In vitro activity of ceftolozane/tazobactam against clinical isolates of Pseudomonas aeruginosa in the planktonic and biofilm states.
TL;DR: The combination of the novel cephalosporin, ceftolozane, with the β-lactamase inhibitor, tazobactam, is tested against planktonic and biofilm forms of 54 clinical isolates of P. aeruginosa, using cefepime as a comparator.
About: This article is published in Diagnostic Microbiology and Infectious Disease.The article was published on 2016-07-01. It has received 14 citations till now. The article focuses on the topics: Ceftolozane & Tazobactam.
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TL;DR: The evaluation of the potential use of ITCs to replace or support the common antibiotics and their mechanism of action against human pathogens for which the current therapeutic solutions are deficient and therefore of prime importance for public health is evaluated.
Abstract: The use of plant-derived products as antimicrobial agents has been investigated in depth. Isothiocyanates (ITCs) are bioactive products resulting from enzymatic hydrolysis of glucosinolates (GLs), the most abundant secondary metabolites in the botanical order Brassicales. Although the antimicrobial activity of ITCs against foodborne and plant pathogens has been well documented, little is known about their antimicrobial properties against human pathogens. This review collects studies that focus on this topic. Particular focus will be put on ITCs’ antimicrobial properties and their mechanism of action against human pathogens for which the current therapeutic solutions are deficient and therefore of prime importance for public health. Our purpose was the evaluation of the potential use of ITCs to replace or support the common antibiotics. Even though ITCs appear to be effective against the most important human pathogens, including bacteria with resistant phenotypes, the majority of the studies did not show comparable results and thus it is very difficult to compare the antimicrobial activity of the different ITCs. For this reason, a standard method should be used and further studies are needed.
120 citations
Cites background from "In vitro activity of ceftolozane/ta..."
...The acquisition of new resistance phenotypes underlines the need for new antibiotic therapeutic strategies and anti-biofilm molecular compounds [90,92,93,98,99]....
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TL;DR: C/T is especially valuable in suspected or documented severe infections due to MDR P. aeruginosa, which is not a rare occurrence in many countries, and may provide an alternative to carbapenems for the treatment of infections caused by ESBL-producers, thus allowing acarbapenem-sparing strategy.
Abstract: Introduction: Ceftolozane/tazobactam (C/T) is a new antibiotic resulting from the combination of a novel cephalosporin, structurally similar to ceftazidime, with tazobactam, a well-known beta-lacta...
91 citations
Cites background from "In vitro activity of ceftolozane/ta..."
...aeruginosa is not affected by functionality of the OprD porin [17,18], ceftolozane exhibits an anti-Pseudomonas activity which is overall superior than that of other anti-Pseudomonas β-lactams (see below, surveillance data), and was also demonstrated against strains grown in biofilms [19,20]....
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TL;DR: This article summarises the new antibiotics that have recently been approved for Gram-negative bacterial infections, looks down the pipeline at promising agents currently in phase I, II, or III clinical trials, and introduces new alternative avenues that show potential in combating multidrug-resistant Gram- negative bacteria.
65 citations
TL;DR: ITCs represent a promising group of natural anti-infective compounds with activity against Pa biofilms and combining ITCs with meropenem synergistically increased antimicrobial efficacy on PaBiofilms.
59 citations
TL;DR: Combinations of colistin plus ceftolozane/tazobactam and meropenem were the most appropriate treatments for biofilm-related infections caused by XDR and MDR P. aeruginosa strains, respectively.
25 citations
References
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01 Jan 2000
16,612 citations
TL;DR: Minimal biofilm eradication concentrations, derived by using the Calgary Biofilm Device, demonstrated that for biofilms of the same organisms, 100 to 1,000 times the concentration of a certain antibiotic were often required for the antibiotic to be effective, while other antibiotics were found to beeffective at the MICs.
Abstract: Determination of the MIC, based on the activities of antibiotics against planktonic bacteria, is the standard assay for antibiotic susceptibility testing. Adherent bacterial populations (biofilms) present with an innate lack of antibiotic susceptibility not seen in the same bacteria grown as planktonic populations. The Calgary Biofilm Device (CBD) is described as a new technology for the rapid and reproducible assay of biofilm susceptibilities to antibiotics. The CBD produces 96 equivalent biofilms for the assay of antibiotic susceptibilities by the standard 96-well technology. Biofilm formation was followed by quantitative microbiology and scanning electron microscopy. Susceptibility to a standard group of antibiotics was determined for National Committee for Clinical Laboratory Standards (NCCLS) reference strains: Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, and Staphylococcus aureus ATCC 29213. Growth curves demonstrated that biofilms of a predetermined size could be formed on the CBD at specific time points and, furthermore, that no significant difference (P > 0.1) was seen between biofilms formed on each of the 96 pegs. The antibiotic susceptibilities for planktonic populations obtained by the NCCLS method or from the CBD were similar. Minimal biofilm eradication concentrations, derived by using the CBD, demonstrated that for biofilms of the same organisms, 100 to 1,000 times the concentration of a certain antibiotic were often required for the antibiotic to be effective, while other antibiotics were found to be effective at the MICs. The CBD offers a new technology for the rational selection of antibiotics effective against microbial biofilms and for the screening of new effective antibiotic compounds.
1,880 citations
TL;DR: Time-kill experiments and animal infection models have demonstrated that the pharmacokinetic–pharmacodynamic index that is best correlated with ceftolozane’s in vivo efficacy is the percentage of time in which free plasma drug concentrations exceed the minimum inhibitory concentration of a given pathogen, as expected of β-lactams.
Abstract: Ceftolozane is a novel cephalosporin currently being developed with the β-lactamase inhibitor tazobactam for the treatment of complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAIs), and ventilator-associated bacterial pneumonia (VABP). The chemical structure of ceftolozane is similar to that of ceftazidime, with the exception of a modified side-chain at the 3-position of the cephem nucleus, which confers potent antipseudomonal activity. As a β-lactam, its mechanism of action is the inhibition of penicillin-binding proteins (PBPs). Ceftolozane displays increased activity against Gram-negative bacilli, including those that harbor classical β-lactamases (e.g., TEM-1 and SHV-1), but, similar to other oxyimino-cephalosporins such as ceftazidime and ceftriaxone, it is compromised by extended-spectrum β-lactamases (ESBLs) and carbapenemases. The addition of tazobactam extends the activity of ceftolozane to include most ESBL producers as well as some anaerobic species. Ceftolozane is distinguished from other cephalosporins by its potent activity versus Pseudomonas aeruginosa, including various drug-resistant phenotypes such as carbapenem, piperacillin/tazobactam, and ceftazidime-resistant isolates, as well as those strains that are multidrug-resistant (MDR). Its antipseudomonal activity is attributed to its ability to evade the multitude of resistance mechanisms employed by P. aeruginosa, including efflux pumps, reduced uptake through porins and modification of PBPs. Ceftolozane demonstrates linear pharmacokinetics unaffected by the coadministration of tazobactam; specifically, it follows a two-compartmental model with linear elimination. Following single doses, ranging from 250 to 2,000 mg, over a 1-h intravenous infusion, ceftolozane displays a mean plasma half-life of 2.3 h (range 1.9–2.6 h), a steady-state volume of distribution that ranges from 13.1 to 17.6 L, and a mean clearance of 102.4 mL/min. It demonstrates low plasma protein binding (20 %), is primarily eliminated via urinary excretion (≥92 %), and may require dose adjustments in patients with a creatinine clearance <50 mL/min. Time-kill experiments and animal infection models have demonstrated that the pharmacokinetic–pharmacodynamic index that is best correlated with ceftolozane’s in vivo efficacy is the percentage of time in which free plasma drug concentrations exceed the minimum inhibitory concentration of a given pathogen (%fT
>MIC), as expected of β-lactams. Two phase II clinical trials have been conducted to evaluate ceftolozane ± tazobactam in the settings of cUTIs and cIAIs. One trial compared ceftolozane 1,000 mg every 8 h (q8h) versus ceftazidime 1,000 mg q8h in the treatment of cUTI, including pyelonephritis, and demonstrated similar microbiologic and clinical outcomes, as well as a similar incidence of adverse effects after 7–10 days of treatment, respectively. A second trial has been conducted comparing ceftolozane/tazobactam 1,000/500 mg and metronidazole 500 mg q8h versus meropenem 1,000 mg q8h in the treatment of cIAI. A number of phase I and phase II studies have reported ceftolozane to possess a good safety and tolerability profile, one that is consistent with that of other cephalosporins. In conclusion, ceftolozane is a new cephalosporin with activity versus MDR organisms including P. aeruginosa. Tazobactam allows the broadening of the spectrum of ceftolozane versus β-lactamase-producing Gram-negative bacilli including ESBLs. Potential roles for ceftolozane/tazobactam include empiric therapy where infection by a resistant Gram-negative organism (e.g., ESBL) is suspected, or as part of combination therapy (e.g., with metronidazole) where a polymicrobial infection is suspected. In addition, ceftolozane/tazobactam may represent alternative therapy to the third-generation cephalosporins after treatment failure or for documented infections due to Gram-negative bacilli producing ESBLs. Finally, the increased activity of ceftolozane/tazobactam versus P. aeruginosa, including MDR strains, may lead to the treatment of suspected and documented P. aeruginosa infections with this agent. Currently, ceftolozane/tazobactam is being evaluated in three phase III trials for the treatment of cUTI, cIAI, and VABP.
278 citations
TL;DR: The findings of this study illustrate that antibiotic sensitivities are dependent on culture conditions and highlight the complexities of choosing appropriate combination therapy for multidrug-resistant P. aeruginosa in the CF lung.
Abstract: Recent studies have determined that Pseudomonas aeruginosa can live in a biofilm mode within hypoxic mucus in the airways of patients with cystic fibrosis (CF). P. aeruginosa grown under anaerobic and biofilm conditions may better approximate in vivo growth conditions in the CF airways, and combination antibiotic susceptibility testing of anaerobically and biofilm-grown isolates may be more relevant than traditional susceptibility testing under planktonic aerobic conditions. We tested 16 multidrug-resistant isolates of P. aeruginosa derived from CF patients using multiple combination bactericidal testing to compare the efficacies of double and triple antibiotic combinations against the isolates grown under traditional aerobic planktonic conditions, in planktonic anaerobic conditions, and in biofilm mode. Both anaerobically grown and biofilm-grown bacteria were significantly less susceptible (P < 0.01) to single and combination antibiotics than corresponding aerobic planktonically grown isolates. Furthermore, the antibiotic combinations that were bactericidal under anaerobic conditions were often different from those that were bactericidal against the same organisms grown as biofilms. The most effective combinations under all conditions were colistin (tested at concentrations suitable for nebulization) either alone or in combination with tobramycin (10 microg ml(-1)), followed by meropenem combined with tobramycin or ciprofloxacin. The findings of this study illustrate that antibiotic sensitivities are dependent on culture conditions and highlight the complexities of choosing appropriate combination therapy for multidrug-resistant P. aeruginosa in the CF lung.
228 citations
TL;DR: Ceftolozane/tazobactam demonstrated high potency and broad-spectrum activity against many contemporary Enterobacteriaceae and P. aeruginosa isolates collected in U.S. medical centers.
Abstract: Ceftolozane/tazobactam, a novel antimicrobial agent with activity against Pseudomonas aeruginosa (including drug-resistant strains) and other common Gram-negative pathogens (including most extended-spectrum-β-lactamase [ESBL]-producing Enterobacteriaceae strains), and comparator agents were susceptibility tested by a reference broth microdilution method against 7,071 Enterobacteriaceae and 1,971 P. aeruginosa isolates. Isolates were collected consecutively from patients in 32 medical centers across the United States during 2011 to 2012. Overall, 15.7% and 8.9% of P. aeruginosa isolates were classified as multidrug resistant (MDR) and extensively drug resistant (XDR), and 8.4% and 1.2% of Enterobacteriaceae were classified as MDR and XDR. No pandrug-resistant (PDR) Enterobacteriaceae isolates and only one PDR P. aeruginosa isolate were detected. Ceftolozane/tazobactam was the most potent (MIC50/90, 0.5/2 μg/ml) agent tested against P. aeruginosa and demonstrated good activity against 310 MDR strains (MIC50/90, 2/8 μg/ml) and 175 XDR strains (MIC50/90, 4/16 μg/ml). Ceftolozane/tazobactam exhibited high overall activity (MIC50/90, 0.25/1 μg/ml) against Enterobacteriaceae and retained activity (MIC50/90, 4/>32 μg/ml) against many 601 MDR strains but not against the 86 XDR strains (MIC50, >32 μg/ml). Ceftolozane/tazobactam was highly potent (MIC50/90, 0.25/0.5 μg/ml) against 2,691 Escherichia coli isolates and retained good activity against most ESBL-phenotype E. coli isolates (MIC50/90, 0.5/4 μg/ml), but activity was low against ESBL-phenotype Klebsiella pneumoniae isolates (MIC50/90, 32/>32 μg/ml), explained by the high rate (39.8%) of meropenem coresistance observed in this species phenotype. In summary, ceftolozane/tazobactam demonstrated high potency and broad-spectrum activity against many contemporary Enterobacteriaceae and P. aeruginosa isolates collected in U.S. medical centers. Importantly, ceftolozane/tazobactam retained potency against many MDR and XDR strains.
186 citations