October ID Update

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Links marked with an asterisk (*) provide details to Sanford Guide Web Edition subscribers, while all other links are universal.

 

New Drug Approvals

    • Bezlotoxumab (Zinplava), a human monoclonal antibody that binds to C. difficile toxin B, indicated to reduce recurrence of C. difficile infection (CDI) in patients 18 years of age and older who are receiving antibacterial drugs for CDI and are at high risk for recurrence. Not indicated for treatment of CDI. The recommended dose is a single infusion of 10 mg/kg IV over 60 minutes.

 

  • Mebendazole* chewable 500 mg tablets (Vermox Chewable) for the treatment of patients one year of age and older with GI infections caused by Ascaris lumbricoides* (roundworm) and Trichuris trichiura(whipworm). The recommended dosage is one tablet taken as a single dose, chewed completely before swallowing and taken without regard to food intake.

Practice Pearls

    • Clindamycin* is a lincosamide antibiotic that inhibits early stage protein synthesis. It is metabolized to several metabolites that are excreted in feces. In vitro data indicate that the biotransformation of clindamycin is mediated primarily by CYP3A4, and also that the drug is a moderate inhibitor of CYP3A4 (Drug Metab Dispos 31:878, 2003). The degree of inhibition of CYP3A4 is probably insufficient for clindamycin to affect the pharmacokinetics of other drugs, but the data suggest that we should at least be aware of the potential for clindamycin to be affected by strong CYP3A4 inducers or inhibitors. In a recent prospective study, 16 patients with staphylococcal osteoarticular infection treated with oral clindamycin plus rifampin experienced a consistent decrease in clindamycin concentrations compared to control (J Infect 71:200, 2015). These results are consistent with an observational study of 61 patients with gram positive bone and joint infections treated with clindamycin in whom concomitant treatment with rifampin significantly decreased clindamycin trough concentrations (Infection 43:473, 2015), and also with an earlier study of patients treated with continuous infusion clindamycin plus rifampin in whom clindamycin concentrations were reduced (Antimicrob Agents Chemother 54:88, 2010). It is important to note that in these studies there was no clear deleterious impact of lowered clindamycin concentrations on clinical outcome, and also that optimal target concentrations of clindamycin have not been defined (J Infect 72:120, 2016).

 

    • Reminder about using fluoroquinolones* in patients with feeding tubes. Administering fluoroquinolones through a feeding tube along with enteral nutrition reduces their bioavailability, presumably due to multivalent cations in the feed such as aluminum, calcium, iron, and magnesium. The extent of the interaction varies among the drugs; ciprofloxacin is affected the most (its bioavailability may be reduced from the usual 70% to about 30-50%), followed by levofloxacin. Moxifloxacin absorption may not be affected at all by enteral feeding. Here are some suggested ways to minimize the fluoroquinolone-enteral feeding interaction: 

      1) Avoid fluoroquinolone use entirely, or administer intravenously

      2) Hold enteral feeding for 1-2 hours before and 2-4 hours after dosing when using ciprofloxacin or levofloxacin (this may not be necessary for moxifloxacin);

      3) Increase the dose (when using ciprofloxacin) to account for reduced bioavailability.

       

      Fluoroquinolone tablets should be thoroughly crushed and then diluted in 20-60 mL of sterile water before administration through a feeding tube; ciprofloxacin suspension should not be used because it may adhere to the tube and clog it (Am J Health-Syst Pharm 65:2347, 2008).

 

    • Can the propylene glycol in intravenous TMP-SMX* cause severe lactic acidosis? A 31-year-old, 106-kg female with pilocytic astrocytoma treated with metronomic temozolomide and steroids was admitted to the ICU for pneumonia and acute respiratory failure requiring mechanical ventilation. Other problems included neurofibromatosis type 1 and hypothyroidism. She was treated initially with cefepime, vancomycin, and azithromycin, and intravenous TMP-SMX 18 mg/kg/day was subsequently added to cover for Pneumocystis jirovecii. Renal and hepatic function were within normal limits. Her respiratory status improved within 36 hours and she was extubated. After three days of TMP-SMX the patient developed a severe metabolic acidosis (pH 7.2, pCO2 19 mm Hg, pO2 107 mm Hg on 2 liters O2, bicarbonate 8 mEq/L, lactate 12.1 mmol/L, anion gap 25 mEq/L). TMP-SMX was discontinued, and within 24 hours the serum bicarbonate increased to 23 and the lactate decreased to 2.9. No cause for lactic acidosis other than TMP-SMX was identified, and the patient’s acid-base status remained normal for the rest of her hospital stay.Propylene glycol is found in many intravenous and oral drugs, including IV TMP-SMX. About half is metabolized in the liver to lactate, pyruvate, and acetate, whereas the other half is excreted unchanged in the urine. Lactic acidosis is a known toxic effect of propylene glycol. Risk factors include renal dysfunction, hepatic dysfunction, and alcoholism, and some authors recommend limiting the intake of propylene glycol to 1 gm/kg/day. TMP-SMX injection contains SMX 80 mg, TMP 16 mg, and propylene glycol 400 mg per mL, and the patient discussed above received 54 gm of propylene glycol per day which, interestingly, is below the recommended daily limit. The only other propylene glycol-containing drug administered to the patient was lorazepam; she received 2 mg, which contributed an additional 0.8 gm. Propylene glycol toxicity has been observed over a wide range of serum concentrations, but unfortunately they were not measured in this patient (Medicine 95:e3478, 2016).

 

  • Trimethoprim (TMP) is structurally and pharmacologically related to amiloride, a potassium-sparing diuretic. TMP inhibits the uptake of sodium by epithelial cell sodium channels in the distal tubule, resulting in wasting of sodium, impaired potassium excretion, and metabolic acidosis. Although hyperkalemia is a well-known toxicity of trimethoprim-sulfamethoxazole (TMP-SMX), hyponatremia may be unappreciated. In a recent retrospective cohort study of 76 hospitalized patients who received high-dose TMP-SMX (>8 mg TMP/kg/day) for at least three days, 55 (72.3%) developed hyponatremia (<136 mEq/L) during treatment. Twenty-four of the 55 (43.6%) had a sodium nadir of <130 mEq/L and eight (14.5%) had a nadir of 125 mEq/L or less; the lowest sodium concentration observed was 117 mEq/L. Sodium nadir occurred at a mean time of 5.5 days after initiation of TMP-SMX, and lower sodium concentrations were associated with longer treatment duration and higher cumulative dose of TMP-SMX. Hyponatremia was more likely among African-American patients. Resolution occurred in the majority of patients within three weeks of discontinuation of TMP-SMX (Am J Med 2016 Aug 16 [Epub ahead of print]).

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, Ampicillin injection, Ampicillin/sulbactam, Cefepime, Cefotetan, Ceftazidime, Ceftriaxone, Chloroquine tablets (250, 500 mg), Ciprofloxacin oral suspension, 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, Oxacillin injection, Penicillin G benzathine, Penicillin G procaine injection, Piperacillin/tazobactam, Poliovirus vaccine inactivated, Tigecycline, Tobramycin, Vancomycin injection, Yellow Fever vaccine
      • [Shortage recently resolved]: Cefpodoxime

 

    • Antimicrobial drugs currently unavailable due to manufacturing delays or product discontinuation:
      • [New on the list] Penicillin G benzathine 900,000 units/Penicillin G Procaine 300,000 units (Bicillin C-R 900/300)
      • [Continue to be unavailable] Cefotaxime injection, Ceftazidime/Avibactam injection, Mupirocin calcium 2% nasal ointment, Penicillin G benzathine/Penicillin G Procaine (Bicillin C-R)

 

    • 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)