Carbapenemase-Producing \u3cem\u3ePseudomonas aeruginosa \u3c/em\u3e – an Emerging Challenge

Carbapenem-resistant Pseudomonas aeruginosa (CR-PA) is a major healthcare-associated pathogen worldwide. In the United States, 10–30% of P. aeruginosa isolates are carbapenem-resistant, while globally the percentage varies considerably. A subset of carbapenem-resistant P. aeruginosa isolates harbour carbapenemases, although due in part to limited screening for these enzymes in clinical laboratories, the actual percentage is unknown. Carbapenemase-mediated carbapenem resistance in P. aeruginosa is a significant concern as it greatly limits the choice of anti-infective strategies, although detecting carbapenemase-producing P. aeruginosa in the clinical laboratory can be challenging. Such organisms also have been associated with nosocomial spread requiring infection prevention interventions. The carbapenemases present in P. aeruginosa vary widely by region but include the Class A beta-lactamases, KPC and GES; metallo-beta-lactamases IMP, NDM, SPM, and VIM; and the Class D, OXA-48 enzymes. Rapid confirmation and differentiation among the various classes of carbapenemases is key to the initiation of early effective therapy. This may be accomplished using either molecular genotypic methods or phenotypic methods, although both have their limitations. Prompt evidence that rules out carbapenemases guides clinicians to more optimal therapeutic selections based on local phenotypic profiling of non-carbapenemase-producing, carbapenem-resistant P. aeruginosa. This article will review the testing strategies available for optimizing therapy of P. aeruginosa infections

Expression of the MexXY-OprM efflux system in Pseudomonas aeruginosa with discordant cefepime/ceftazidime susceptibility profiles

While MIC distributions and percent susceptibility for cefepime and ceftazidime are generally similar among Pseudomonas aeruginosa, we noted an increasing discordance in susceptibility favoring ceftazidime at our hospital. Quantitative reverse transcriptase-polymerase chain reaction was utilized to explore overexpression of the MexXY-OprM efflux as the mechanism for this phenotype profile. Thirteen of 15 (87%) randomly selected isolates had mexY gene expression levels of 5.8–40.8-fold relative to the wild-type reference strain. While mexY overexpression was noted in the majority of isolates, other resistance mechanisms appear to contribute to the observed phenotypic profile of the Pseudomonas aeruginosa studied. Clinicians must understand not only the magnitude of difference in the MIC profiles between agents, but also the mechanism(s) responsible for these observations if strategies (ie, pharmacodynamic dosing) are to be designed to optimize patient care outcomes in the face of increasing resistance

Prospective role of cefiderocol in the management of carbapenem-resistant Acinetobacter baumannii infections: Review of the evidence

Carbapenem-resistant Acinetobacter baumannii (CRAB) has been classified by the World Health Organization as being in the critical category of pathogens requiring urgent new antibiotic treatment options. Cefiderocol, the first approved siderophore cephalosporin, was designed for the treatment of carbapenem-resistant Gram-negative pathogens, particularly the non-fermenting species A. baumannii and Pseudomonas aeruginosa. Cefiderocol is mostly stable against hydrolysis by serine β-lactamases and metallo-β-lactamases, which are leading causes of carbapenem resistance. This review collates the available evidence on the in vitro activity, pharmacokinetics/pharmacodynamics, and efficacy and safety of cefiderocol, and outlines its current role in the management of CRAB infections. In vitro surveillance data show susceptibility rates of \u3e90% for cefiderocol against CRAB isolates as well as in vitro synergism with a variety of antibiotics recommended in guidelines. Clinical efficacy of cefiderocol monotherapy against CRAB infections has been demonstrated in the descriptive, open-label CREDIBLE-CR and the non-inferiority, double-blind APEKS-NP randomised clinical trials as well as in real-world cases in patients with underlying health problems. To date, the frequency of on-therapy development of cefiderocol resistance in A. baumannii appears to be low, but monitoring is highly recommended. Within current treatment guidelines for moderate-to-severe CRAB infections, cefiderocol is recommended for infections in which other antibiotics failed and in combination with other active antibiotics. In vivo pre-clinical data support the combination of sulbactam or avibactam with cefiderocol to enhance efficacy and to suppress the emergence of cefiderocol resistance. The benefit of combination therapy in the clinical setting is yet to be determined in prospective studies

Lung penetration, bronchopulmonary pharmacokinetic/pharmacodynamic profile and safety of 3 g of ceftolozane/tazobactam administered to ventilated, critically ill patients with pneumonia

Objectives: Ceftolozane/tazobactam is approved for hospital-acquired/ventilator-associated bacterial pneumonia at double the dose (i.e. 2 g/1 g) recommended for other indications. We evaluated the bronchopulmonary pharmacokinetic/pharmacodynamic profile of this 3 g ceftolozane/tazobactam regimen in ventilated pneumonia patients. Methods: This was an open-label, multicentre, Phase 1 trial (clinicaltrials.gov: NCT02387372). Mechanically ventilated patients with proven/suspected pneumonia received four to six doses of 3 g of ceftolozane/tazobactam (adjusted for renal function) q8h. Serial plasma samples were collected after the first and last doses. One bronchoalveolar lavage sample per patient was collected at 1, 2, 4, 6 or 8 h after the last dose and epithelial lining fluid (ELF) drug concentrations were determined. Pharmacokinetic parameters were estimated by noncompartmental analysis and pharmacodynamic analyses were conducted to graphically evaluate achievement of target exposures (plasma and ELF ceftolozane concentrations >4 mg/L and tazobactam concentrations >1 mg/L; target in plasma: similar to 30% and similar to 20% of the dosing interval, respectively). Results: Twenty-six patients received four to six doses of study drug; 22 were included in the ELF analyses. Ceftolozane and tazobactam T-max (6 and 2 h, respectively) were delayed in ELF compared with plasma (1h). Lung penetration, expressed as the ratio of mean drug exposure (AUC) in ELF to plasma, was 50% (ceftolozane) and 62% (tazobactam). Mean ceftolozane and tazobactam ELF concentrations remained >4 mg/L and >1mg/L, respectively, for 100% of the dosing interval. Therewere no deaths or adverse event-related study discontinuations. Conclusions: In ventilated pneumonia patients, 3 g of ceftolozane/tazobactam q8h yielded ELF exposures considered adequate to cover ceftolozane/tazobactam-susceptible respiratory pathogens

Directed Carbapenemase Testing Is No Longer Just for Enterobacterales: Cost, Labor, and Workflow Assessment of Expanding Carbapenemase Testing to Carbapenem-Resistant \u3cem\u3eP. aeruginosa\u3c/em\u3e

Molecular carbapenem-resistance testing, such as for the presence of carbapenemases genes, is commonly implemented for the detection of carbapenemase-producing Enterobacterales. Carbapenemase-producing P. aeruginosa is also associated with significant morbidity and mortality, although; prevalence may be underappreciated in the United States due to a lack of carbapenemase testing. The present study sought to compare hands-on time, cost and workflow implementation of carbapenemase gene testing in Enterobacterales and P. aeruginosa isolates versus sending out isolates to a public health laboratory (PHL) for testing to assess if in-house can provide actionable results. The time to carbapenemase gene results were compared. Differences in cost for infection prevention measures were extrapolated from the time of positive carbapenemase gene detection in-house versus PHL. The median time to perform carbapenemase gene testing was 7.5 min (range 5–14) versus 10 min (range 8–22) for preparation to send isolates to the PHL. In-house testing produced same day results compared with a median of 6 days (range 3–14) to receive results from PHL. Cost of in-house testing and send outs were similar ($46.92 versus$40.53, respectively). If contact precautions for patients are implemented until carbapenemase genes are ruled out, in-house testing can save an estimated $76,836.60 annually. Extension of in-house carbapenemase testing to include P. aeruginosa provides actionable results 3–14 days earlier than PHL Standard Pathway testing, facilitating guided therapeutic decisions and infection prevention measures. Supplemental phenotypic algorithms can be implemented to curb the cost of P. aeruginosa carbapenemases testing by identifying isolates most likely to harbour carbapenemases

Multidrug-Resistant Pseudomonas aeruginosa Infection in a Child with Cystic Fibrosis

ABSTRACT We describe a pediatric cystic fibrosis patient who developed a pulmonary exacerbation due to two multidrug-resistant (MDR) Pseudomonas aeruginosa isolates. In addition to these MDR organisms, the case was further complicated by β-lactam allergy. Despite the MDR phenotype, both isolates were susceptible to an antimicrobial combination

Carbapenem-resistant enterobacterales, carbapenem resistant organisms, carbapenemase-producing enterobacterales, and carbapenemase-producing organisms:Terminology past its 'sell-by-date' in an era of new antibiotics and regional carbapenemase epidemiology

Carbapenem resistance in Gram-negative bacteria is a public health concern. Consequently, numerous government and agency reports discuss carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant organisms (CROs). Unfortunately, these terms are fuzzy. Do they include (1) Proteeae with inherent imipenem resistance; (2) porin-deficient Enterobacterales resistant to ertapenem but not other carbapenems; (3) Enterobacterales with OXA-48-like enzymes that remain "carbapenem susceptible" at breakpoint; and (4) Pseudomonas aeruginosa that merely lack porin OprD? Counting CPE or CPOs is better but still insufficient, because different carbapenemases have differing treatment implications, particularly for new β-lactam/β-lactamase inhibitor combinations. At the least, it is essential for authors, journals, and regulatory agencies to specify the carbapenemases meant. The future may demand even greater precision, for mutations can alter hydrolytic activity, and the ability to confer resistance, within carbapenemase families

A pharmacodynamic analysis of resistance trends in pathogens from patients with infection in intensive care units in the United States between 1993 and 2004

<p>Abstract</p> <p>Background</p> <p>Increasing nosocomial pathogen resistance to available antimicrobial agents is of growing concern. While higher MICs can diminish antimicrobial effectiveness, dose adjustments often mitigate this effect. This study's objective was to ascertain whether MICs among major pathogens in the ICU to several commonly used agents have increased enough to significantly impact their ability to achieve bactericidal effect.</p> <p>Methods</p> <p>Cefepime, ceftriaxone, imipenem and piperacillin-tazobactam MICs were determined with 74,394 Gram-negative bacilli obtained from ICU patients with various infections in the US between 1993 and 2004. Results were grouped into four 3-year periods. The predicted cumulative fraction of response (CFR) was estimated based on patient-derived pharmacokinetic values and Monte Carlo simulation. Trends in CFR over the four study periods were assessed using the Cochran-Armitage test. The primary analysis included all organisms combined; <it>Pseudomonas aeruginosa </it>and <it>Acinetobacter </it>species were also evaluated individually.</p> <p>Results</p> <p>In the primary analysis, imipenem 500 mg q6h showed CFRs from 87% to 90% across all four study periods, with a trend toward slightly improved bactericidal target attainment (p < 0.01). CFRs for cefepime 2 g q12h and piperacillin-tazobactam 4.5 g q6h both declined by 2% (p < 0.01 and p < 0.05, respectively), reflecting upward shifts in the underlying MIC distributions. Ceftriaxone had <52% CFR for all regimens in all periods, with no significant trend. Against <it>P. aeruginosa</it>, significant declines in CFR were seen for (range, p-value): imipenem 1 g q8h (82%–79%, p < 0.01), cefepime 1 g q12h (70%–67%, p < 0.01), cefepime 2 g q12h (84%–82%, p < 0.05), piperacillin-tazobactam 3.375 g q6h (76%–73%, p < 0.01), piperacillin-tazobactam 4.5 g q8h (71%–68%, p < 0.01), and piperacillin-tazobactam 4.5 g q6h (80%–77%, p < .01). Against <it>Acinetobacter </it>spp., all regimens of imipenem, cefepime and piperacillin-tazobactam showed significant declines in CFR over time (p < 0.01).</p> <p>Conclusion</p> <p>Our observations suggest that as a result of increasing antimicrobial resistance among ICU pathogens in the US, drug effectiveness, assessed as a function of individual agents' ability to attain pharmacodynamic targets, has declined, especially with <it>P. aeruginosa </it>and <it>Acinetobacter </it>spp. Cefepime 2 g q8h and imipenem were the most potent agents against these species, respectively. More aggressive dosing of all of the agents characterized could preserve their clinical utility, but this must be balanced with safety and tolerability issues by the physician.</p