scholarly journals Carbapenem-Nonsusceptible Pseudomonas aeruginosa Isolates from Intensive Care Units in the United States: a Potential Role for New β-Lactam Combination Agents

2019 ◽  
Vol 57 (8) ◽  
Author(s):  
Tomefa E. Asempa ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Intensive Care ◽  
Respiratory Tract ◽  
Potential Role ◽  
The United States ◽  
Content Type ◽  
New Antibiotics ◽  
Susceptibility Profiles ◽  
Lactamase Inhibitor

ABSTRACT Pseudomonas aeruginosa, a frequent pathogen in the intensive care unit (ICU), has the propensity to develop antibiotic resistance. In particular, carbapenem-nonsusceptible (NS) P. aeruginosa poses tremendous challenges, and new antibiotics will be needed to treat this phenotype. Here we determine carbapenem nonsusceptibility rates for contemporary P. aeruginosa isolates from U.S. ICUs and in vitro activities of new β-lactam combination agents. Between July 2017 and June 2018, consecutive nonduplicate P. aeruginosa isolates from blood and respiratory tract sources were recovered from patients admitted to the ICUs of 36 geographically diverse U.S. hospitals. Antimicrobial susceptibility to the following antipseudomonal agents was tested: ceftazidime, imipenem, meropenem, ceftazidime-avibactam, and imipenem-relebactam (an investigational β-lactam/β-lactamase inhibitor). MICs and susceptibility rates were measured using Clinical and Laboratory Standards Institute reference broth microdilution methodology. Among the 538 consecutive ICU P. aeruginosa isolates collected, carbapenem nonsusceptibility was observed for 35% of the isolates and was more common among respiratory tract versus bloodstream specimens. Susceptibility rates, MIC50 values, and MIC90 values were as follows: ceftazidime-avibactam, 92.8%, 2 μg/ml, and 8 μg/ml; imipenem-relebactam, 91.5%, 0.25 μg/ml, and 2 μg/ml; ceftazidime, 77.1%, 4 μg/ml, and 64 μg/ml; meropenem, 72.7%, 1 μg/ml, and 16 μg/ml; imipenem, 67.1%, 2 μg/ml, and 16 μg/ml. Most (>75%) of the carbapenem-NS isolates were susceptible to ceftazidime-avibactam and imipenem-relebactam. In these U.S. hospital ICUs, carbapenem-NS P. aeruginosa isolates from respiratory sources were frequently observed. Novel β-lactam combination agents appear to retain active in vitro susceptibility profiles against these isolates and may play a role in the treatment of infections caused by carbapenem-NS P. aeruginosa strains.

scholarly journals In VitroAntibacterial Activity of the Ceftazidime-Avibactam (NXL104) Combination against Pseudomonas aeruginosa Clinical Isolates

2012 ◽  
Vol 56 (3) ◽  
pp. 1606-1608 ◽  
Author(s):  
Premavathy Levasseur ◽  
Anne-Marie Girard ◽  
Monique Claudon ◽  
Herman Goossens ◽  
Michael T. Black ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Antibacterial Activity ◽  
Content Type ◽  
Reference Treatment ◽  
Common Reference ◽  
Class A ◽  
Potent Inhibition ◽  
Efficient Protection ◽  
Lactamase Inhibitor

ABSTRACTThe β-lactamase inhibitor avibactam (NXL104) displays potent inhibition of both class A and C enzymes. Thein vitroantibacterial activity of the combination ceftazidime-avibactam was evaluated against a clinical panel ofPseudomonas aeruginosaisolates. Avibactam offered efficient protection from hydrolysis since 94% of isolates were susceptible to ceftazidime when combined with 4 μg/ml avibactam, compared with 65% susceptible to ceftazidime alone. Ceftazidime-avibactam also demonstrated better antipseudomonal activity than imipenem (82% susceptibility), a common reference treatment.

scholarly journals A Combination Antibiogram Evaluation for Pseudomonas aeruginosa in Respiratory and Blood Sources from Intensive Care Unit (ICU) and Non-ICU Settings in U.S. Hospitals

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Laura Puzniak ◽  
Daryl D. DePestel ◽  
Arjun Srinivasan ◽  
Gang Ye ◽  
John Murray ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Pseudomonas Aeruginosa ◽  
Intensive Care ◽  
Single Agent ◽  
Empirical Therapy ◽  
New Drugs ◽  
Research Database ◽  
Cross Sectional ◽  
Content Type

ABSTRACT Pseudomonas aeruginosa is an important pathogen associated with significant morbidity and mortality. U.S. guidelines for the treatment of hospital-acquired and ventilator-associated pneumonia recommend the use of two antipseudomonal drugs for high-risk patients to ensure that ≥95% of patients receive active empirical therapy. We evaluated the utility of combination antibiograms in identifying optimal anti-P. aeruginosa drug regimens. We conducted a retrospective cross-sectional analysis of the antimicrobial susceptibility of all nonduplicate P. aeruginosa blood and respiratory isolates collected between 1 October 2016 and 30 September 2017 from 304 U.S. hospitals in the BD Insights Research Database. Combination antibiograms were used to determine in vitro rates of susceptibility to potential anti-P. aeruginosa combination regimens consisting of a backbone antibiotic (an extended-spectrum cephalosporin, carbapenem, or piperacillin-tazobactam) plus an aminoglycoside or fluoroquinolone. Single-agent susceptibility rates for the 11,701 nonduplicate P. aeruginosa isolates ranged from 72.7% for fluoroquinolones to 85.0% for piperacillin-tazobactam. Susceptibility rates were higher for blood isolates than for respiratory isolates (P < 0.05). Antibiotic combinations resulted in increased susceptibility rates but did not achieve the goal of 95% antibiotic coverage. Adding an aminoglycoside resulted in higher susceptibility rates than adding a fluoroquinolone; piperacillin-tazobactam plus an aminoglycoside resulted in the highest susceptibility rate (93.3%). Intensive care unit (ICU) isolates generally had lower susceptibility rates than non-ICU isolates. Commonly used antipseudomonal drugs, either alone or in combination, did not achieve 95% coverage against U.S. hospital P. aeruginosa isolates, suggesting that new drugs are needed to attain this goal. Local institutional use of combination antibiograms has the potential to optimize empirical therapy of infections caused by difficult-to-treat pathogens.

scholarly journals New β-Lactam–β-Lactamase Inhibitor Combinations

2020 ◽  
Vol 34 (1) ◽  
Author(s):  
Dafna Yahav ◽  
Christian G. Giske ◽  
Alise Grāmatniece ◽  
Henrietta Abodakpi ◽  
Vincent H. Tam ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Treatment Option ◽  
Clinical Data ◽  
Multidrug Resistant ◽  
Drug Resistant ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Lactamase Inhibitor

SUMMARY The limited armamentarium against drug-resistant Gram-negative bacilli has led to the development of several novel β-lactam–β-lactamase inhibitor combinations (BLBLIs). In this review, we summarize their spectrum of in vitro activities, mechanisms of resistance, and pharmacokinetic-pharmacodynamic (PK-PD) characteristics. A summary of available clinical data is provided per drug. Four approved BLBLIs are discussed in detail. All are options for treating multidrug-resistant (MDR) Enterobacterales and Pseudomonas aeruginosa. Ceftazidime-avibactam is a potential drug for treating Enterobacterales producing extended-spectrum β-lactamase (ESBL), Klebsiella pneumoniae carbapenemase (KPC), AmpC, and some class D β-lactamases (OXA-48) in addition to carbapenem-resistant Pseudomonas aeruginosa. Ceftolozane-tazobactam is a treatment option mainly for carbapenem-resistant P. aeruginosa (non-carbapenemase producing), with some activity against ESBL-producing Enterobacterales. Meropenem-vaborbactam has emerged as treatment option for Enterobacterales producing ESBL, KPC, or AmpC, with similar activity as meropenem against P. aeruginosa. Imipenem-relebactam has documented activity against Enterobacterales producing ESBL, KPC, and AmpC, with the combination having some additional activity against P. aeruginosa relative to imipenem. None of these drugs present in vitro activity against Enterobacterales or P. aeruginosa producing metallo-β-lactamase (MBL) or against carbapenemase-producing Acinetobacter baumannii. Clinical data regarding the use of these drugs to treat MDR bacteria are limited and rely mostly on nonrandomized studies. An overview on eight BLBLIs in development is also provided. These drugs provide various levels of in vitro coverage of carbapenem-resistant Enterobacterales, with several drugs presenting in vitro activity against MBLs (cefepime-zidebactam, aztreonam-avibactam, meropenem-nacubactam, and cefepime-taniborbactam). Among these drugs, some also present in vitro activity against carbapenem-resistant P. aeruginosa (cefepime-zidebactam and cefepime-taniborbactam) and A. baumannii (cefepime-zidebactam and sulbactam-durlobactam).

scholarly journals Determination of the Dynamically Linked Indices of Fosfomycin for Pseudomonas aeruginosa in the Hollow Fiber Infection Model

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Arnold Louie ◽  
Michael Maynard ◽  
Brandon Duncanson ◽  
Jocelyn Nole ◽  
Michael Vicchiarelli ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Hollow Fiber ◽  
The United States ◽  
Infection Model ◽  
Combination Regimen ◽  
Bacterial Cells ◽  
Time Curve ◽  
Minimum Concentration ◽  
Content Type

ABSTRACT Fosfomycin is the only expoxide antimicrobial and is currently under development in the United States as an intravenously administered product. We were interested in identifying the exposure indices most closely linked to its ability to kill bacterial cells and to suppress amplification of less susceptible subpopulations. We employed the hollow fiber infection model for this investigation and studied wild-type strain Pseudomonas aeruginosa PAO1. Because of anticipated rapid resistance emergence, we shortened the study duration to 24 h but sampled the system more intensively. Doses of 12 and 18 g/day and schedules of daily administration, administration every 8 h, and administration by continuous infusion for each daily dose were studied. We measured fosfomycin concentrations (by liquid chromatography-tandem mass spectrometry), the total bacterial burden, and the burden of less susceptible isolates. We applied a mathematical model to all the data simultaneously. There was a rapid emergence of resistance with all doses and schedules. Prior to resistance emergence, an initial kill of 2 to 3 log 10 (CFU/ml) was observed. The model demonstrated that the area under the concentration-time curve/MIC ratio was linked to total bacterial kill, while the time that the concentration remained above the MIC (or, equivalently, the minimum concentration/MIC ratio) was linked to resistance suppression. These findings were also seen in other investigations with Enterobacteriaceae ( in vitro systems) and P. aeruginosa (murine system). We conclude that for serious infections with high bacterial burdens, fosfomycin may be of value as a new therapeutic and may be optimized by administering the agent as a continuous or prolonged infusion or by use of a short dosing interval. For indications such as ventilator-associated bacterial pneumonia, it may be prudent to administer fosfomycin as part of a combination regimen.

scholarly journals Factors Associated with Relative Rates of Antibiotic Resistance in Pseudomonas aeruginosa Isolates Tested in Clinical Laboratories in the United States from 1999 to 2002

2004 ◽  
Vol 48 (7) ◽  
pp. 2431-2436 ◽  
Author(s):  
Robert K. Flamm ◽  
Mellany K. Weaver ◽  
Clyde Thornsberry ◽  
Mark E. Jones ◽  
James A. Karlowsky ◽  
...  
Keyword(s):  
United States ◽  
Pseudomonas Aeruginosa ◽  
Nursing Home ◽  
Respiratory Tract ◽  
Antimicrobial Agents ◽  
The United States ◽  
Upper Respiratory Tract ◽  
Surveillance Network ◽  
Old Patients

ABSTRACT For the period from 1999 to 2002 in the United States, the in vitro susceptibilities of 52,637 Pseudomonas aeruginosa isolates to 10 antimicrobial agents were evaluated. The isolates were from 29 laboratories, 11 of which participated in The Surveillance Network for four consecutive years. Isolates were collected from adult patients (≥18 years of age) in intensive care units (ICU), non-ICU inpatients, nursing home patients, and outpatients; data were analyzed to evaluate factors, such as year of isolation, patient age group, isolate specimen source, and patient type (hospitalized patients [ICU, non-ICU, or nursing home] or outpatients). Rates of resistance for the 4-year period were highest for isolates from patients in ICU and 18- to 39-year-old patients and for isolates from the lower respiratory tract. Resistance decreased with age. Resistance was lowest in isolates from outpatients, in isolates from ≥70-year-old patients, and from specimens from the upper respiratory tract. Multidrug resistance (MDR) (resistance to three or more antimicrobial agents) accounted for 24.9% of all isolates. The MDR rate was highest in isolates from patients in nursing homes (29.9%) and ICU (29.5%).

scholarly journals Emergence of Ceftolozane-Tazobactam-Resistant Pseudomonas aeruginosa during Treatment Is Mediated by a Single AmpC Structural Mutation

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Shawn H. MacVane ◽  
Ruchi Pandey ◽  
Lisa L. Steed ◽  
Barry N. Kreiswirth ◽  
Liang Chen
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Wound Infection ◽  
Clinical Isolates ◽  
Content Type ◽  
Structural Mutation ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor

ABSTRACT Ceftolozane-tazobactam is a cephalosporin-β-lactamase inhibitor combination that exhibits potent in vitro activity against Pseudomonas aeruginosa, including strains that are resistant to other β-lactams. The emergence of ceftolozane-tazobactam resistance among clinical isolates of P. aeruginosa has rarely been described. Here we characterized ceftolozane-tazobactam-resistant P. aeruginosa strains recovered from a patient who was treated with this agent for 6 weeks for a recurrent wound infection. The results showed that the resistance was mediated by a single AmpC structural mutation.

scholarly journals Bacterial and Clinical Characteristics of Health Care- and Community-Acquired Bloodstream Infections Due to Pseudomonas aeruginosa

2013 ◽  
Vol 57 (8) ◽  
pp. 3969-3975 ◽  
Author(s):  
Angela Hattemer ◽  
Alan Hauser ◽  
Maureen Diaz ◽  
Marc Scheetz ◽  
Nirav Shah ◽  
...  
Keyword(s):  
Health Care ◽  
Pseudomonas Aeruginosa ◽  
Mortality Rate ◽  
Bacterial Resistance ◽  
Severity Of Illness ◽  
Bloodstream Infections ◽  
Content Type ◽  
Treatment Data ◽  
Susceptibility Profiles

ABSTRACTHealth care-associated infections, includingPseudomonas aeruginosabloodstream infection, have been linked to delays in appropriate antibiotic therapy and an increased mortality rate. The objective of this study was to evaluate intrinsic virulence, bacterial resistance, and clinical outcomes of health care-associated bloodstream infections (HCABSIs) in comparison with those of community-acquired bloodstream infections (CABSIs) caused byP. aeruginosa. We conducted a retrospective multicenter study of consecutiveP. aeruginosabacteremia patients at two university-affiliated hospitals. Demographic, clinical, and treatment data were collected. Microbiologic analyses includedin vitrosusceptibility profiles and type III secretory (TTS) phenotypes. Sixty CABSI and 90 HCABSI episodes were analyzed. Patients with HCABSIs had more organ dysfunction at the time of bacteremia (P= 0.05) and were more likely to have been exposed to antimicrobial therapy (P< 0.001) than those with CABSIs. Ninety-two percent of the carbapenem-resistantP. aeruginosainfections were characterized as HCABSIs. The 30-day mortality rate for CABSIs was 26% versus 36% for HCABSIs (P= 0.38). The sequential organ failure assessment score at the time of bacteremia (hazard ratio [HR], 1.2; 95% confidence interval [CI], 1.1 to 1.3) and the TTS phenotype (HR 2.1; 95% CI, 1.1 to 3.9) were found to be independent predictors of the 30-day mortality rate. No mortality rate difference was observed between CABSIs and HCABSIs caused byP. aeruginosa. Severity of illness and expression of TTS proteins were the strongest predictors of the 30-day mortality rate due toP. aeruginosabacteremia. FutureP. aeruginosabacteremia trials designed to neutralize TTS proteins are warranted.

scholarly journals Italian Survey on Comparative Levofloxacin Susceptibility in 334 Clinical Isolates of Pseudomonas aeruginosa

1999 ◽  
Vol 43 (2) ◽  
pp. 428-431 ◽  
Author(s):  
Bernardetta Segatore ◽  
Domenico Setacci ◽  
Mariagrazia Perilli ◽  
Nicola Franceschini ◽  
Annalisa De Santis ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Intensive Care ◽  
The Other ◽  
Clinical Isolates ◽  
In Vitro Activity ◽  
Italian Survey ◽  
Clinical Investigations ◽  
Susceptibility Profiles ◽  
Susceptibility Patterns

A national survey on susceptibility patterns of 334Pseudomonas aeruginosa isolates from intensive care units and hematology and oncology wards from 13 Italian hospitals compared the in vitro activity of levofloxacin, an injectable oral fluoroquinolone, to those of ciprofloxacin, ofloxacin, ceftazidime, imipenem, amikacin, and gentamicin. Amikacin and imipenem had the best susceptibility profiles. The activity of levofloxacin was superior to those of the other quinolones and was comparable to that of ceftazidime. The effect of levofloxacin in vitro on P. aeruginosa clinical isolates suggests that further clinical investigations are warranted.

scholarly journals In VitroActivity of Imipenem-Relebactam Alone or in Combination with Amikacin or Colistin againstPseudomonas aeruginosa

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Tomefa E. Asempa ◽  
David P. Nicolau ◽  
Joseph L. Kuti
Keyword(s):  
Potential Role ◽  
Multidrug Resistant ◽  
Synergistic Activity ◽  
Content Type ◽  
Class A ◽  
Susceptible Isolate ◽  
Time Kill ◽  
Lactamase Inhibitor

ABSTRACTRelebactam is a novel class A/C β-lactamase inhibitor that restores imipenemin vitroactivity against multidrug-resistant and carbapenem-nonsusceptiblePseudomonas aeruginosa. Time-kill analyses were performed to evaluate the potential role of imipenem-relebactam in combination with amikacin or colistin againstP. aeruginosa. Ten clinicalP. aeruginosaisolates (9 imipenem nonsusceptible) with imipenem-relebactam MICs ranging from 1/4 to 8/4 μg/ml were included. The isolates had varied susceptibilities to imipenem (1 to 32 μg/ml), amikacin (4 to 128 μg/ml), and colistin (0.5 to 1 μg/ml). Duplicate 24-h time-kill studies were conducted using the average steady-state concentrations (Cssavg) observed after the administration of imipenem-relebactam at 500 mg/250 mg every 6 hours (q6h) alone and in combination with theCssavgof 25 mg/kg of body weight/day amikacin and 360 mg/day colistin in humans. Imipenem-relebactam alone resulted in 24-h bacterial densities of −2.93 ± 0.38, −1.67 ± 0.29, +0.38 ± 0.96, and +0.15 ± 0.65 log10CFU/ml at imipenem-relebactam MICs of 1/4, 2/4, 4/4, and 8/4 μg/ml, respectively. No synergy was demonstrated against the single imipenem-susceptible isolate. Against the imipenem-nonsusceptible isolates (n = 9), imipenem-relebactam combined with amikacin resulted in synergy (−2.61 ± 1.50 log10CFU/ml) against all amikacin-susceptible isolates and in two of three amikacin-intermediate (i.e., MIC, 32 μg/ml) isolates (−2.06 ± 0.19 log10CFU/ml). Synergy with amikacin was not observed when the amikacin MIC was >32 μg/ml. Imipenem-relebactam combined with colistin demonstrated synergy in eight out of the nine imipenem-resistant isolates (−3.17 ± 1.00 log10CFU/ml). Against these 10 P. aeruginosaisolates, imipenem-relebactam combined with either amikacin or colistin resulted in synergistic activity against the majority of strains. Further studies evaluating combination therapy with imipenem-relebactam are warranted.

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