September ID Update

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New Guidelines

Practice Pearls

  • The emergence and spread of carbapenem-resistant Enterobacteriaceae* (CRE) represents a significant threat to public health. Carbapenem resistance among Enterobacteriaceae is due to 1) mutation in outer membrane porin channels (restricting drug entry) plus a beta-lactamase enzyme such as an ESBL or AmpC, or 2) the presence of a carbapenemase enzyme such as KPC, NDM, VIM, and others. Although the optimal treatment for CRE infections is not established, polymyxins (colistin, polymyxin B) are among our key drugs (Open Forum Infect Dis 2:ofv050, 2015).
     
    In the July/August 2016 issue of mBio we find the first US report of a clinical isolate of E. coli* resistant to both colistin and carbapenem antibiotics. The patient was a 76-year-old male with recurrent urinary tract infections and no recent travel history. The E. coli isolate, obtained from a urine sample, was resistant to colistin and all beta-lactam antibiotics except aztreonam but susceptible to gentamicin, amikacin, nitrofurantoin, tigecycline, and TMP-SMX. It was found to contain a plasmid harboring mcr-1 and one harboring blaNDM-5. Both plasmids were sequenced and shown to be highly similar to plasmids previously reported from China. No other resistance genes were identified on the plasmids. The blaNDM-5 gene, encoding a variant of the New Delhi metallo-beta-lactamase (NDM), confers carbapenem resistance; the mcr-1 gene, conferring resistance to colistin, was first reported in 2015 in food, animal, and patient isolates from China and is also the first plasmid-mediated colistin resistance mechanism to be identified (MMWR 65:979, 2016). The first report of mcr-1 in the US, posted online in late May 2016, describes an isolate of E. coli cultured in late April 2016 (Antimicrob Agents Chemother 60:4420, 2016); the second report of mcr-1 in the US concerns an E.coli originally isolated in May 2015. The colistin-resistant, carbapenem-resistant E. coli discussed in this pearl was originally obtained in August 2014, raising the specter of undetected transmission of mcr-1 (mBio 7:e01191, 2016).
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  • Bell’s palsy* is an acute, generally one-sided paralysis or weakness of facial musculature consistent with peripheral facial nerve dysfunction. Viral infection (most commonly herpes simplex virus) is the likely etiology. Most patients recover, even without treatment, although about one in five is left with permanent facial disfigurement or pain. Oral corticosteroids are widely used to treat Bell’s palsy but the role of concomitant antiviral therapy is uncertain. In a recent Cochrane review, treatment of Bell’s palsy of varying degrees of severity with antiviral drugs (acyclovir, valacyclovir, or famciclovir) plus oral corticosteroids resulted in improved rates of incomplete recovery at three to 12 months compared to corticosteroids alone. Adverse effects were not worsened by antivirals. The quality of evidence was assessed as low due to heterogeneity, imprecision of study results, and risk of bias (Cochrane Database Syst Rev 11:CD001869, 2015; JAMA 316:874, 2016).
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  • Nitrofurantoin*, a nitrofuran, was introduced into clinical practice in 1953. About 40% of an oral dose is eliminated unchanged in the urine in normal renal function, and antibacterial activity is enhanced in acidic conditions. Poor tissue penetration limits the clinical utility of nitrofurantoin to the treatment of lower urinary tract infection. For decades the admonition has been to avoid nitrofurantoin in patients with creatinine clearance (CrCl) below 60 mL/min. Is this still our belief?
     
    The origin of the recommendation is sketchy and based on old data. A commonly cited paper was published in 1968. Study subjects were administered a single 100 mg dose of nitrofurantoin one hour after the morning meal. A few patients with renal impairment already receiving nitrofurantoin were also studied. The product used was probably microcrystalline nitrofurantoin. Urinary recovery of drug at 0-2, 2-4, and 4-10 hours post-dose was measured. During the first two hours, subjects with CrCl <60 mL/min excreted very little drug (<5 mg); by ten hours, total urinary recovery was still considerably less than 40 mg (40% of the dose). Subjects with CrCl <20 mL/min excreted little to no drug in their urine even after ten hours. The authors further showed that in most subjects with CrCl <60 mL/min, the concentration of nitrofurantoin achieved in the urine was below the typical MIC for E. coli and Enterococcus. Finally, they evaluated urinary recovery data in the renally impaired patients already on the drug. Patients had CrCl <30 mL/min, yet some were receiving full doses. All of these patients had only marginally adequate amounts of nitrofurantoin recovered in their urine. There is no discussion of toxicities the renally impaired patients receiving full doses may have experienced (N Engl J Med 278:1032, 1968).
     
    In their discussion the authors cite a 1958 paper in which azotemic patients receiving nitrofurantoin 50 mg four times daily allegedly had inadequate urine concentrations after 7 or more days of therapy (J Urol 80:77, 1958). They also cite a 1967 paper reporting nitrofurantoin toxicity in uremic patients receiving apparently unadjusted doses (Tr Am A Genito-Urin Surg 59:32, 1967).
     
    We now have a new recommendation to mull over, at least for patients aged 65 and older. In 2011 the American Geriatric Society assumed responsibility for updating and maintaining the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Medications on this list have been associated with poor health outcomes including confusion, falls, and mortality. In 2015 the AGS released their second update of the Beers Criteria. Noteworthy is a change in recommendation for nitrofurantoin. Based on retrospective data, the AGS recommendation is that nitrofurantoin can be used with relative safety and efficacy in patients with CrCl above 30 mL/min. Long-term use should still be avoided because of toxicity concerns, such as pulmonary fibrosis, hepatotoxicity, and peripheral neuropathy (J Am Geriatr Soc 63:2227, 2015).
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  • We may have a new way of thinking about isoniazid (INH)*-induced liver injury. There are two phenotypes of INH-induced liver injury: a mild, often asymptomatic form that is only detected by measurement of AST and ALT and usually resolves despite continued treatment with the drug, and a more severe form that may progress to fulminant liver failure. The traditional belief has been that INH-induced liver injury results from oxidation of acetylhydrazine (formed from INH) to a reactive metabolite that binds covalently to liver proteins. The immune system was thought not to be involved.
     
    However, more recent evidence suggests that INH-induced liver injury is indeed related to an immune response, mediated by lymphocytes. We now know that there is a reactive metabolite formed from INH itself that is capable of covalent binding to liver proteins; furthermore, tissue binding of this metabolite is more likely to lead to an immune response than the reactive metabolite of acetylhydrazine, which would only acetylate proteins. The mild form of INH-induced liver injury resolves with immune tolerance (preventing significant damage), whereas the severe form is associated with the production of anti-INH and anti-CYP450 antibodies. Having a more accurate understanding of the mechanism of hepatotoxicity may lead to therapies that prevent progression of liver injury after INH is discontinued (Br J Clin Pharmacol 81:1030, 2016).

Drug Shortage Updates (US)

  • Antimicrobial drugs or vaccines in reduced supply due to increased demand, manufacturing delays, product discontinuation by a specific manufacturer, or unspecified reasons:
    • [New on the list] Ciprofloxacin oral suspension, Oxacillin injection, Penicillin G benzathine 900,000 units/Penicillin G Procaine 300,000 units (Bicillin C-R 900/300)
    • [Continue to be in reduced supply] Amikacin, Ampicillin injection, Ampicillin/sulbactam, Cefepime, Cefotetan, Cefpodoxime, Ceftazidime, Ceftriaxone, Chloroquine tablets (250, 500 mg), Clindamycin injection, DTaP (Daptacel) vaccine, DTaP-IPV/Hib (Pentacel) vaccine, Erythromycin lactobionate injection, Gentamicin injection, Haemophilus B conjugate vaccine, Imipenem-cilastatin, Meningococcal vaccines (various), Mupirocin calcium 2% cream, Ofloxacin 0.3% ophthalmic solution, Penicillin G benzathine, Penicillin G procaine injection, Piperacillin/tazobactam, Poliovirus vaccine inactivated, Tigecycline, Tobramycin, Vancomycin injection, Yellow Fever vaccine
    • [Shortage recently resolved]: None
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  • Antimicrobial drugs currently unavailable due to manufacturing delays or product discontinuation:
    • [New on the list] Cefotaxime injection, Penicillin G benzathine/Penicillin G Procaine (Bicillin C-R)
    • [Continue to be unavailable] Ceftazidime/Avibactam injection, Mupirocin calcium 2% nasal ointment
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  • Antimicrobial drugs discontinued: 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)
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  • For detailed information including estimated resupply dates, see http://www.ashp.org/menu/DrugShortages