June 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 Approval

  • Delafloxacin*, the first new fluoroquinolone antibiotic in many years, was approved by the U.S. FDA in late June. The drug is indicated for acute bacterial skin and skin structure infections caused by gram positive organisms, including MRSA, and gram negative organisms. Both oral and IV formulations are available.

New Dosage Form Approval

  • Ritonavir* (Norvir) oral powder, 100 mg packet, for use in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection.

Updated Treatment Guidelines

  • The tuberculosis* section of the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents has been updated. In this revision, the epidemiology, diagnosis, and treatment sections for latent TB infection and TB disease are updated to include more recent statistics, diagnostic tests, and data regarding treatment. In addition, Tables 1-3 of the Guidelines have been updated to include preferred and alternative treatment regimens, and drug-drug interactions with commonly used medications. The guidelines are available for download on the AIDSinfo website.

Practice Pearls

    • The Advisory Committee on Immunization Practices (ACIP) has updated its recommendations regarding the use of MenB-FHbp serogroup B vaccine. MenB-FHbp (Trumenba) is one of two serogroup B vaccines currently licensed in the US for persons 10-25 years of age (the other one is MenB-4C (Bexsero). The vaccines are not interchangeable (a vaccine series must be completed using the same product) and the ACIP does not indicate a product preference. The minimum interval between any two doses of MenB vaccine is four weeks.

      The updated recommendations replace previous ACIP recommendations published in 2015. For persons at increased risk for meningococcal disease (e.g., persons with persistent complement component deficiencies, anatomic or functional asplenia, or microbiologists who are routinely exposed to isolates of N. meningitidis) and for use during outbreaks of serogroup B meningococcal disease, ACIP recommends that three doses of MenB-FHbp be administered at 0, 1-2, and 6 months. For healthy adolescents who are not at increased risk for meningococcal disease, two doses administered at 0 and 6 months are recommended. ACIP recommendations regarding the use of MenB-4C have not changed (MMWR 66:509, 2017).

 

    • Why is Candida krusei* intrinsically resistance to fluconazole*?

      Candida employs four main mechanisms of resistance to azoles: 1) active efflux pumps belonging either to the ATP-binding cassette (ABC) family of transporters or the major facilitator superfamily of transporters, 2) alteration of the target site, lanosterol 14α-demethylase (also known as Erg11p or Cyp51p), via mutations in its encoding gene ERG11, 3) increased expression of the target site, and 4) development of bypass pathways that replace ergosterol (depleted by azoles) with another functional product (Clin Infect Dis 46:120, 2008).

      As of now, the mechanism is incompletely understood. The original explanation for fluconazole resistance in C. krusei was the second mechanism above: reduced susceptibility of Erg11p to inhibition by fluconazole compared to Erg11p proteins of other Candida species (Antimicrob Agents Chemother 42:2645, 1998). However, more recent work has shown that efflux pumps also play a role to some degree, such as the ABC transporter Abc1p (Antimicrob Agents Chemother 53:354, 2009). Upregulation of ABC transporters is thought to explain intrinsic fluconazole resistance in C. glabrata. In support of the role of efflux pumps in C. krusei is an interesting study in which the calcineurin inhibitor tacrolimus was shown to reverse the intrinsic resistance of C. krusei to fluconazole in vitro, possibly by acting as an inhibitor of Abc1p (FEMS Yeast Res 14:808, 2014). It is likely that the mechanism of fluconazole resistance in C. krusei is a combination of poor affinity of Erg11p for fluconazole coupled with efflux pump activity.

 

    • What is the story behind pyridoxine supplementation of isoniazid* (INH)?

      Vitamin B6, erroneously thought to be synonymous with pyridoxine, is actually six substances of equal potency: pyridoxine, pyridoxal, pyridoxamine, and the monophosphate of each. The active form in humans is pyridoxal phosphate. Pyridoxal phosphate is required by at least one hundred enzymes in humans. Important functions of these enzymes include amino acid synthesis, neurotransmitter synthesis (such as epinephrine, dopamine, serotonin, and GABA), hemoglobin manufacture, and the conversion of tryptophan to niacin, to name a few. Rich dietary sources of vitamin Binclude meats, grains, fish, eggs, and carrots; it is found as pyridoxine in vegetables and as pyridoxal or pyridoxamine in animal products. An adequate diet contains 1.5-2 mg per day.

      INH was introduced into clinical practice in the early 1950s. By 1953, reports of peripheral neuropathy were appearing in the medical literature. Numbness and tingling of the extremities in a “stocking-glove” pattern, more severe in the feet than in the hands, was observed, followed by more severe symptoms in untreated patients. The similar clinical appearance to vitamin B6 deficiency suggested the possibility of a vitamin B6 deficiency state existing in patients treated with INH, which was supported by subsequent biochemical investigations. Clinical data supporting the value of pyridoxine supplementation for preventing INH-induced peripheral neuropathy began appearing in the literature in the late 1950s (Tubercle 61:191, 1980).

      Functional vitamin B6 deficiency is the probable mechanism of INH-induced peripheral neuropathy. There are at least two mechanisms. First, INH and metabolites bind directly to and inactivate pyridoxine species. Second, INH inhibits the enzyme pyridoxine phosphokinase, an enzyme necessary to convert pyridoxine to pyridoxal phosphate. In the current ATS/CDC/IDSA practice guidelines for drug-susceptible tuberculosis, pyridoxine 25-50 mg po qd is recommended along with INH for all persons at risk of neuropathy (e.g., pregnant or nursing women, breastfeeding infants, persons with INH, patients with diabetes, alcoholism, malnutrition, or chronic renal failure, or patients of advanced age). For patients with peripheral neuropathy, the dose should be increased to 100 mg po qd (Clin Infect Dis 63:e147, 2016).

 

  • Multiple factors influence cerebrospinal fluid (CSF) drug concentrations including molecular weight, plasma protein binding, hydrophobicity, and affinity for transport mechanisms. Vancomycin* penetration into the CSF is widely believed to be poor, with CSF:serum ratios in the range of 7-30% depending on the reference source. When vancomycin is used to treat bacterial meningitis, a target serum trough concentration of 15-20 μg/mL is believed to help compensate for limited drug penetration.

    New data suggest that CSF concentrations of vancomycin may be better than we think. In a recent review of the literature, thirteen studies evaluating serum and CSF concentrations of intravenous vancomycin were identified for further analysis. Studies that included pediatric patients or patients administered intrathecal or intraventricular vancomycin were excluded. Overall, the vancomycin CSF:serum ratio varied from 0 to 81%. Stratified by disease, penetration ranged from 6-81% in meningitis, 5-17% in ventriculitis patients, 0-36% in patients with other infections, and 0-13% in uninfected patients. Clinical cure rates in these studies were 83% of meningitis patients and all the ventriculitis patients, but no clear relationship between CSF concentration and bacteriologic or clinical cure was identified. Perhaps the best description of vancomycin penetration, as suggested by the authors, is not universally low but highly variable (Clin Pharmacokinet 2017 May 20 [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]: Albendazole tablets, Cefotaxime injection (unavailable), Fluconazole injection, Hepatitis B vaccine recombinant, Metronidazole injection
    • [Continue to be in reduced supply]:
      • Aminoglycosides: Amikacin injection, Gentamicin injection, Tobramycin injection
      • Cephalosporins: Cefepime, 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 antimicrobials: Clindamycin injection, Erythromycin lactobionate injection, Mupirocin calcium 2% cream, Mupirocin calcium 2% nasal ointment (unavailable), Vancomycin injection
      • Vaccines: Hepatitis A Virus Vaccine Inactivated, Rabies vaccine (RabAvert), Tetanus and Diphtheria Toxoids Adsorbed, Yellow Fever vaccine
    • [Shortage recently resolved]: Cefotetan injection
  • Antimicrobial drugs newly discontinued: No recent discontinuations
  • 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