June 2018: Antimicrobial Agents

When it comes to treating Candida glabrata fungemia with fluconazole, it's the dose that matters most. When I was a resident, I was taught that C. albicans was always sensitive to fluconazole, C. krusei was always resistant to fluconazole, and C. glabrata followed the rule of thirds: one third were susceptible, one third were resistant, and one third were "dose-dependent susceptible." Well, this study suggests that most C. glabrata have dose-dependent susceptibility to fluconazole. The authors looked at 127 patients with C. glabrata fungemia who’d been treated with fluconazole. They found neither the isolate's MIC or the achieved fluconazole AUC/MIC correlated with a good outcome. Instead, patient survival was strongly associated with increased fluconazole dose, with patients who received at least 400mg/day of fluconazole having a 28-day survival rate of 90% and nearly 4-fold higher rate of survival than those who received lower doses.

Of note, the only subgroup in the study with 100% survival was the group treated with 600-800mg of fluconazole (n=3 though so take it with a grain of salt), which suggests that the IDSA guideline's expert opinion recommendation to use the 800mg daily dose of fluconazole for C. glabrata fungemia is on the right track. PMID: 29581112


Which drug is safer for long-term use with OPAT: vancomycin or daptomycin? It probably won't surprise anyone that the answer to a question about drug safety is "not vancomycin." The authors looked at three years of OPAT data including 312 patients treated with vancomycin and 105 patients treated with daptomcyin. In multivariate analysis, they found vancomycin was associated with more adverse events than daptomycin (aOR 3.71; the raw adverse event rates were 19% in the vanco arm versus 8% in the dapto arm). Additionally, AEs with daptomycin were more likely to occur late in the course of treatment, and 50% of daptomycin AEs were "CK elevation" (not including rhabdomyolysis), which is questionably relevant versus the vancomycin adverse events, which included DRESS, AIN, AKI, and cytopenias. Notably, the authors report a 38% incidence of rhabdomyolysis among the daptomycin recipients in this study. That seems high, and I thought the paper would have benefited from stating how they defined rhabdomyolysis (e.g. just myalgias and abnormal CK?).

So does this mean we should ditch vancomycin for OPAT and treat everybody with outpatient daptomycin? I wonder. Say what you will about vancomycin, but it's robust against the development of resistance; doctors have been giving vanc all willy-nilly for half a century, and their still isn't significant acquired resistance among gram-positive organisms other than Enterococcus. On the other hand, daptomycin seems safer and its dosing is way less of a headache. What do you think? PMID: 29893658


The synergy between beta-lactams and vancomycin is probably a class effect. Data suggests that antistaphylococcal penicillins attenuate the virulence of MRSA and that that attenuation might offer therapeutic benefit. This in vitro study shows that cefazolin, cefepime, ceftaroline, and nafcillin all demonstrate synergy with vancomycin, and that each of these drugs can "restore" the bactericidal activity of vancomycin against hVISA and VISA isolates. But should we routinely combine a beta-lactam with vancomycin for MRSA with high MICs to vancomycin? I don’t know. The CAMERA study, published in CID in 2016, showed that adding flucloxacillin to vancomycin for MRSA bacteremia (with any MIC to vancomycin) shortened the duration of bacteremia by a day but didn't improve more meaningful outcomes like mortality. I think we need more clinical data showing a meaningful synergistic effect in vivo before widely changing our practice. PMID: 29555635


Is combination antibiotic therapy superior for severe MRSA pneumonia following influenza? The data on combination antibiotic therapy for MRSA infections is pretty sparse. There's plenty of in vitro data (e.g. for the synergistic effect of daptomycin and ceftaroline), some support for using protein synthesis inhbitors in toxic shock, and the CAMERA trial mentioned above, but otherwise clinical data is limited to case reports and series. This multicenter retrospective study looked at outcomes of children with post-influenza MRSA pneumonia stratified by treatment with one or two anti-MRSA drugs.

First, they found that post-influenza MRSA pneumonia in children is severe: over 90% of patients either had acute lung injury or needed vasopressors, 70% ended up on ECMO, and 40% died (it's worth mentioning they also looked at non-MRSA post-influenza pneumonias and found much lower rates of these outcomes). Many of these patients were profoundly neutropenic on admission, which was not true of the patients with MSSA pneumonia. Half of the MRSA pneumonia patients received vancomycin plus a second antibiotic, which was clindamycin in most cases, though 4 patients received ceftaroline and 1 linezolid. Mortality was a whopping 69% in the patients who received vancomycin monotherapy versus 13% in those who got a second drug (RR 5.5, p=0.003), which would make the # needed to treat to prevent one death a mere two patients.

Although the small sample size (n=30) and many potential confounding factors should be noted, I found these results compelling. I'm not sure if these findings can be generalized to adults with post-influenza MRSA pneumonia, severe MRSA pneumonia that is not due to influenza, or combination therapies other than vancomycin plus clindamycin (which is important for my practice, as 50% of MRSA in Houston are resistant to clindamycin). However, if I see a patient with a severe MRSA pneumonia following influenza, I'll be tempted to try two-drug therapy including some sort of protein synthesis inhibitor. 29893805


Anaerobic antimicrobials do not improve the outcome of bacteremia biliary tract infections without anaerobic bacteremia. This was a retrospective cohort study of 87 patients with such infections, 63 of whom received antimicrobials with anaerobic activity and 24 of whom did not. Together E. coli and Klebsiella pneumoniae accounted for nearly 80% of cases. Treatment failure (defined as relapse of infection or 28-day mortality) was similar with vs without anaerobic coverage (20.6% vs 16.7%, p=0.667), and in multivariate analysis lack of anaerobic coverage was not associated with treatment failure (OR = 0.92, p = 0.916). PMID: 29902981