ID Update

  • ID Update™ is the Sanford Guide infectious diseases news page. Each month, we summarize new or updated practice guidelines, recent clinical trials, new reviews, relevant drug safety notices, new drug approvals, new dosage forms, new treatment indications and other current developments.
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Recent Updates

  • Beginning in November 2016, Sanford Guide Web Edition content will be updated on a continual basis. Sanford Guide mobile applications will continue to be updated monthly. For Web Edition users, the date a page was last modified is shown under the page Title. For app users, the date is shown at the bottom of each page.

NOVEMBER 2016

New Drug Approval

  • Tenofovir alafenamide (Vemlidy) has been approved by the FDA for the treatment of chronic hepatitis B in adults with compensated liver disease. The recommended dosage is 25 mg orally once daily with food. Product availability: 25 mg tablets.

 New Dosage Form Approval

  • The FDA has approved Maraviroc (Selzentry) 20 mg/mL oral solution, 25 mg tablets, and 75 mg tablets. The prescribing information has been updated to include use in pediatric patients 2 years of age and older and weighing at least 10 kg.

New Treatment Guidelines

  •  New clinical practice guidelines for the management of leishmaniasis have been prepared by a panel of the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). The guidelines are available for download on the IDSA website.

Practice Pearls

  • Candida auris, an emerging fungus capable of invasive infection, is associated with high mortality and possible resistance to multiple antifungal drugs. It was first isolated in 2009 from the external ear canal of an inpatient in a Japanese hospital and has since been reported in a number of countries. A recent report describes the first seven US cases of C. auris infection reported to CDC as of August 31. C. auris is a serious concern because accurate laboratory identification requires specialized methods, it tends to be resistant to two or even three antifungal drug classes (azoles, echinocandins, polyenes), and it has caused outbreaks in health care settings. The optimal treatment regimen is not known (MMWR 65:1234, 2016).

  • Drug interactions that result in prolongation of the QT interval (QT-DDI) are often discovered many years after the drugs are marketed, suggesting the need for a more efficient strategy. A group of investigators recently mined the FDA Adverse Event Reporting System (FAERS) for signals indicating a QT-DDI. They then combined those data with ECGs from their institutional electronic health records (EHR). An unexpected interaction between lansoprazole (a proton-pump inhibitor) and ceftriaxone was identified. Mean prolongation of the QTc (corrected QT interval) was 12 ms in males and 9 ms in females; men taking the combination were 1.4 times as likely to have a QTc above 500 ms as men taking a single drug. The largest effects were observed in white males and black females. The investigators then used patch-clamp electrophysiology to show that, in combination, the drugs block the hERG channel (the main mechanism by which drugs prolong the QT interval). As a negative control, no evidence of a QT-DDI was identified in the FAERS or EHR data, or in the electrophysiologic experiments, for the combination of lansoprazole and cefuroxime. Further class analysis found no evidence in the FAERS or EHR for an interaction between any other cephalosporin and proton-pump inhibitor. The mechanism for this intriguing drug interaction, identified using a novel approach of data mining followed by laboratory experimentation, is not known (J Am Coll Cardiol 68:1756, 2016).

  • Many clinical trials have evaluated the use of cranberry products for UTI prevention, with inconsistent results (often negative, or positive results with flawed methodology). A recent report in JAMA describes a well-designed randomized, double-blind, placebo-controlled trial in elderly female nursing home residents intended to evaluate the effect of cranberry capsules on clinical and microbiologic outcomes. Study participants were administered two oral cranberry capsules (each capsule containing 36 mg of the active ingredient proanthocyanidin) or placebo once a day for a year. There was no significant difference in the primary outcome of bacteriuria plus pyuria, and also no significant differences in any of the secondary outcomes of the study such as symptomatic UTI, rates of death, or hospitalizations. The results of this study are consistent with the view that cranberry products cannot, at this time, be recommended for UTI prevention on the basis of proven benefit (JAMA 316:1879, 2016).

  • Vancomycin-induced thrombocytopenia, first described in 1985, is uncommon, poorly characterized, and probably under-diagnosed. The mechanism appears to involve vancomycin-dependent, platelet-reactive antibodies (N Engl J Med 356:904, 2007). A group of researchers conducted a systematic search of the English-language literature using the PubMed, Scopus, and Web of Science databases; 29 case reports, five observational studies, two clinical trials, two letters, and one case series were identified for analysis and the results were recently published. In summary, the precise incidence of vancomycin-induced thrombocytopenia remains unclear. The reaction appears to be duration-dependent with a mean time to platelet nadir of eight days after the first exposure (and significantly shorter in cases of re-exposure). Nadir platelet counts ranged from 2,000 to 100,000 in patients who experienced bleeding. In the case reports, vancomycin-specific antibodies were detected in 13 of 17 patients who were tested. No conclusive association between vancomycin serum concentration and thrombocytopenia was observed. The platelet count returned to normal in a mean time of 5-6 days following discontinuation of vancomycin. Platelet transfusions were used in some patients with variable results; other measures such as corticosteroids, intravenous immunoglobulin, or rituximab were employed in a few patients with unclear benefit (Drug Safety 2016 Nov 15 [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]: Cefoxitin injection, Cefuroxime injection

    • [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, Erythromycin lactobionate injection, Gentamicin injection, Haemophilus B conjugate vaccine, Meningococcal vaccines (various), Mupirocin calcium 2% cream, Ofloxacin 0.3% ophthalmic solution, Oxacillin injection, Penicillin G benzathine, Piperacillin/tazobactam, Poliovirus vaccine inactivated, Tigecycline, Tobramycin, Vancomycin injection, Yellow Fever vaccine

    • [Shortage recently resolved]: DTaP (Daptacel) vaccine, DTaP-IPV/Hib (Pentacel) vaccine, Imipenem-cilastatin injection

  • Antimicrobial drugs currently unavailable due to manufacturing delays or product discontinuation:

    • [New on the list]: None

    • [Continue to be unavailable]: Cefotaxime injection, Ceftazidime/Avibactam injection, Mupirocin calcium 2% nasal ointment, Penicillin G benzathine/Penicillin G Procaine (Bicillin C-R), Penicillin G procaine injection, Penicillin G benzathine 900,000 units/Penicillin G Procaine 300,000 units (Bicillin C-R 900/300)

  • 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

 

OCTOBER 2016

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)

  • For detailed information including estimated resupply dates, see http://www.ashp.org/menu/DrugShortages

SEPTEMBER 2016

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).

  • 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).

  • 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).

  • 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

  • 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

  • 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

AUGUST 2016

New Guidelines

Updated Guidelines

Practice Pearls

  • Tubulointerstitial diseases involve kidney structures outside the glomerulus. They include acute and chronic interstitial nephritis (AIN and CIN, respectively) and acute tubular necrosis (ATN). Most cases of AIN (over 2/3) are a result of drug-induced hypersensitivity (not direct toxicity). Many infectious processes as well as immune disorders have also been implicated. Drugs commonly associated with AIN are NSAIDs, antibiotics (beta-lactams, sulfonamides, fluoroquinolones, rifampin, and a few others), diuretics, phenytoin, and allopurinol.

    Drug-induced AIN typically presents as non-oliguric renal dysfunction that appears gradually about 2-3 weeks or more following initiation of the offending drug. Laboratory markers of tubular dysfunction, which vary depending on the major site of injury, are generally observed before the appearance of increased BUN and serum creatinine. The classic clinical triad of low-grade fever (35-70% of patients), skin rash (25-40%), and eosinophilia (35-60%) is fully seen in less than 1/3 of patients. Flank pain is present in 25-40% of patients and may be the presenting symptom. At least 25% of patients have arthralgia, and 5-15% exhibit gross hematuria. Urinalysis typically reveals pyuria, hematuria, and mild proteinuria; NSAID-induced AIN is unusual in that patients may present with heavy (nephrotic-range) proteinuria. Eosinophiluria is nonspecific for AIN but is a better marker when more than 5% of the urinary leukocytes are eosinophils (Clin Nephrol 82:149, 2014).

    AIN is commonly suspected based on clinical presentation, but definitive diagnosis requires kidney biopsy. Discontinuation of the offending drug usually results in quick recovery and full return of renal function, although irreversible injury occasionally occurs. There are no prospective randomized trials supporting the use of corticosteroids for AIN although they may improve recovery. In a retrospective study a commonly used regimen was intravenous methylprednisolone (250-500 mg daily) for 3-4 days followed by oral prednisone 1 mg/kg/day tapered off over 8-12 weeks (Kidney Int 73:940, 2008).

  • Effective management of a drug interaction includes the ability to accurately assess the time course of the interaction. The situation with CYP enzyme inhibitors and inducers is different, and a brief review is useful.

    Estimating enzyme inhibition is fairly straightforward. There are a number of mechanisms of inhibition, but the most common is competition for the same metabolic enzyme. Inhibition begins with the first dose of inhibitor, and because most inhibitors have relatively short half-lives, inhibition is maximal in just a few days. The full effect of the interaction may take longer than that if the affected drug has a long half-life. The time required for resolution of inhibition also depends on the half-lives of the involved drugs, although there are situations in which the situation is more complex than that. In contrast, enzyme induction is not as predictable using just the half-lives of the interacting drugs. Induction represents an increase in the amount and/or activity of a drug metabolizing enzyme and tends to be a more gradual process than inhibition, requiring a week or more for maximal effect. Rifampin is a good example. Although the elimination half-life of rifampin is only a few hours, full CYP enzyme induction caused by rifampin takes much longer because of the time required to upregulate the metabolizing enzymes. Affected drugs may require two weeks or more to reach their new (lower) steady-state concentrations. Similarly, the time required for resolution of induction is slower than for inhibition; in the case of rifampin, two to four weeks is a reasonable range. This time period reflects mainly the natural degradation half-life of the involved enzyme(s).

    In short: enzyme inhibition (time to onset and time to resolution) is typically a quicker process than induction. Drug half-lives are helpful for estimating onset and resolution of inhibition but they usually underpredict onset and resolution of induction.

  • It is important to realize that some commonly used drugs, including antimicrobial agents, may cause an increase in serum creatinine (SCr) without altering glomerular filtration rate (GFR). This nonpathologic elevation of Scr is thought to be due to reversible inhibition of key renal transporters. Here is a brief review.

    Creatinine is an endogenous low molecular weight (113 Da) cation produced mainly by muscle metabolism. It is eliminated solely via renal excretion through a combination of glomerular filtration and proximal tubular secretion. Tubular secretion accounts for 10-40% of total creatinine elimination (up to 50-60% in chronic renal failure). The serum half-life of creatinine is about four hours in normal renal function, but is prolonged to about 16 hours at a GFR of 30 mL/min.

    Organic cation transporter 2 (OCT2), multidrug and toxin extrusion protein 1 (MATE1), and MATE2K are the major transporters involved in proximal tubular secretion of creatinine. OCT2 is an influx transporter (blood → proximal tubular cell), and MATE1 and MATE2K are efflux transporters (proximal tubular cell → urine).

    There are four antimicrobial agents (plus cobicistat) with the capability to increase SCr without changing GFR. They are listed below, with the predominant inhibited transporter(s) shown in parentheses:

    The increase in SCr is typically 0.24-0.37 mg/dL (a decrease in CrCl of 15-34 mL/min per 1.73 m2), occurring within the first few days or weeks after initiation of treatment. Trimethoprim and pyrimethamine have the greatest effect. Such non-progressive changes in SCr should not raise concerns of renal toxicity unless accompanied by other markers of renal damage (AIDS Rev 16:199, 2014; Drug Metab Dispos 44:1498, 2016).

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] None
    • [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, 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]: Ofloxacin 0.3% otic solution
  • Antimicrobial drugs currently unavailable due to manufacturing delays or product discontinuation:
    • [New on the list] Ceftazidime/Avibactam injection, Mupirocin calcium 2% nasal ointment

    • [Continue to be unavailable] None

  • 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

JULY 2016

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

JUNE 2016

Practice Pearls

  • Tenofovir disoproxil fumarate (TDF) is an important antiretroviral agent that was approved by the FDA in 2001. A diester prodrug, TDF is first hydrolyzed in the plasma to form tenofovir (TFV; a nucleotide containing one phosphate group), which then enters lymphocytes and macrophages and is phosphorylated twice to form tenofovir diphosphate (TFV-DP), a potent inhibitor of HIV reverse transcriptase. TDF is generally well tolerated except for nephrotoxicity and decreased bone mineral density, which are associated with higher circulating plasma concentrations of TFV.

    Three antiretroviral combination products have recently been approved that contain tenofovir alafenamide fumarate (TAF) instead of TDF. Also an ester prodrug, TAF is more stable than TDF in plasma and is thus predominantly metabolized intracellularly to TFV via cathepsin A. The key point is that TAF at 25 mg results in plasma TFV exposure about one-tenth of what we observe with a 300 mg dose, yet intracellular TFV-DP concentrations are at least equal to, and often exceed, intracellular levels of the active diphosphate moiety generated by TDF.  Therefore, TAF has reduced impact on renal function and bone mineralization as demonstrated by multiple parameters during clinical trials, while clinical efficacy is maintained.

    The first TAF-containing product to be approved was Genvoya (elvitegravir, cobicistat, emtricitabine, TAF), analogous to the TDF-containing Stribild. This was followed by Odefsey (rilpivirine, emtricitabine, TAF), analogous to Complera, and then Descovy (emtricitabine, TAF), analogous to Truvada. The dose of TAF in Descovy and Odefsey is 25 mg, but because cobicistat increases the bioavailability of TAF via inhibition of P-glycoprotein, the dose of TAF in Genvoya is only 10 mg (Antiviral Res 125:63, 2016).

  • A primer on the Bicillins. The Bicillins consist of long-acting salts of Penicillin G. Bicillin L-A is benzathine penicillin G whereas Bicillin C-R contains the benzathine and procaine salts in a 1:1 ratio (except for Bicillin C-R 900/300, which has 900,000 units of the benzathine salt and 300,000 units of the procaine salt). Procaine penicillin G (no benzathine salt) is also available. These salts have low solubility and slowly release drug from a deep intramuscular injection site, resulting in low but sustained blood concentrations of penicillin; the benzathine salt yields detectable concentrations for about four times as long as those produced by the procaine salt. Here is a listing of the currently available products (disposable syringes):

    • Bicillin L-A: 600,000 units/1 mL, 1.2 million units/2 mL, 2.4 million units/4 mL
    • Bicillin C-R: 1.2 million units/2 mL (600,000 units of each salt)
    • Bicillin C-R 900/300: 1.2 million units/2 mL (900,000 units benzathine, 300,000 units procaine)
    • Procaine penicillin G: 600,000 units/1 mL, 1.2 million units/2 mL

    The C-R products are indicated for streptococcal infection, and Bicillin L-A is indicated for both streptococcal infection and Treponema. Prolonged spirocheticidal concentrations are considered essential to treated the slowly reproducing causative pathogen of syphilis, T. pallidum. CDC recommends Bicillin L-A for all stages of syphilis except neurosyphilis. For primary, secondary, and early latent infection the dose is 2.4 million units IM x1 dose; for late latent and tertiary the dose is 2.4 million units IM weekly x3 doses. An unfortunate (and not uncommon) error in syphilis management is the use of Bicillin C-R 2.4 million units rather than Bicillin L-A 2.4 million units. As a result, the packaging material for the C-R products is now clearly labeled “Not for the Treatment of Syphilis” in red letters.

    Bicillin pharmacokinetics in adults. After a single IM injection of benzathine penicillin G 2.4 million units to 15 subjects (mean age 22), the mean penicillin G concentration was 0.2 µg/mL at 48 hours, 0.05 µg/mL at six days, and 0.02 µg/mL at 13 days. 33% of the subjects already had negligible penicillin G concentrations at day 13, and thereafter no subjects had significant serum concentrations. The same dose was also administered to 25 elderly subjects (mean age 76). The mean penicillin G concentration was 0.4 µg/mL at 48 hours, 0.09 µg/mL at six days, and 0.05 µg/mL at 13 days. At 20 days the penicillin G concentration was 0.04 µg/ml. Compared to the young subjects, the elderly subjects experienced higher and more prolonged serum concentrations of penicillin G (Br J Vener Dis 56:355, 1980).

    For purposes of comparison, 2 million units of IV penicillin G results in a peak serum concentration of 20 µg/mL.

    Bicillin pharmacokinetics in children. Seven children weighing <27 kg were administered a single dose of Bicillin L-A 600,000 units, and six children weighing ≥27 kg were administered 1.2 million units. Serum level-time curves over 30 days were similar for the two groups. The mean peak serum concentration, attained at 24 hours, was 0.16 µg/mL; subsequent mean concentrations were 0.075 µg/mL (day 5), 0.04 µg/mL (day 10), and 0.01 µg/mL (day 18). No penicillin G was detectable in any child on day 30.

    A dose of Bicillin C-R 900/300 was also administered to 13 children (mean weight 16.6 kg). In contrast to the children receiving Bicillin L-A, considerably higher peak penicillin G concentrations were reached much sooner (3.93 µg/mL in one hour), and the concentrations at two and four hours were significantly larger than those in patients receiving Bicillin L-A. Concentrations of penicillin G at 5-30 days were comparable to those in the Bicillin-LA treated children (Pediatrics 69:452, 1982).

  • Oral azithromycin is available in the US as 250, 500, and 600 mg tablets, 100 mg/5 ml and 200 mg/5 ml pediatric suspension, 1 gm single-dose suspension, and 2 gm extended-release single-dose suspension. The food and antacid recommendations can be confusing so we offer the chart below to help.

    The only form of azithromycin that must be taken on an empty stomach is the 2 gm extended-release suspension (Zmax). Meal-triggered gastric acid secretion speeds drug release from the formulation’s microspheres, which we don't want, and it may also increase nausea.

    Zmax is also the only form of azithromycin that purportedly is not affected by concomitant antacids, based on actual study data (Clin Pharmacokinet 46:247, 2007). For all other forms of azithromycin the manufacturer recommends avoiding simultaneous antacid administration. This recommendation is apparently based on a study with azithromycin capsules, which are no longer available; moreover, in that study the Cmax was decreased by 24% but AUC was not affected, suggesting a slowing of the rate of absorption but no change in extent. Since the pharmacodynamic parameter associated with azithromycin efficacy is AUC/MIC, the recommendation thus seems questionable.

      All tablets Susp (100 mg/5 mL,
    200 mg/5 mL)
    1 gm SD susp 2 gm ER SD susp
    Food ± ± ± avoid
    Antacids avoid avoid avoid ±

    ± means with or without, SD means single dose

Drug Shortage Updates

  • 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, Cefotaxime, Cefotetan, Cefpodoxime, Ceftazidime, Ceftriaxone, Chloroquine tablets (250, 500 mg), Clindamycin injection, Doxycycline hyclate injection, DTaP (Daptacel) vaccine, DTaP-IPV/Hib (Pentacel) vaccine, Gentamicin injection, Haemophilus B conjugate vaccine, Imipenem-cilastatin, Meningococcal vaccines (various), Mupirocin calcium 2% cream, Neomycin and Polymyxin B sulfates and Dexamethasone ophthalmic ointment, Penicillin G benzathine, Penicillin G procaine injection, Piperacillin-tazobactam, Poliovirus inactivated vaccine, Tigecycline, Tobramycin, Vancomycin injection, Yellow Fever vaccine

    • Shortage resolved: Cefazolin, Cefuroxime injection, Chloramphenicol sodium succinate injection

  • Antimicrobial drugs currently unavailable due to manufacturing delays or product discontinuation:

    • New on the list: Ofloxacin 0.3% ophthalmic solution

    • Continues to be unavailable: Ofloxacin 0.3% otic 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