July ID Update

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Updated Antiretroviral Therapy Guidelines

  • Updated guidelines from the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents are available for download at https://aidsinfo.nih.gov. The last update was January 28, 2016.
  • The International Antiviral Society-USA (IAS-USA) has also updated its recommendations for the use of antiretroviral agents to treat or prevent HIV infection in adults (JAMA 316:191, 2016).

Other Updated Guidelines

New Drug Approvals

  • Viekira XR (Ombitasvir 8.33 mg + Paritaprevir 50 mg + Ritonavir 33.33 mg + Dasabuvir 200 mg in an extended-release formulation) for adults with HCV. The recommended dose is three tablets orally once daily with food (with or without Ribavirin).
  • Epclusa (Sofosbuvir + Velpatasvir), a new fixed dose combination drug for Hepatitis C, genotypes 1, 2, 3, 4, 5 and 6.

Get Smart

  • Most providers appreciate the need for more judicious use of antibiotics in outpatient settings. Keeping up with guidelines and educating patients are challenging. CDC has pulled together a number of resources on their Get Smart Pages, including guidelines for common outpatient problems in adult medicine and pediatrics as well as resources for educating patients. November 14-20 is 2016 Get Smart Week: an annual one-week observance to raise awareness of the threat of antibiotic resistance and the importance of appropriate antibiotic prescribing and use.

Practice Pearls

  • The Gonococcal Isolate Surveillance Project (GISP) was established in 1986 to monitor trends in antimicrobial susceptibilities of N. gonorrhoeae strains in the United States. Isolates are collected each month from up to the first 25 men with gonococcal urethritis attending each of the participating STD clinics at 27 sites (21-30 sites participate each year). This month, CDC released its report summarizing data collected during January-December 2014 and describing susceptibility trends in the US for the past 15 years. Because the primary gonorrhea treatment option recommended by CDC is dual therapy with ceftriaxone plus azithromycin, it is critical to monitor trends in cephalosporin and azithromycin susceptibility. Isolates of N. gonorrhoeae with reduced azithromycin susceptibility (MIC ≥2.0 μg/mL) increased from 0.6% in 2013 to 2.5% in 2014; the increase was greatest in the Midwest (but occurred in all geographic regions) and was observed in all categories of sex to sex partners. Reduced susceptibility to ceftriaxone (MIC ≥0.125 μg/mL), which had increased to 0.4% in 2010 and 2011, fell to 0.1% in 2013 and remained constant in 2014. Reduced susceptibility to cefixime (MIC ≥0.25 μg/mL), which decreased from 1.4% in 2011 to 0.4% in 2013 (CDC revised its guidelines in 2012 to no longer recommend cefixime as part of dual therapy), increased to 0.8% in 2014. No isolates with reduced azithromycin susceptibility exhibited reduced ceftriaxone or cefixime susceptibility. The significance of the increased percentage of isolates with reduced azithromycin susceptibility is unclear but concerning (MMWR Surveill Summ 65:1, 2016).
  • Delirium is common in hospitalized patients, particularly the critically ill. Drugs are frequently identified as causative agents but antibiotics are probably an underrecognized etiology. In a recent review, a comprehensive search of the literature yielded 292 articles describing 391 individual cases of antibiotic-associated encephalopathy (AAE) associated with 54 different antibiotics. Three distinct clinical phenotypes emerge:
    Type Features Drugs
    1 Time to onset: within 5 days
    Myoclonus or seizures common
    Abnormal EEG
    Normal brain MRI
    Time to resolution: 5 days
    Cephalosporins (usually in renal failure)
    Penicillins (not procaine penicillin G)
    2 Time to onset: within 5 days
    Psychosis frequent
    Seizures rare
    EEG often normal
    Normal brain MRI
    Time to resolution: 5 days
    Fluoroquinolones
    Macrolides
    Procaine penicillin G
    Sulfonamides
    3 Time to onset: within 21 days
    Cerebellar dysfunction frequent
    Seizures rare
    Nonspecific EEG abnormalities
    Brain MRI always abnormal
    Time to resolution: 13 days
    Metronidazole

    In the above chart, the median times to onset and resolution are listed (and ranges are broad). Additionally, isoniazid (INH) does not clearly fit into any category. INH in the non-overdose setting has a time to onset similar to that of metronidazole, frequent psychotic symptoms, rare seizures, and nonspecific EEG abnormalities; time to resolution, like most of the other antibiotics, is about five days.

    The pathophysiology of AAE is a bit murky. Type 1 AAE is thought to be related to disruption of inhibitory synaptic transmission via inhibition of GABA receptors. Type 2 AAE may be due to perturbations of the D2 dopamine and NMDA glutamate receptors, although not all the drugs in the phenotype fit this explanation well. Type 3 AAE appears to be related to free radical formation and altered thiamine metabolism. It is important to appreciate the role of pharmacokinetic and patient-specific factors in the development of AAE. For example, some antibiotics (because of hydrophobicity) may have enhanced ability to enter the brain whereas others (such as imipenem) may have delayed clearance from the CSF. Advanced age, poor renal function, and pre-existing cerebral disease increase the risk of AAE for some antibiotics (Neurology 86:963, 2016).

  • There continues to be a data gap regarding voriconazole dosing in obese patients. The manufacturer’s prescribing information provides no recommendation as to which body weight (actual, ideal, or adjusted) should be used when dosing voriconazole. Similarly, the IDSA provides no recommendation in their latest candidiasis or aspergillosis clinical practice guidelines although they suggest in the aspergillosis guidelines that obese patients represent a clinical scenario in which therapeutic drug monitoring is useful (Clin Infect Dis 2016 Jun 29 [Epub ahead of print]). Two factors that dramatically complicate the situation are 1) voriconazole exhibits nonlinear pharmacokinetics, and 2) the drug is metabolized primarily by CYP2C19 and to a lesser extent by CYP2C9 and CYP3A4. There are dozens of variant CYP2C19 alleles in the population which, depending on the genetics of a given patient, result in a metabolic phenotype that ranges from poor metabolizer to ultrarapid metabolizer (Eur J Clin Pharmacol 65:281, 2009). The potential for drug interactions is also affected by this genetic polymorphism. For example, if a patient has normal CYP2C19 activity, an inhibitor of CYP3A4 would have little effect on voriconazole concentrations. However, if a patient is a CYP2C19 poor metabolizer, a CYP3A4 inhibitor might increase voriconazole concentrations markedly because the CYP3A4 pathway would be of greater importance.The evidence available to us suggests that dosing voriconazole in obese patients based on actual body weight often results in supratherapeutic concentrations, but it is also insufficient to firmly support the use of ideal versus adjusted body weight (Clin Infect Dis 63:286, 2016). The prudent approach for now is to employ ideal body weight with therapeutic drug monitoring that targets a voriconazole trough concentration of 1-5.5 μg/mL.

Drug Shortage Updates (U.S.)

  •  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] Erythromycin lactobionate injection
    • [Continue to be in reduced supply] Amikacin, Ampicillin injection, Ampicillin/sulbactam, Cefepime, Cefotaxime, Cefotetan, Cefpodoxime, Ceftazidime, Ceftriaxone, Chloroquine tablets (250, 500 mg), Clindamycin injection, DTaP (Daptacel) vaccine, DTaP-IPV/Hib (Pentacel) vaccine, Gentamicin injection, Haemophilus B conjugate vaccine, Imipenem-cilastatin, Meningococcal vaccines (various), Mupirocin calcium 2% cream, Ofloxacin 0.3% otic solution, Penicillin G benzathine, Penicillin G procaine injection, Piperacillin-tazobactam, Poliovirus inactivated vaccine, Tigecycline, Tobramycin, Vancomycin injection, Yellow Fever vaccine
    • [Shortage recently resolved]: Neomycin and Polymyxin B sulfates and Dexamethasone ophthalmic ointment, Doxycycline hyclate injection
  • Antimicrobial drugs currently unavailable due to manufacturing delays or product discontinuation:
    • [New on the list] None
    • [Continue to be unavailable] Ofloxacin 0.3% ophthalmic solution
  • 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)
  • For detailed information including estimated resupply dates, see http://www.ashp.org/menu/DrugShortages