August ID Update

ID Update is The Sanford Guide’s monthly summary of significant developments in the treatment of infectious diseases. Want to receive ID Update by e-mail? Click here to subscribe. We won’t spam you or share your contact information.

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New Drug Approvals

  • Mavyret*, a fixed-dose combination of glecaprevir 100 mg (NS3/4A protease inhibitor) and pibrentasvir 40 mg (NS5A inhibitor), for the treatment of adult patients with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis and with compensated cirrhosis (Child-Pugh A). The combination is also indicated for the treatment of adult patients with genotype 1 infection who have previously been treated with a regimen containing either an NS5A inhibitor or an NS3/4A protease inhibitor (but not both).
  • Vosevi*, a fixed-dose combination of sofosbuvir 400 mg (NS5B RNA polymerase inhibitor), velpatasvir 100 mg (NS5A inhibitor), and voxilaprevir 100 mg (NS3/4A protease inhibitor), for the treatment of adult patients with chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have:
    • genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with a regimen containing an NS5A inhibitor.
    • genotype 1a or 3 infection and have previously been treated with a regimen containing sofosbuvir without an NS5A inhibitor.

Treatment Guidelines

  • Brazilian guidelines for the diagnosis and treatment of cystic fibrosis have been published. The guidelines were prepared in partnership with several Brazilian medical societies and received contributions from multiple Brazilian professionals involved in the care of CF patients (J Bras Pneumol 43:219, 2017).
  • Brazilian guidelines for the clinical management of paracoccidioidomycosis have been published. These guidelines update the first Brazilian consensus on paracoccidioidomycosis by providing evidence-based recommendations for bedside management (Rev Soc Bras Med Trop 2017 July 20 [Epub ahead of print].

Antimicrobial Stewardship

  • A provocative analysis in BMJ calls into question our standard instruction to patients to complete the entire prescribed course of antibiotics in hopes of lessening or preventing antibiotic resistance (and treatment failure). There is value in a clear and simple message, but it deserves reassessment.In some pathogens such as M. tuberculosis, N. gonorrhoeae, and HIV, genetic mutations conferring resistance may arise spontaneously and be selected for during treatment if dosing is inadequate or monotherapy is employed (the authors term this “target selected resistance”). But for other problematic bacteria such as S. aureus, Enterococcus, Klebsiella, Acinetobacter, and Pseudomonas (all opportunistic microbes that are present in the human gut, on skin and mucus membranes, and in the environment), the predominant driver of resistance is “collateral selection.” When antibiotics are taken for any reason, the pressure leads to antibiotic-susceptible strains being replaced by resistant strains. The longer the antibiotics are taken, the greater the pressure. These resistant strains are often transmitted to asymptomatic persons, or the genetic material conferring resistance can be passed to other bacteria.

    Recommended durations of therapy are generally based on limited evidence and probably, in most cases, do not represent the minimum effective length. At the time they were set there was more concern about undertreating the patient than overusing the drug. Recent trials, however, have already led to shorter durations of therapy for some infections such as community-acquired pneumonia, nosocomial pneumonia, and pyelonephritis. The situation is complicated by newer drugs with different pharmacologic properties, such as longer half-lives, and it is also important to note that patients respond differently to the same antibiotic. A reasonable conclusion is this: we should continue to aggressively conduct research into administering the shortest course of antibiotics possible for all infections (BMJ 358:j3418, 2017).

New Sanford Guide Release

  • In July, the Sanford Guide to HIV/AIDS Therapy 2017 print edition was released in pocket-size and larger-print library editions. This latest guide includes the latest fixed-dose combination and once-daily formulations of ARV drugs, updated differential diagnosis of related syndromes and OIs, and more.

Practice Pearls

  • Optic neuropathy is a serious complication of ethambutol* therapy. At a dose of ≤15 mg/kg/day the risk is <1%, but higher ethambutol doses are associated with substantially increased risk. Other risk factors include age >65, hypertension, the presence of renal disease, and possibly the concomitant use of isoniazid. Visual symptoms develop in most patients within the first nine months of treatment, although they can occur much faster than that; patients experience loss of visual acuity and abnormal color vision, and also central or cecocentral scotoma. The best treatment is primary prevention, which means baseline followed by regular screening (e.g. monthly in high-risk patients). If detected early with prompt drug discontinuation, about 30-60% of patients will show improvement over a period of several months although few will have full recovery. Ethambutol, a metal chelator, impedes mycobacterial cell wall synthesis by inhibiting arabinosyltransferase; chelation of copper or zinc is thought to play an important role in the pathogenesis of optic neuropathy. Zinc or copper supplementation has not been shown to reduce the likelihood of optic neuropathy, however (Curr Opin Ophalmol 2017 Jul 28 [Epub ahead of print].
  • One of the most serious, although usually reversible, neurotoxic effects associated with metronidazole* is encephalopathy. The mechanism of metronidazole-induced encephalopathy, or its relationship to cumulative metronidazole dose or treatment duration, is not clear. It is interesting that the symptoms and brain MRI findings of metronidazole-induced encephalopathy can be similar to those of acute Wernicke’s encephalopathy, a neurologic disorder induced by thiamine deficiency. Given that metronidazole metabolites inhibit thiamine pyrophosphokinase, it is possible that the resulting thiamine antagonism plays a key role in the pathogenesis of metronidazole-induced encephalopathy. It is currently unknown if thiamine supplementation, particularly in thiamine-deficient patients, is a useful treatment strategy (J Neurol Sci 379:324, 2017).
  • Moxifloxacin* is an option for treatment of drug-susceptible tuberculosis when a first-line drug is not tolerated, or for isoniazid monoresistance. It is also being investigated in treatment-shortening regimens for drug-susceptible tuberculosis. We know that adequate antituberculous drug concentrations in the blood and at the infection site(s) are important for maximizing treatment outcomes. The optimal dose of moxifloxacin for tuberculosis has not been firmly established, for at least three reasons: one, drug exposure resulting from standard 400 mg once-daily dosing may not be optimal for efficacy, prevention of resistance, or achieving proposed PK/PD targets; two, the coadministration of rifamycin drugs (e.g rifampin, rifapentine) decreases moxifloxacin Cmax and AUC up to 31%; and three, moxifloxacin distributes heterogeneously in tissues and granulomatous lesions, contributing to substantial interpatient variability in pharmacokinetics. Higher-than-standard doses of moxifloxacin may be necessary to maximize treatment outcomes, but further research is necessary (J Clin Pharmacol 2017 July 24 [Epub ahead of print]).

Drug Shortages (US)

  • Antimicrobial drugs or vaccines in reduced supply or unavailable due to increased demand, manufacturing delays, product discontinuation by a specific manufacturer, or unspecified reasons:
    • [New on the list]: No new antimicrobial shortages
    • [Continue to be in reduced supply]:
      • Aminoglycosides: Amikacin injection, Gentamicin injection, Tobramycin injection
      • Cephalosporins: Cefepime, Cefotaxime injection (unavailable), Cefoxitin, Ceftazidime, Ceftriaxone, Cefuroxime injection
      • Fluoroquinolones: Ciprofloxacin oral suspension, Ofloxacin 0.3% ophthalmic solution
      • Penicillins: Amoxicillin/clavulanate 1000 mg/62.5 mg ER tablets, Ampicillin/sulbactam, Oxacillin injection, Penicillin G benzathine, Penicillin G benzathine 900,000 units/Penicillin G procaine 300,000 units (Bicillin C-R 900/300), Penicillin G benzathine/Penicillin G procaine 1.2 million units (Bicillin C-R), Penicillin G procaine injection (unavailable), Piperacillin/tazobactam
      • Other antibacterials: Clindamycin injection, Erythromycin lactobionate injection (unavailable), Metronidazole injection, Mupirocin calcium 2% cream, Mupirocin calcium 2% nasal ointment (unavailable), Vancomycin injection
      • Antifungal drugs: Fluconazole injection
      • Antiparasitic drugs: Albendazole tablets (unavailable)
      • Vaccines: Hepatitis A Virus Vaccine Inactivated (Vaqta), Hepatitis B vaccine recombinant, Tetanus and Diphtheria Toxoids Adsorbed, Yellow Fever vaccine
  • [Shortage recently resolved]: Tigecycline injection
  • Antimicrobial drugs newly discontinued:
    • Recent discontinuations: MenHibrix (in February 2017), Elvitegravir (Vitekta, in December 2016), Peginterferon alfa-2b (in February 2016; 50 mcg vials still available in limited quantities), Boceprevir (in December 2015), Permethrin 1% topical lotion (in September 2015)
    • For detailed information including estimated resupply dates, see http://www.ashp.org/menu/DrugShortages