January 2019: Antimicrobial agents

Are standard doses of ceftriaxone adequate for critically ill patients with augmented renal clearance?  These data say no.  One of my favorite things about ceftriaxone is its simple dosing:  one gram daily for most indications, occasionally two grams daily (endocarditis, osteomyelitis, weird stuff like whipple’s and lyme) or twice daily (CNS infections), and no adjustments for renal or liver disease.  But alas, nothing can ever be simple. 

The authors conducted a prospective observational study in a single French SICU, examining the pharmacokinetics of ceftriaxone in adults who were given that drug for “sepsis” (defined here as suspected or proven infection along with end-organ dysfunction); they excluded patients with renal impairment or who were receiving renal replacement therapy.  The patients received 2g of ceftriaxone a day given as a 30-minute infusion, and the authors measure levels of ceftriaxone and albumin as well as creatinine clearance from days 1-3.  The authors stratified the patients into three groups by creatinine clearance: no augmented clearance (CrCl <150 ml/min), moderately augmented clearance (150-200 ml/min), and severely augmented clearance (>200 ml/min).  The clinical outcomes of interest included rates of death and therapeutic failure (defined as poor clinical response leading to a change in antimicrobials during therapy or within the following two weeks) as well as length of ICU stay.  The PK/PD outcomes included were the rates of ceftriaxone underdosing, defined both as the trough drug levels under the MIC (fTcmi<100%) and the trough drug levels under 4 times the MIC (fT4xcmi<100%).  The back half of the methods I really need a PharmD to explain to me using small words – but the gist is that the authors used population pharmacokinetic modeling to generate more generalizable conclusions.

Twenty-one patients were enrolled during the study period, all of whom received 2g ceftriaxone once daily, and from whom the authors obtained 126 drug concentrations.  The authors found empirical underdosing of ceftriaxone in 63% of patients, with a strong correlation between underdosing and CrCl >150 ml/min (OR 8.8; p<0.0001).  Among the 18 patients with proven infection, 24% of collected serum samples demonstrated underdosing using the definition of drug trough under the MIC, whereas 70% demonstrated underdosing using the drug trough under 4x MIC definition.  They did not find a significant association between underdosing of ceftriaxone and therapeutic failure – but with such a small sample size, what does that really mean?

In the population pharmacokinetic modeling analysis, probability of ceftriaxone target attainment (PTA) was significantly lower for individuals with a CrCl >200 ml/min versus others across multiple dosing regimens.  For an organism with a ceftriaxone MIC of 2 mg/L, the standard 2g daily dose given in this study resulted in a 76% PTA for people with a CrCl <150 ml/min, 55% with those with a CrCl 150-200 ml/min, and only 45% for those with a CrCl >200 min/min.  However, a dosing of 2g twice daily resulted in 99% PTA for an organism with an MIC of 2 across all three CrCl groups.

For me, the bottom line here is that standard daily dosing of ceftriaxone may not be adequate for patients with augmented renal function, particularly versus organisms with higher MICs to ceftriaxone.  Maybe it’s worth exploring more routine use of twice-daily dosing of ceftriaxone in the ICU setting?  30602511

Speaking of ceftriaxone, these French researchers performed a multicenter cohort study examining the tolerability of high-dose ceftriaxone in CNS infections.  They identified a total 196 patients who received a median 7 grams of ceftriaxone for a median 8 days.  Only 9% of patients had an adverse drug reaction, and only one patient had a drug reaction necessitating cessation of therapy.  Older age, male gender, renal impairment, and high trough levels of ceftriaxone were associated with adverse events.  So, don’t worry too much about pushing the ceftriaxone dose.  30698733


Dalbavancin appears to have a broad class synergy with beta-lactams. But will it prove clinically relevant?  Dalbavancin has the same mechanism of action as vancomycin but also has a lipid moiety that lets it anchor in the bacterial cell membrane and maximize its contact with the peptidoglycan wall, potentially giving it enhanced activity against bacterial with higher vancomycin MICs.  The authors took a convenience sample of 50 isolates of S. aureus with varying susceptibility patterns, then determined each isolate’s MICs to dalvabancin and a few beta-lactams (cefazolin, ceftraroline, cefepime, ertapenem, and oxacillin).  Next, they determined each isolate’s MICs to dalvabancin in the presence of 0.5x MIC of each beta-lactam to look for evidence of synergy.  Finally, the authors performed time-kill experiments in which they looked at the growth of each isolate in the presence of various combinations of dalbavancin and beta-lactams at subinhibitory MICs. 

The authors found dalbavancin MICs to be low even among the daptomycin-nonsusceptible and VISA isolates of MRSA; furthermore, combination with any beta-lactam consistently decreased the dalbavancin MIC  between 2 and >16-fold, and no beta-lactam was particularly more effective at this than another.  In the time-kill studies, all of the dalbavancin-beta-lactam combinations prevented bacterial regrowth and most lead to a >2-log kill at 24 hours.  Interestingly, dalvabancin-ceftaroline seemed to often be the least or second-least potent of the combinations – which supports the idea put forward by Berti et al that perhaps nonlethal effects on PBPs preventing bacteria from responding to glycopeptide attacks are what explain the synergy between glycopeptides and beta-lactams, rather than a direct antibacterial effect of the beta-lactam.  30260409


Daptomycin is supposed to synergize with beta-lactams – but versus a beta-lactam alone for MSSA bacteremia, it didn’t seem to do much. The next paper is a retrospective study comparing the outcomes of MSSA bacteremia treated with either beta-lactam monotherapy (i.e. an antistaphylococcal penicillin or cefazolin) or combination therapy with a beta-lactam plus 10mg/kg/day of daptomycin.  The authors obtained data from patients treated at a large medical center in Spain between 2011 and 2017; in total, 350 records were included in the cohort.  Patients who died within 48 hours of initiating antibiotics and patients who received other antibiotics were excluded from the analysis, and because the combination and monotherapy groups were clinically dissimilar, the authors used 2:1 propensity matching to create more comparable groups.

The cohort was 70% male, had a mean age of 63, and had a mean charlson score of 5 (i.e. a fair degree of comorbidity at baseline).  Catheter-related infections were most common and accounted for 31% of the bacteremias; 25% had high-risk sources of infection (e.g. endocarditis), 14% had septic shock at diagnosis, and 15% had persistent bacteremias.  Overall, 39% of the patients received the combination of daptomycin and a beta-lactam, most often cloxacillin (in 82%).  These patients were more likely to have endocarditis, had higher Pitt bacteremia scores, and were more likely to have persistent bacteremia.  In total, all-cause mortality at 30 and 90 days was not statistically different between the monotherapy and combination groups, though death occurred with greater numeric frequency in the combination group.  The lack of association between receipt of combination therapy and mortality remained after multivariate analysis and propensity matching. 

Now, one might argue that just because daptomycin and a beta-lactam isn’t better than a beta-lactam alone for MSSA, that doesn’t mean that said combination wouldn’t be better than daptomycin alone for MRSA.  But, it also seems increasingly probable that we’re just wasting a ton of money when we coprescribe daptomycin and ceftaroline.  30615122


When combining a beta-lactam with vancomycin in persistent MRSA bacteremia, does class matter?  This was a retrospective analysis of two observational studies - and should be interpreted with caution, as patients receiving beta-lactams in addition to vancomycin were probably being empirically treated for suspected gram-negative and/or anaerobic infections and hence clinically dissimilar from those given vancomycin alone.  The authors included patients from both studies who had received at least 72 hours of vancomycin, stratifying them into those who received at least 48 hours of concurrent beta-lactam therapy (combo group) and those who did not (vancomycin monotherapy group).  The primary outcome of interest was persistent S. aureus bacteremia (SAB) (>5 days), and was stratified by the type of beta-lactam used.

One hundred and fifty-six of the 177 patients in the previous two studies (88%) were included in this study’s cohort.  The median duration of beta-lactam therapy in the combo group was 5 days (IQR 3-8 days) and the groups were similar except for modestly higher vancomycin troughs in the combo group (17.8 vs 15.7).  Persistent SAB was less common in patients who received combination therapy (27% vs 44%; p=0.03) and receipt of combination therapy was the only factor associated with persistent bacteremia in multivariate analysis (aOR 0.423; 95% CI 0.21-0.84).  On the other hand, receipt of combination versus monotherapy also trended toward association with AKI (19% vs 8%; p=0.06).  When stratifying the results by class of beta-lactam used, persistent bacteremia occurred in 0% of carbapenem recipients, 32% of cephalosporin recipients, and 27% of penicillin recipients, whereas AKI occurred in 13% of carbapenem recipients, 16% of cephalosporin recipients, and 21% of penicillin recipients.  The last finding is presumably attributable to the known increased incidence of AKI with the combination of vancomycin and piperacilling-tazobactam, as well as the increased incidence of AKI with antistaphylococcal penicillins versus cephalosporins generally. 

It’s hard to compare these rates meaningfully as the individual sample sizes are so small – my takeaway is that that adding a beta-lactam to vancomycin for SAB might sterilize the blood cultures a few days earlier, but comes at the cost of AKI.  Is that a tradeoff of any meaningful consequence for length of hospitalization, long-term morbidity, or mortality?  We don’t have enough data to answer that properly, but I kinda doubt it. 30617094 


Good news: the macrolide & cardiac death association seems to be mostly linked to erythromycin, a drug no one should be using for CAP in anymore anyway.  The authors performed a post-hoc analysis of a previously conducted RTC comparing macrolides and fluoroquinolones for the treatment of community acquired pneumonia.  They included patients who had been admitted to the hospital wards (not the ICU) with a working diagnosis of CAP and who had not had a cardiac event on admission, then calculated the effect of patients’ exposure to macrolides and quinolones on their risk of subsequent cardiac event, defined as new or worsening heart failure, arrhythmia, or myocardial ischemia during the hospitalization.

A total 146 of the 2107 patients included in the analysis (7%) experienced cardiac events, including 101 with heart failure, 53 with arrhythmias, and 14 with myocardial infarctions.  Cardiac events occurred in 11/207 (5% ) of patients exposed to azithromycin, 18/250 (7%) of those exposed to clarithromycin, and 31/277 (11%) of those exposed to erythromycin; cardiac events occurred in 4%, 3%, and 4% of those exposed to ciprofloxacin, levofloxacin, and moxifloxacin, respectively.

(this is where we all take a moment to remind ourselves that ciprofloxacin is relatively impotent versus pneumococcus and is an accordingly lousy drug for CAP)

When compared to patients who received a beta-lactam, risk of developing a cardiac event was significantly elevated for erythromycin (HR 1.6; 95% CI 1.1-2.4), which was particularly driven by increased risk of heart failure (HR 1.8;95% CI 1.2-2.9).  In contrast, receipt of levofloxacin (HR 0.4; 95% CI 0.2-0.9) and moxifloxacin (HR 0.6; 95% CI 0.4-0.9) proved protective, and no association was observed with the other drugs.  These findings were unchanged after adjustment for confounders and in a subgroup analysis of patients with radiologically proven CAP.  So, at least in the case of CAP, the increased risk of cardiac events with macrolide therapy seems to be specifically associated with erythromycin.  Which is good, because erythromycin is terribly tolerated from a GI standpoint and there’s no good reason to be prescribing it over other macrolides anyway. 30612559