February ID Update

The Sanford Guide ID Update features current developments in infectious diseases, curated by the Sanford Guide Editorial Board. Links marked with an asterisk (*) provide details to Web Edition subscribers, while all other links are universal. To receive monthly ID Updates by e-mail, subscribe now. We will not share your e-mail address, and you may unsubscribe at any time.

FEBRUARY 2017

Updated Treatment Guidelines

  • Updated guidelines for the treatment of Helicobacter pylori infection from the American College of Gastroenterology have been published (Am J Gastroenterol 112:212, 2017). The guidelines are available for download on the ACG website.

Practice Pearls

    • Carbapenem* antibiotics are known to rapidly decrease valproic acid (VPA) concentrations. Doripenem, ertapenem, imipenem, meropenem, and panipenem have all been implicated, but the precise mechanism of the interaction is not fully understood. The most important metabolite of VPA is the inactive glucuronide, and it has been suggested that the key step is inhibition by carbapenems of acylpeptide hydrolase, an enzyme that hydrolyzes VPA-glucuronide (VPA-G) back to the parent compound (resulting in enhanced VPA-G urinary excretion). Other possible mechanisms include carbapenem-induced inhibition of intestinal VPA absorption, increased synthesis of VPA-G, and inhibition of VPA efflux from erythrocytes. In a retrospective study, VPA concentrations were reduced approximately 60% within 24 hours; the magnitude of decrease in VPA concentration was higher with ertapenem and meropenem than with imipenem (Ther Drug Monit 38:587, 2016).

      The interaction between meropenem and VPA was further examined on a large scale using a retrospective analysis of VPA therapeutic drug monitoring records from neurosurgery inpatients at a hospital in China. 381 records from 301 patients treated with VPA with or without meropenem over a three-year period were collected. Two findings extend our knowledge of this interaction: 1) the occurrence of the interaction is independent of the daily dose of VPA and meropenem, suggesting that the decrease in VPA concentration cannot be reversed by simply increasing the VPA dose, and 2) discontinuation of meropenem for more than seven days is necessary for recovery of the VPA concentration (J Clin Pharm Ther 2017 Feb 1 [Epub ahead of print]).

 

  • Clindamycin* is a lipophilic drug that may require dosage adjustment in obese patients, yet we have little to no pharmacokinetic or outcomes data in obesity (adult or pediatric) to guide us. Data from three separate prospective trials were recently combined to perform a clindamycin population pharmacokinetic analysis in 220 children, 76 of whom had a BMI ≥95th percentile for age. Total body weight was found to be the most appropriate weight for dosing in obese and non-obese children. Alternative measures of body composition (normal fat mass, fat free mass, and lean body weight) resulted in inferior model performance. Study limitations acknowledged by the authors include the use of multiple study designs and populations possibly introducing variability into the model, missing laboratory data for many study subjects, and possible misclassification of obesity status for some subjects (Antimicrob Agents Chemother 2017 Jan 30 [Epub ahead of print]).
    • In 2008, the U.S. Food and Drug Administration (FDA) notified fluoroquinolone manufacturers that a boxed warning in the product labeling concerning the increased risk of tendinitis and tendon rupture was necessary. Last year, the FDA announced it was requiring a stronger black box warning for all fluoroquinolones, advising that the serious side effects associated with fluoroquinolones generally outweigh the benefits for patients with acute sinusitis, acute bronchitis, and uncomplicated UTI who have other treatment options. The side effects can involve the tendons, muscles, joints, nerves, and CNS. For patients with the aforementioned diseases, fluoroquinolones should be reserved for those who do not have alternative treatment options. The need for an upgraded warning was fueled in part by recent studies such as a nested, case-control analysis from the Taiwan National Health Insurance Research Database in which fluoroquinolone usage was associated with an approximately 2-fold increase in risk of aortic aneurysm and dissection within 60 days of exposure (JAMA Intern Med 175:1839, 2015).

      In light of this, a reader inquired as to whether the first-line status of fluoroquinolones for CAP in certain patient subgroups might be downgraded. In our response, we pointed out that the warning pertains to the use of fluoroquinolones for relatively minor infections, of which two (sinusitis and bronchitis) are often self-limited, viral in etiology, and for which the benefit of any antibiotic is marginal. Bacterial pneumonia is another matter, and for now a change in our recommendations is not anticipated. IDSA has a guidelines committee working on CAP recommendations and it will be interesting to see what comes from that. In addition, emerging data suggest that current treatment recommendations are based on a distorted perception of the cause of CAP (N Engl J Med 373:415, 2015; Clin Infect Dis 62:817, 2016). For now, the benefit of an antibiotic in CAP is well established and the use of a fluoroquinolone as a first-line agent in the older, more medically complicated adult remains reasonable.

 

  • Metronidazole*, in clinical use for over 50 years, has an important role in the treatment of trichomoniasis, giardiasis, amebiasis, bacterial vaginosis, H. pylori, and various anaerobic bacterial infections. Why does metronidazole lack activity against aerobic bacteria?

    Metronidazole enters the bacterial cell via passive diffusion. It is then reduced in the cytoplasm to a short-lived nitroso free radical intermediate that binds nonspecifically to bacterial DNA. This results in inhibition of DNA synthesis and strand breakage, killing the cell. Aerobic bacterial cells lack electron-transfer proteins with sufficient negative redox potential to donate the necessary electrons to metronidazole. In anaerobes, there are electron-transfer proteins like flavodoxin and ferredoxin that have a redox potential lower than metronidazole, so they will give their electrons up and reduce the drug. Redox potential describes the tendency of a chemical species to accept or donate electrons from/to another species; positive potential is the tendency to accept electrons, negative potential is the tendency to donate electrons.

    Resistance to metronidazole among Bacteroides group species is rare, although a few case reports of multidrug-resistant B. fragilis have recently appeared (MMWR 62:694, 2013). However, there are at least two anaerobes in which metronidazole resistance is common. One is Propionibacterium acnesP. acnes is typically highly susceptible to clindamycin but resistant to metronidazole, which explains the superiority of topical clindamycin for mild-to-moderate acne. Topical metronidazole is useful for acne rosacea, however, presumably due to its antiinflammatory properties (Curr Med Res Opin 15:298, 1999).

    The other one is Clostridium tertiumC. tertium distinguishes itself among other members of the Clostridium genus as a non-toxin-producing, aerotolerant species. C. tertium is rarely associated with bacteremia. Patients are typically (but not always) neutropenic with injury to the gastrointestinal mucosa, and they frequently have a history of exposure to beta-lactam antibiotics (especially third-generation cephalosporins). C. tertium is commonly (but not always) resistant to clindamycin as well (Clin Infect Dis 32:975, 2001).

Drug Shortages (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]: None
      • [Continue to be in reduced supply]: Amikacin, Amoxicillin/clavulanate 1000 mg/62.5 mg ER tablets, Ampicillin injection, Ampicillin/sulbactam, Cefepime, Cefotetan, Cefoxitin, Ceftazidime, Ceftriaxone, Cefuroxime injection, Ciprofloxacin oral suspension, Clindamycin injection, Erythromycin lactobionate injection, Gentamicin injection, Hepatitis A Virus Vaccine Inactivated, Meningococcal vaccines (various), Mupirocin calcium 2% cream, Ofloxacin 0.3% ophthalmic solution, 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), Piperacillin/tazobactam, Tetanus and Diphtheria Toxoids Adsorbed, Tobramycin injection, Vancomycin injection, Yellow Fever vaccine
      • [Shortage recently resolved]: Tigecycline

 

    • Antimicrobial drugs currently unavailable due to manufacturing delays or product discontinuation:
      • [New on the list]: None
      • [Continue to be unavailable]: Cefotaxime injection, Mupirocin calcium 2% nasal ointment, Penicillin G procaine injection

 

  • Antimicrobial drugs discontinued: 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