinations as comparators, against 1632 Enterobacterales, 745 Pseudomonas aeruginosa and 450 other non-fermenters, as submitted to the UK National Reference Laboratory. These were categorised by carbapenemase-gene detection and interpretive reading of phenotypes, with MICs determined by British Society for Antimicrobial Chemotherapy agar dilution.ResultsAlthough higher breakpoints may be justifiable, based on the pharmacodynamics, the results were reviewed against current cefepime criteria. On this basis, cefepime/tazobactam was broadly active against Enterobacterales with AmpC enzymes and extended-spectrum β-lactamases (ESBLs), even when they had ertapenem resistance, suggesting porin loss. At 8+8 mg/L, activity extended to > 90% of Enterobacterales with OXA-48 and KPC carbapenemases, although the MICs for KPC producers belonging to the international Klebsiella pneumoniae ST258 lineage were higher; metallo-β-lactamase producers remained resistant. Cefepime/tazobactam was less active than ceftolozane/tazobactam against Pseudomonas aeruginosa with AmpC de-repression or high-level efflux but achieved wider antipseudomonal coverage than piperacillin/tazobactam. Activity against other non-fermenters was species-specific.ConclusionOverall, cefepime/tazobactam had a spectrum exceeding those of piperacillin/tazobactam and ceftolozane/tazobactam and resembling or exceeding that of carbapenems. Used as a ‘new-combination of old-agents’ it has genuine potential to be ‘carbapenem-sparing’.     

Phylogenetic analysis of resistance to ceftazidime/avibactam,ceftolozane/tazobactam and carbapenems in piperacillin/tazobactam-resistant Pseudomonas aeruginosa from cystic fibrosis patients

Pseudomonas aeruginosa is one of the most important pathogens in cystic fibrosis. This study was conducted to analyse the genetic basis and phylogenetic profile of resistance to ceftazidime/avibactam, ceftolozane/tazobactam and carbapenems in cystic fibrosis P. aeruginosa isolates. Whole genome sequence analysis was conducted of isolates resistant to piperacillin/tazobactam collected from seven hospitals in Scotland since the introduction of these two cephalosporin/β-lactamase inhibitor combinations. Ceftazidime resistance was primarily related to AmpC induction, as tested by cloxacillin inhibition assays, while high-level ceftazidime resistance not reversed by cloxacillin was associated with amino acid variations in AmpC. Only isolates resistant to both ceftazidime/avibactam and ceftolozane/tazobactam carried AmpD mutations, likely resulting in ampC overexpression. All isolates resistant to ceftazidime/avibactam and/or ceftolozane/tazobactam were resistant to carbapenems and showed inactivating mutations in the chromosomal oprD gene. None of the isolates bore class A, B, D plasmid-encoded carbapenemases. This study showed that mutational resistance emerged in phylogenetically distant lineages, which indicates the mutations occur independently without conferring a selective advantage to any phylogenetic lineage. These findings confirm the strong contribution of mutation-driven evolution to the population structure of P. aeruginosa.     

Activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and Enterobacterales isolates recovered from intensive care unit patients in Spain: The SUPERIOR multicentre study

Patients in intensive care units (ICUs) present a high risk of developing an infection caused by multidrug-resistant bacteria. Consequently, new antimicrobials and combinations are required. In this study, the activity of ceftolozane/tazobactam (C/T) was evaluated against Enterobacterales (n?=?400) and Pseudomonas aeruginosa (n?=?80) clinical isolates collected from patients in Spanish ICUs with complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI). Overall susceptibility to C/T in P. aeruginosa isolates by infection type was 95.7% in cUTI (MIC_50/90, 1/4 mg/L) and 85.3% in cIAI (MIC_50/90, 1/64 mg/L). Activity against P. aeruginosa was maintained regardless of its resistance pattern, confirming that C/T is one of the best antipseudomonal agents along with colistin and amikacin. Susceptibility to C/T in Enterobacterales by infection type was 79.5/81.9% and 89.3/92.3% (EUCAST/CLSI) in cIAI and cUTI isolates, respectively. Activity was excellent against wild-type organisms, with 100% susceptible and inhibited at MIC ≤1 mg/L. Nevertheless, C/T susceptibility decreased against extended-spectrum β-lactamase (ESBL)-producing isolates: Escherichia coli (80.4/84.8% susceptible by EUCAST/CLSI) and Klebsiella pneumoniae (59.1/77.3% susceptible by EUCAST/CLSI). No activity of C/T was observed in carbapenemase-producing isolates. The in vitro activity of C/T observed in this surveillance study suggests that this agent can be considered as a therapeutic option for cUTI and cIAI due to Enterobacterales and P. aeruginosa in ICU patients, particularly when carbapenemase-producing isolates are not involved.     

In vitro pharmacodynamic evaluation of ceftolozane/tazobactam against β-lactamase-producing Escherichia coli in a hollow-fibre infection model

The proliferation of multidrug-resistant Gram-negative pathogens has been exacerbated by a lack of novel agents in current development by pharmaceutical companies. Ceftolozane/tazobactam was recently approved by the FDA for the treatment of complicated intra-abdominal infections and complicated urinary tract infections. In the present study, the activity of ceftolozane/tazobactam against four isogenic Escherichia coli strains was investigated in a hollow-fibre infection model simulating various clinical dosing regimens. The four investigational E. coli strains included #2805 (no β-lactamase), #2890 (AmpC β-lactamase), #2842 (CMY-10 β-lactamase) and #2807 (CTX-M-15 β-lactamase). Each strain was exposed to regimens simulating 1?g ceftolozane, 2?g ceftolozane, 1?g ceftolozane/0.5?g tazobactam, and 2?g ceftolozane/1?g tazobactam utilising a starting inoculum of ca. 10⁶ CFU/mL. Whereas 1?g of ceftolozane eradicated strains #2805 and #2842 without subsequent regrowth, 1?g ceftolozane/0.5?g tazobactam was required to eradicate strain #2890. For strain #2890, ceftolozane monotherapy led to bacterial growth on plates impregnated with 20?mg/L ceftolozane by 24?h, whilst combination treatment with tazobactam completely suppressed the development of ceftolozane resistance. In contrast, none of the regimens, including 2?g ceftolozane/1?g tazobactam, were able to entirely suppress bacterial growth in strain #2807, with bacterial counts exceeding 10⁸?CFU/mL by 48?h and ceftolozane-resistant populations being amplified after 24?h. Thus, the combination of ceftolozane and tazobactam achieved bactericidal activity followed by sustained killing over 10 days for three of four isogenic E. coli strains. Ceftolozane/tazobactam is a promising new agent to counter multidrug-resistant Gram-negative bacteria.     

Surveillance of tigecycline activity tested against clinical isolates from a global (North America,Europe, Latin America and Asia-Pacific) collection (2016)

Tigecycline and comparators were tested by the reference broth microdilution method against 33 348 non-duplicate bacterial isolates collected prospectively in 2016 from medical centres in the Asia-Pacific (3443 isolates), Europe (13 530 isolates), Latin America (3327 isolates) and the USA (13 048 isolates). Among 7098 Staphylococcus aureus isolates tested, >99.9% were inhibited by ≤0.5?mg/L tigecycline (MIC_50/90, 0.06/0.12?mg/L), including >99.9% of methicillin-resistant S. aureus and 100.0% of methicillin-susceptible S. aureus. Tigecycline was slightly more active against Enterococcus faecium (MIC_50/90, 0.03/0.06?mg/L) compared with Enterococcus faecalis (MIC_50/90, 0.06/0.12?mg/L) and its activity was not adversely affected by vancomycin resistance when tested against these organisms. Tigecycline potency was comparable for Streptococcus pneumoniae (MIC_50/90, 0.03/0.06?mg/L), viridans group streptococci (MIC_50/90, 0.03/0.06?mg/L) and β-haemolytic streptococci (MIC_50/90, 0.06/0.06?mg/L) regardless of species and penicillin susceptibility. Tigecycline was active against Enterobacteriaceae (MIC_50/90, 0.25/1?mg/L; 97.8% inhibited at ≤2?mg/L) but was slightly less active against Enterobacteriaceae isolates expressing resistant phenotypes: carbapenem-resistant Enterobacteriaceae (MIC_50/90, 0.5/2?mg/L; 98.0% susceptible); multidrug-resistant (MIC_50/90, 0.5/2?mg/L; 93.1% susceptible); and extensively drug-resistant (MIC_50/90, 0.5/4?mg/L; 87.8% susceptible). Tigecycline inhibited 74.4% of 888 Acinetobacter baumannii isolates at ≤2?mg/L (MIC_50/90, 2/4?mg/L) and demonstrated good in vitro activity against Stenotrophomonas maltophilia (MIC_50/90, 1/2?mg/L; 90.6% inhibited at ≤2?mg/L) Tigecycline was active against Haemophilus influenzae (MIC_50/90, 0.12/0.25?mg/L) regardless of β-lactamase status. Tigecycline represents an important treatment option for resistant Gram-negative and Gram-positive bacterial infections.     

Successful Use of Ceftolozane‐Tazobactam to Treat a Pulmonary Exacerbation of Cystic Fibrosis Caused by Multidrug‐Resistant Pseudomonas aeruginosa

Ceftolozane‐tazobactam, a novel β‐lactam/β‐lactamase inhibitor, was recently approved for the treatment of complicated urinary tract and intraabdominal infections, as monotherapy and in combination with metronidazole, respectively. Ceftolozane‐tazobactam exhibits a wide spectrum of activity against both gram‐positive bacteria, gram‐negative bacteria including multidrug‐resistant (MDR) Pseudomonas aeruginosa, and some anaerobic bacteria. Although not currently approved for any pulmonary indication, studies have demonstrated excellent distribution to epithelial lining fluid, indicating that it may be an alternative agent to use in the treatment of respiratory tract infections caused by MDRP. aeruginosa. Unfortunately, data are lacking regarding the use of ceftolozane‐tazobactam in the treatment of respiratory tract infections including patients with cystic fibrosis (CF). We describe the first case report, to our knowledge, of a 25‐year‐old white man successfully treated with ceftolozane‐tazobactam for a pulmonary exacerbation of his CF caused by MDRP. aeruginosa. He was admitted for his fourth hospitalization in 7 months for a pulmonary exacerbation of his CF. After blood and sputum were cultured, prednisone, cefepime, inhaled tobramycin, and intravenous ciprofloxacin were started. On day 4, after no signs of clinical improvement, respiratory cultures revealed nonmucoid MDRP. aeruginosa, susceptible only to colistin. β‐Lactam therapy was subsequently changed to ceftolozane‐tazobactam 3 g intravenously every 8 hours while continuing ciprofloxacin and inhaled tobramycin. Ceftolozane‐tazobactam susceptibility was determined by the Etest method (minimum inhibitory concentration 1.5 μg/ml). By day 3 of therapy, the patient showed signs of clinical improvement and was discharged after completion of a 12‐day course of antibiotics. Until additional research is available, we hope this evidence will provide consideration of ceftolozane‐tazobactam for this novel off‐label indication.     

In vitro activity of avibactam (NXL104) in combination with β-lactams against Gram-negative bacteria, including OXA-48 β-lactamase-producing Klebsiella pneumoniae

The objective of this study was to investigate the in vitro antibacterial activity of avibactam (formerly NXL104) in combination with imipenem, cefepime or ceftazidime against Gram-negative bacteria. Bacterial isolates included: Pseudomonas aeruginosa harbouring PER-1 β-lactamase (n = 14); Acinetobacter baumannii harbouring PER-1, OXA-51 and OXA-58 (n = 20); carbapenem-non-susceptible Klebsiella pneumoniae (n = 25) and Escherichia coli (n = 1) harbouring OXA-48; carbapenem-non-susceptible E. coli (n = 1) harbouring both IMP-1 metallo-β-lactamase and extended-spectrum β-lactamase (ESBL); carbapenem-non-susceptible Serratia marcescens (n = 1); and carbapenem-susceptible E. coli (n = 20) and K. pneumoniae isolates (n = 12) with CTX-M-15 ESBL. Minimum inhibitory concentrations (MICs) of imipenem, cefepime and ceftazidime were determined in combination with 4 mg/L avibactam by the Clinical and Laboratory Standards Institute (CLSI) method on Mueller-Hinton agar. Imipenem/avibactam and ceftazidime/avibactam displayed limited potency against A. baumannii isolates, whereas cefepime/avibactam and ceftazidime/avibactam were active against P. aeruginosa. Klebsiella pneumoniae isolates with OXA-48 β-lactamase were resistant to imipenem [MIC for 90% of the organisms (MIC₉₀) ≥4 mg/L]. MIC₉₀ values for the combination of avibactam 4 mg/L with imipenem, cefepime and ceftazidime were in the susceptible range for all strains (MIC₉₀ ≤ 0.5 mg/L). All E. coli and K. pneumoniae isolates with CTX-M-15 β-lactamase were inhibited at ≤1 mg/L for combinations with avibactam and 100% were susceptible by CLSI breakpoint criteria to imipenem, cefepime and ceftazidime. In conclusion, combinations of imipenem, cefepime and ceftazidime with avibactam may present a promising therapeutic strategy to treat infections due to K. pneumoniae with OXA-48 enzyme as well as K. pneumoniae and E. coli with CTX-M-15 enzyme.     

Antimicrobial susceptibility of non-fermenting Gram-negative pathogens isolated from cystic fibrosis patients

Non-fermenting Gram-negative bacteria (NFGNB) are increasingly cultured in respiratory samples from cystic fibrosis (CF) patients. This study determined the antimicrobial susceptibility of clinical CF respiratory isolates from distinct geographical regions. A total of 286 isolates (106 Stenotrophomonas maltophilia, 100 Burkholderia spp., 59 Achromobacter spp., 12 Pandoraea spp., 9 Ralstonia spp.) from the Netherlands, Northern Ireland, Spain, USA and Australia were tested. MIC_50/90 values and susceptibility categorisation were determined. Trimethoprim/sulfamethoxazole (SXT) was the most active compound for all micro-organisms (MIC₅₀, 0.12–4 mg/L; MIC₉₀, 1–16 mg/L). For S. maltophilia, 47% and 62% of isolates were susceptible to SXT according to CLSI and EUCAST breakpoints, respectively. Ceftazidime presented lower susceptibility (35%; MIC₅₀, 32 mg/L; MIC₉₀, 256 mg/L). MIC₉₀ values for tobramycin and colistin were >128 mg/L and >16 mg/L, respectively. Regarding Burkholderia, 72%, 56% and 44% were susceptible to SXT, ceftazidime and meropenem, respectively. For both ceftazidime and meropenem, MIC₅₀ and MIC₉₀ values were within the intermediate or resistant category. The most active antibiotics for Achromobacter spp. were SXT (MIC₅₀, 0.5 mg/L; MIC₉₀, 8 mg/L) and imipenem (MIC₅₀, 2 mg/L; MIC₉₀, 8 mg/L). SXT, imipenem and ciprofloxacin were active against 12 Pandoraea spp. (MIC₅₀, 0.12–4 mg/L; MIC₉₀, 1–8 mg/L). Ciprofloxacin (MIC₅₀, 4 mg/L) and SXT (MIC₅₀, 1 mg/L) were the only active antibiotics for Ralstonia spp. There were no statistically significant differences in susceptibility rates between countries. NFGNB other than Pseudomonas aeruginosa are potential pathogens in CF. SXT was demonstrated to be the most active compound against these isolates.     

Optimising antibiotic dosing regimens based on pharmacodynamic target attainment against Pseudomonas aeruginosa collected in Hungarian hospitals

Owing to increasing resistance rates in Europe, pharmacodynamic analyses were proposed to determine optimal empirical antibiotic therapy against Pseudomonas aeruginosa isolated in Hungary. Minimum inhibitory concentrations for 180 non-duplicate P. aeruginosa collected from 14 hospitals in Hungary were determined by Etest methodology. A 5000-subject Monte Carlo simulation was performed to calculate the bactericidal cumulative fraction of response (CFR) for standard dosing regimens of cefepime, ceftazidime, ciprofloxacin, imipenem, meropenem and piperacillin/tazobactam. In the case of poor CFR, alternative dosage regimens were simulated for selected agents by increasing the infusion time, dose and frequency. Owing to high resistance rates in Hungary, no regimen achieved >90% CFR. CFRs for standard dosing regimens were: meropenem 1g every 8h (q8h), 77.1%; ceftazidime 2g q8h, 75.3%; imipenem 0.5 g every 6h (q6h), 71.7%; and piperacillin/tazobactam 4.5 g and 3.375 g q6h, 72.4% and 71.0%, respectively. Ciprofloxacin achieved significantly lower bactericidal CFRs than any beta-lactam. Prolonged infusion regimens improved the CFR for cefepime, imipenem, meropenem and piperacillin/tazobactam. Overall, the highest CFR (88.1%) was achieved by a 3-h infusion of meropenem 2g q8h. Given the poor CFR predicted with standard dosage regimens against these isolates, it seems prudent to consider alternative dosage strategies such as increasing doses, frequencies or infusion times as well as combination therapy when empirically treating infections caused by P. aeruginosa in Hungary.     

Carbapenems versus other beta-lactams in the treatment of hospitalised patients with infection: a mixed treatment comparison

ABSTRACT

Objective: To compare the effectiveness of meropenem with cefepime and piperacillin/tazobactam in the absence of direct comparisons in randomised controlled trials.

Data sources: Two previously conducted systematic reviews, one comparing the carbapenems (ertapenem and imipenem/cilastatin) versus 4th-generation cephalosporins (cefepime) or antipseudomonal penicillins (piperacillin/tazobactam), and the other comparing the carbapenems (imipenem/cilastatin versus meropenem), were updated to provide the basis for this mixed treatment comparison. Searching was completed in April 2007. No restriction was placed on language of publication.

Study selection and data extraction: Randomised controlled trials of adult patients hospitalised with infection and treated with a carbapenem or cefepime or piperacillin/tazobactam. Two reviewers independently assessed the papers against the inclusion/exclusion criteria and for methodological quality with any differences in opinion adjudicated by a third party. Two reviewers independently extracted data on clinical response, bacteriological response, mortality, and adverse events.

Data synthesis: A mixed treatment comparison meta-analysis using Bayesian Markov Chain Monte Carlo simulation was used to perform the indirect comparison. The dataset comprised 34 trials: four comparing ertapenem versus piperacillin/tazobactam, one imipenem/cilastatin versus cefepime, 26 imipenem/cilastatin versus meropenem, three imipenem/cilastatin versus piperacillin/tazobactam. We calculated odds ratios (OR) using imipenem/cilastatin as the common comparator. Meropenem was associated with the highest probability of being the most effective treatment for clinical response (OR?1.52, 95% credible interval [CrI] 1.23–1.87) and bacteriological response (OR?1.45, 95%?CrI?1.15–1.80) with a reduced risk of serious adverse events (overall: OR?0.88, 95%?CrI?0.76–1.02; serious adverse events leading to withdrawal: OR?0.73, 95%?CrI?0.42–1.20; and GI-related: OR?0.76, 95%?CrI?0.55–1.02). There was little difference between the three carbapenems and cefepime on all-cause mortality.

Conclusions: This mixed treatment comparison suggests meropenem has substantial advantages over cefepime, ertapenem, imipenem/cilastatin and piperacillin/tazobactam in the treatment of hospitalised patients with infection.     

Extended-spectrum cephalosporins and the inoculum effect in tests with CTX-M-type extended-spectrum β-lactamase-producing Escherichia coli: Potential clinical implications of the revised CLSI interpretive criteria

Based on the new recommendations of the Clinical and Laboratory Standards Institute (CLSI), the revised cephalosporin breakpoints may result in many CTX-M-producing Escherichia coli being reported as susceptible to ceftazidime. We determined the activity of ceftazidime and other parenteral β-lactam agents in standard- and high-inoculum minimum inhibitory concentration (MIC) tests against CTX-M-producing E. coli isolates. Antimicrobial susceptibility was determined using a broth microdilution MIC method with inocula that differed 100-fold in density. An inoculum effect was defined as an eight-fold or greater increase in MIC on testing with the higher inoculum. When the revised CLSI ceftazidime breakpoint of 4 μg/mL was applied, 34 (34.3%) of the 99 CTX-M-producers tested were susceptible. More specifically, for 42 CTX-M-14-producing E. coli isolates, 32 (76.2%) were susceptible at 4 μg/mL. Cefotaxime, ceftazidime, cefepime and piperacillin/tazobactam were found to be associated with inoculum effects in 100% of the evaluable tests for extended-spectrum β-lactamase-producing E. coli isolates. The MIC₅₀ (MIC required to inhibit 50% of isolates) of ceftazidime was 16 μg/mL in the standard-inoculum tests and >512 μg/mL in the high-inoculum tests. In the high-inoculum tests including isolates encoding CTX-M-14, ceftazidime was dramatically affected, with susceptibility decreasing from 82.1% of isolates inhibited at 4 μg/mL in the standard-inoculum tests to 0% at high inoculum. Although further studies may demonstrate that ceftazidime has a role in the treatment of infections caused by these organisms, we suggest that until more data become available, clinicians should be cautious about treating serious CTX-M-producing E. coli infections with ceftazidime or cefepime.     

Antimicrobial susceptibility of inducible AmpC beta-lactamase-producing Enterobacteriaceae from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Programme,Europe 1997-2000

Among 11345 clinical isolates from 31 European centres in the MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) Programme (1997-2000), the potential AmpC-producing pathogens were Enterobacter spp. (904 cases), Citrobacter spp. (144) and Serratia marcescens (288). Resistance to ceftazidime or cefotaxime (11-34%) and piperacillin/tazobactam (12%) was observed, indicating stably derepressed expression of AmpC cephalosporinases. Meropenem (MIC(90), 0.25 mg/l; >99% susceptible) and imipenem (MIC(90), 2 mg/l; 98% susceptible) were active, even against these stably derepressed AmpC-producers: Enterobacter spp. (305 strains), Citrobacter spp. (29) and S. marcescens (35). The overall rank order of spectrum (% susceptible) versus the stably derepressed subset of isolates was: meropenem=imipenem (98%)>cefepime (89%)>gentamicin (73%)>ciprofloxacin (62%)>tobramycin (60%) >piperacillin/tazobactam (21%). We suggest increased attention in Europe to: (1) the recognition of these resistant phenotypes, (2) infection control practices, and (3) limiting the overuse of certain selecting extended-spectrum beta-lactam agents (e.g. ceftazidime).     

Ceftolozane/tazobactam for the treatment of complicated intra-abdominal infections

Introduction: Decisions regarding empirical antimicrobial therapy for complicated intra-abdominal infections (cIAIs) are increasingly difficult because of the threat of antimicrobial resistance. Extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae are a particular challenge, as is multidrug-resistant (MDR) Pseudomonas aeruginosa, both of which are encountered in cIAI. Ceftolozane/tazobactam is a new antimicrobial that provides an effective solution for treating cIAI.

Areas covered: Evidence concerning the mechanism of action of ceftolozane/tazobactam, its in vitro activity against common cIAI pathogens, and pharmacokinetic and pharmacodynamic properties are reviewed. The clinical efficacy and safety of ceftolozane/tazobactam plus metronidazole, as determined by the Phase II and III clinical trials in hospitalized adults with cIAI, are discussed.

Expert opinion: Ceftolozane/tazobactam has demonstrated efficacy and safety in patients with cIAI, including those who are infected with ESBL-producing Enterobacteriaceae and P. aeruginosa. High rates of clinical cure by ceftolozane/tazobactam in Phase II and III trials suggest that this antimicrobial will be valuable for treating infections caused by MDR Gram-negative bacteria. In recent years, clinicians have become dependent on carbapenems for treating MDR infections. There is concern that this could lead to emergence of carbapenem-resistant strains, emphasizing the importance of antimicrobial stewardship. Ceftolozane/tazobactam appears to be an effective carbapenem-sparing alternative for treating cIAI.