July 2020: Antimicrobial Agents

Adjunctive daptomycin did not shorten the duration of MSSA bacteremia when added to cefazolin or cloxacillin in a randomized-controlled trial.  Daptomycin produces synergistic killing of S.aureus when added to beta-lactams in vitro.  But also, lots of things work in vitro and not in patients.  This RTC out of Montreal enrolled adults with MSSA bloodstream infection within 72 hours of the first positive culture’s collection, excluding those expected to die within 72 hours, not receiving ICU level of care due to advance directives, needing other antibiotics, or not able to receive one or both study drugs.  The subjects were then randomized to receive monotherapy with an antistaphylococcal beta-lactam (cefazolin or cloxacillin) or that plus five days of daptomycin 6mg/kg.  All patients had daily blood cultures for 5 days or until the cultures cleared, whichever was longer, and the primary outcome was duration of MSSA bacteremia. Secondary outcomes included all-cause 30-day mortality, relapsed bacteremia (i.e.; after culture clearance of at least 48 hours) within 30 days, metastatic infection within 30 days, and hepatotoxicity, nephrotoxicity, and/or rhabdomyolysis within 5 days of enrollment.

Over a 3 year period the authors enrolled 115 patients into the study, of whom 71 were included in the mITT analysis; the median age was 67, and about a third were women.  Most sources of bacteremia were endovascular (39%), followed by SSTI (24%), osteo (8%), and pneumonia (7%); 79% of bacteremias were considered complicated; cefazolin was the most commonly selected beta-lactam (73%).  There was no difference in bacteremia duration between patients receiving adjunctive daptomycin or monotherapy in the entire study population (mean difference 0.4 days with 95% CI -0.6 to 1.4) or in the mITT analysis (mean difference 0.1 days with 95% CI -1.1 to 1.3).  30-day mortality rates were similar between recipients of adjunctive daptomycin and monotherapy (19% vs 18%), as were rates of relapsed infection at 30 days (1 in the daptomycin group vs none in the monotherapy group); both regimens were well tolerated.

The authors conclude that that adding daptomycin confers no advantage over monotherapy with antistaphylococcal beta-lactam for MSSA bloodstream infection.  While the sample size is small, I note that the addition of daptomycin to (mostly) cefazolin for (mostly) complicated S. aureus bacteremia did not improve clinical outcomes, which I think should help allay fears about the cefazolin inoculum effect if you weren’t already convinced by the mountain of retrospective data indicating cefazolin’s equivalent to antistaphylococcal penicillins in this scenario.  It also makes me wonder whether an RTC comparing daptomycin/ceftaroline to either agent alone for MRSA bacteremia (an RTC that is adequately powered and not stopped early) would show benefit of combination therapy either. 32667982

Speaking of daptomycin, an RTC out of Spain showed that addition of IV fosfomycin to 10 mg/mg daptomycin versus daptomycin alone yielded lower rates of microbiologic failure, but not mortality benefit (albeit a clinically-but-not-statistically-significant reduction of 12% with RR 1.3 and 95% CI 0.9-1.8 for monotherapy).  This did come at the cost of a much higher rate of treatment discontinuation in the combination group (18% vs 5%).  Alas, IV fosfomycin has been tied up in FDA regulatory approval hell for over a year, and it’s still unclear when (or indeed if) it will be commercially available in the US. 32725216

Baloxavir is an effective prophylaxis for household contacts of patients with seasonal influenza.  Baloxavir is a novel influenza polymerase inhibitor FDA-approved for treatment of influenza in 2019.  The clinical trial data indicates it is about as effective as oseltamivir (don’t laugh) and can be administered in a single dose; high-quality data on the value of combination therapy for severe influenza and influenza in immunocompromised hosts will hopefully be forthcoming soon.  This study asked whether baloxavir could serve as a prophylaxis for household contacts of someone with influenza.  Investigators randomized household contacts of patients with confirmed influenza during Japan’s 2018-2019 flu season to receive a dose of either baloxavir or placebo.  Subjects who were already symptomatic at enrollment were excluded.  Monitoring included for symptoms (temperature monitoring and a self-assessed seven-symptom score) and nasopharyngeal swabs on days 1, 3-7, and 11-14.  The primary outcome was laboratory-confirmed influenza disease, defined as a positive swab PCR plus both fever and a moderate or severe respiratory symptom.

A total 752 household contacts were randomized and 749 were included in the mITT population.  Characteristics were similar between groups; a fifth were under 12 years of age, 3% were over 65, 13% had at least one risk factor for influenza complications, and 66% were unvaccinated for the current influenza season.  Most (73%) of participants received the study drug within 24 hours of their contact’s illness onset.  The primary endpoint occurred in 2% of subjects who received baloxavir vs 14% who received placebo (aRR 0.14 with 95% CI 0.06-0.3).  Efficacy was similar across age, vaccination status, and underlying risk factors, and the endpoint was reached left often in the baloxavir group both because those recipients had fewer positive swab PCRs and were less likely to have accompanying clinical illness when swabs were positive. Rates of adverse events were similar between baloxavir and placebo (22% vs 21%) and the only severe AE occurred in the placebo arm.

To summarize, a single dose of baloxavir appears highly effective for prophylaxis against seasonal influenza.  Hopefully resistance to this agent will be slow to emerge, because it seems a much more convenient choice vs oseltamivir for influenza prophylaxis. 32640124 

Oral vancomycin may not be any more likely than metronidazole to result in infection or colonization with VRE. So says a retrospective study of 10 years of VA patient data, which examined rates of VRE culture-positivity among veterans who received either oral vancomycin or metronidazole for C.difficile colitis. 31504328

Rifampin may not improve outcomes in prosthetic valve endocarditis. This was a retrospective study of 180 patients with S.aureus or CONS endocarditis of a biopresthetic or mechanical calve, of whom 28% received surgical treatment.  56% of these patients received rifampin treatment for median 33 days, with one-year mortality rates of 38% vs 32% in the rifampin and no rifampin arms, respectively (p=0.6)  Relapse rates were also no different, though of note the longer lengths of stay in the rifampin arm (42 vs 31 days) raises the questions of how comparable the populations in this study really were. 32706879

Oral fosfomycin for pyelonephritis and complicated UTI? Traditional teaching holds that fosfomycin does not achieve adequate levels in renal tissue and is not appropriate for upper urinary tract infections.  The LA county department of health’s docs seem to disagree, and published this retrospective study of 99 patients with complicated UTI, of whom 37 had pyelonephritis.  Of the patients with 30-day followup data available, the clinical success rate was 78%, including 80% of the 20 such patients with pyelonephritis.  Factors associated with treatment failure included male sex, urologic abnormality, non-E.coli pathogen, and receipt of <25% of therapy as IV prior to switch to fosfomycin.  The last bit makes me wonder – is this is a study challenging the efficacy of fosfomycin for pyelonephritis, or a study challenging pyelo’s minimum duration of treatment? 32303061

In this case report, IV phage therapy allowed limb salvage of an MDR K.pneumoniae prosthetic joint infection of a right knee arthroplasty.  Caveats here that the patient also received minocycline (though he had previously been on mino with breakthrough clinical infection), and also followup was only 34 weeks – the ortho literature typically looks for a followup of 1-2 years at minimum.  That said, this is promising, particularly for ID docs and orthopedic surgeons practicing in global areas of extensive drug resistance, where this type of infection is not rare and typically results in amputation. 32699879