July 2019: Antimicrobial agents

Imipenem-relebactam is active against KPC-type CREs, but you’ll need to look elsewhere for reliable coverage of isolates with OXA-48-mediated carbapenem resistance.  Imipenem-cilastin-relebactam (hereafter, imipenem-relebactam) was approved by the FDA a couple of weeks ago and should be available in the US later this year.  The approval was based on the RESTORE-IMI trial, which showed comparable activity of this drug vs colistin + regular imipenem-cilastin in 47 patients with HAP/VAP, cUTI, or cIAI.  You’ll all recognize imipenem-cilastin as that weird carbapenem with the pharmacokinetic booster your hospital’s formulary passed over for meropenem; relebactam, which is new, is a non-beta-lactam beta-lactamase inhibitor that’s structurally most closely related to avibactam. 

In this study, researchers from Cornell took 106 KPC-type and 20 OXA-48-type carbapenem-resistant Enterobactericaea (CRE) bloodstream isolates and determined their susceptibility to a number of antimicrobials, including imipenem-relebactam and ceftrazidime-avibactam.  They used standard CLSI breakpoints for each drug; for imipenem-relebactam, which has no official breakpoints yet, they used the breakpoints for imipenem.  Of the tested agents, only eight (imipenem-relebactam, ceftaz-avi, colistin, polymixin B, amikacin, gentamicin, minocycline, and tigecycline) were active against >50% of all 126 isolates, and only two (imipenem-relebactam and ceftaz-avi) were active against >90%.  Within the subset of CREs with OXA-48 mediated resistance, only four agents (ceftaz-avi, colistin, polymixin B, and tigecycline) were active against >50% of isolates, and only three (ceftaz-avi, colistin, and polymixin B) were active against >90%.  Relebactam failed to restore the activity of imipenem against OXA-48 mediated CREs. In contrast, both imipenem-relebactam and ceftaz-avibactam retained >98% activity against KPC-type CREs.

So to summarize, imipenem-relebactam works just as well as ceftaz-avi for the KPC-type CREs that predominate in US medical centers; however, imipenem-relebactam is ineffective for CREs with OXA-48 mediated carbapenem resistance, making ceftaz-avi the beta-lactam of choice in that scenario. 31262761 

fAUC/MIC modeling of combination antibiotic therapy with daptomycin for enterococcal bacteremia supports a preference for 10-12mg/kg daily dosing. (Disclosure: I know and trained with one of the authors, Sam Aitken, at MDACC). Previous research has established a fAUC/MIC cutoff associated with 30-day survival in daptomycin monotherapy for enterococcal bacteremia; however, in practice many of these patients receive some sort of combination therapy.  In this study, the authors pooled data from 7 clinical trials of daptomycin treatment for enterococcal bacteremia, including patients who received at least 72 hours of daptomycin in combination with either a beta-lactam, aminoglycoside, linezolid, tigecycline, or vancomycin.  They calculated the patients’ daptomycin exposures based on previously published model, then used CART analysis to identify a fAUC/MIC threshold associated with 30-day survival. Finally, they used Monte Carlo simulation to determine the probability of attaining the fAUC/MIC threshold using daptomycin doses of 8, 10, and 12mg/kg, in a patient population with CrCl ranging from 30 to 150 mL/min and a distribution of body weights abstracted from the pooled study cohort.

Their pooled cohort included 240 patients, >90% of whom received a beta-lactam as the second drug, and the overwhelming majority of whom had enterococcal isolates with daptomycin MICs ranging from 1-4 mg/L.  The overall 30-day survival rate was 57%; CART analysis identified an optimally discriminatory fAUC/MIC threshold of 12.2, with 59% of patients reaching the threshold surviving to 30 days versus 33% of those with a fAUC/MIC <12.2 (p=0.099).  The researchers observed similar findings in subset of low-acuity patients analyzed in attempt to account for non-infectious syndromes confounding mortality (fAUC/MIC threshold of 12.3 with 63% 30-day survival in those reaching the threshold versus 20% in those not reaching the threshold, p=0.015).  In the Monte Carlo simulation, probability of target attainment for a fAUC/MIC of 12.3 dropped below 90% for the 6mg/kg and 8mg/kg daptomycin doses when the daptomycin MIC reached 4 mg/L, but was preserved for the 10mg/kg and 12mg/kg daptomycin doses.

So, these data suggest that while combination antibiotic therapy with standard dose daptomycin may be effective for bacteremia with enterococci in the fully susceptible range (i.e. daptomycin MIC <1 mg/L), isolates in the dose-dependent susceptible range (2-4 mg/L) will be treated more effectively with high-dose daptomycin. Good job, whoever set those MIC thresholds for “dose-dependent susceptible”! 31284042

Patients with enhanced renal function may require higher than standard doses of cefazolin to reach therapeutic targets.   This is potentially a critical component of dealing with MSSA bacteremia in our young patients who use injection drugs. When we consult on such patients getting standard doses of vancomycin for MRSA bacteremia (e.g. 1g q12h), they frequently have vancomycin trough levels ranging from ~5 to undetectable on account of their awesome kidneys, and while vancomycin troughs don’t actually predict outcome in SAB and we should all be dosing for AUC/MIC targets instead, I suspect an undetectable vancomcyin trough reflects subtherapeutic dosing in the majority of cases.  Anyway, given that maintaining beta-lactam concentrations over the MIC >50% (or even better, 100%) of the time is associated with a better outcome in patients with severe infections (see also: 24429437), why should cefazolin dosing in the glomerularly gifted be any different?

This group out of France examined data from a cohort of patients treated with continuous infusion cefazolin with therapeutic dose monitoring for bacteremia and endocarditis over a five year period. They split the data into model training and validation sets, then built a population pharmacokinetic model for cefazolin elimination.  Finally, they used Monte Carlo simulation (n=1000) with total daily doses ranging from 500mg to 500,000mg and a distribution of GFRs reflecting their actual patient population. Their goal was to generate probabilities of target attainment for cefazolin at 40mg/L (the target for 100% T>MIC at the EUCAST S.aureus breakpoint of 2mg/L).  They converted this data into a dosing nomogram showing the lowest cefazolin doses needed to achieved >90% PTA across a range of renal functions.

The authors generated their model based on 162 patients with a total 346 cefazolin plasma concentrations; of these patients, 16% had a GFR >120 mL/min. The authors described the model as one-compartment and elaborate with some equations that a PharmD would understand but I don’t; cutting to the chase, the validation cohort showed that the model accurately predicted the relationship between cefazolin dosing and serum concentrations, though it lost accuracy when the the GFR fell to very low values.

Figure 3 of the paper shows the resultant dosing nomogram, with the lower full line indicating the total daily doses needed to achieve >90% PTA at 40mg/L, which again would be optimal for treating MSSA at the breakpoint of susceptibility. Six grams a day of cefazolin was adequate for someone with a GFR of up to ~90mL/min - though remember that this is cefazolin given by continuous infusion, which is pharmacokinetically optimal dose administration for a beta-lactam, so 2g every eight hours with 30min infusions is probably NOT adequate for someone with that GFR.  Conversely, someone with a GFR of 120mL/min would need 8g of cefazolin a day, and someone with a GFR of 140mL/min 10g a day.  Consider this the next time you see a young person with persistent MSSA bacteremia being treated with cefazolin. 31307987

Which is better for Enterobacter pneumonia: piperacillin-tazobactam, or either cefepime or ertapenem?  The antimicrobial resistance subtext of this question is “can you get away with treating an organism with an inducible ampC beta-lactamase with a beta-lactam that is susceptible to but doesn’t strongly induce the ampC (i.e. pip-taz), or are you better off picking a drug that is ampC-resistant? (i.e.; cefepime or erta).  I’m not sure why anyone would go out of their way to choose pip-taz over cefepime in this situation in the first place, though I guess pip-taz, if it worked well enough for inducible ampC producers, would be a more stewardship-friendly alternative to ertapenem.  So, does it work well enough?

The authors examined the records of 114 patients given definitive treatment for Enterobacter pneumonia (59, pip-tazo; 26 cefepime; 29 ertapenem).  Their inclusion criteria included isolation of an Enterobacter from a respiratory culture + radiographic and clinical evidence of pneumonia and switch to definitive therapy within 72 hours; their exclusion criteria included ESBL positivity, concomitant pneumonia with non-lactose fermenting GNRs, and other inadequately treated concomitant infections. The primary outcome of interest was clinical cure at seven days (or at discharge, if that occurred sooner).  The studied patients had a median age of 61 and were mostly men; baseline characteristics were similar between groups.  Nearly two-thirds of the isolates were E.cloacae and 98% demonstrated cefoxitin resistance (traditionally considered the harbinger of the ampC phenotype, though these data drive home the point that it’s easier and reasonable to simply regard all Enterobacter as having an inducible ampC).  Across all 114 isolates, susceptibility to pip-taz was reported as intermediate or resistant in 18% of cases, versus 6% for cefepime and 2% for ertapenem.

Patients given cefepime or ertapenem had comparable but modestly higher rates of clinical cure than those given pip-taz (87% vs 76%; p=0.13); in multivariate analysis, pip-taz was associated with a lower rate of clinical cure, to a clinically important degree but with wide confidence intervals (OR 0.59; 95% CI 0.15-2.37).  The authors report these data as suggesting that pip-taz and cefepime/erta yield equivalent outcomes, but I think most ID docs would regard an absolute difference in cure rates of 11% as worth preferring cefepime or ertapenem if only that p value was lower.  In my mind, these data suggest caution in using pip-taz for Enterobacter pneumonia until more data (and ideally prospective or clinical trial data) are available. 31319191

Beware subtherapeutic dosing of ethambutol in patients receiving TB treatment in combination with ART.  The authors prostpectively studied ethambutol pharmacokinetics in Botswanan patients starting TB treatment before and after initiation of ART.  They excluded patients who were pregnant or had renal insufficiency (defined here as CrCl <50mL/min).  Five days to 4 weeks after starting TB therapy, the participants had serum ethambutol levels measured; all participants were eligible for a second visit after starting ART.  At each visit, patients received six blood draws over the course of 8 hours.  The researchers used these data to general a population pharmacokinetic model of ethambutol in patients with HIV who are receiving treatment for tuberculosis, then used Monte Carlo simulations to generate probabilities of target attainment for an ethambutol 24hr AUC/MIN of 119 in lung tissue (chosen based on prior ethambutol modelling papers) for both the standard weight-based ethambutol dosing and an intensified strategy consisting of a second 400mg dose administered daily regardless of body weight.

A total 40 patients attended the first visit, and 24 of these returned for the post-ART initiation visit a mean 33 days later.  A two-compartment model best described ethambutol’s pharmacokinetics; bootstrap analysis and data from a second HIV/TB pharmacokinetic study validated the model.  Monte Carlo simulations demonstrated that probability of target attainment for ethambutol given an isolate with an MIC of 2mg/L was 16% for standard dosing versus 38% for intensified dosing before initiation of ART, and 17% versus 64% for standard and intensified dosing after ART.  PTA was higher among patients with greater body weight under all conditions.  The model also suggested that therapeutic doses of ethambutol were unattainable with either standard or intensified treatment regimens given an isolate with an ethambutol MIC of 4mg/L, suggesting that may be an appropriate breakpoint for this organism in patients with HIV on ART.

So, this paper suggests that therapeutic dosing of ethambutol may be difficult to achieve in patients with TB and HIV, and that an intensified schedule of ethambutol include a second 400mg dose each day may improve the odds of reaching therapeutic drug levels, particularly in patients who have started ART.  Speaking of which – my biggest beef with this paper is that I couldn’t find a description of the types of ART these patients received in either the main text or the supplementary data.  Given that this is a pharmacokinetics paper and that antiretrovirals have a wide and class-dependent variety of drug interactions, that seems like an important omission. 31273386