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

  • 40+ topics were updated in April. 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.

APRIL 2016

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] Doxycycline hyclate injection, Penicillin G benzathine

    • [Continue to be in reduced supply] Amikacin, Ampicillin injection, Ampicillin/sulbactam, Cefazolin, Cefepime, Cefotaxime, Cefotetan, Cefpodoxime, Ceftazidime, Ceftriaxone, Chloroquine tablets (250, 500 mg), Clindamycin injection, DTaP (Daptacel) vaccine, DTaP-IPV/Hib (Pentacel) vaccine, Haemophilus B conjugate vaccine, Imipenem-cilastatin, Meningococcal vaccines (various), Mupirocin calcium 2% cream, Neomycin and Polymyxin B sulfates and Dexamethasone ophthalmic ointment, Piperacillin-tazobactam, Poliovirus inactivated vaccine, Tigecycline, Tobramycin, Vancomycin injection, Yellow Fever vaccine

    • [Shortage resolved]: Meropenem

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

    • [New on the list] None

    • [Continue to be unavailable] Chloramphenicol sodium succinate injection, 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

 New Drug Approvals

  • Anthim (obiltoxaximab injection) for the treatment of inhalational anthrax in adult and pediatric patients in combination with appropriate antibacterial drugs. It is also approved for prophylaxis of inhalational anthrax when alternative therapies are not available or appropriate. Obiltoxaximab is a monoclonal antibody directed against the protective antigen (PA) component of Bacillus anthracis toxin, a three-component exotoxin consisting of PA, edema factor, and lethal factor. The dosage in adults (body weight >40 kg) is a single dose of 16 mg/kg IV over 90 minutes; pediatric patients >15 to 40 kg receive 24 mg/kg, ≤15 kg receive 32 mg/kg. Patients should be premedicated with diphenhydramine.

  • Descovy (emtricitabine 200 mg + tenofovir alafenamide 25 mg) for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. This is the third fixed-dose antiretroviral combination product to include TAF (the others are Genvoya and Odefsey). The recommended dose of Descovy is one tablet daily, with or without food.

New or Updated Treatment Guidelines

  • A new IDSA/SHEA 2016 clinical practice guideline for implementing an antibiotic stewardship program is available for download (http://www.idsociety.org).

  • CDC has updated its interim guidance for US health care providers caring for women of reproductive age with possible Zika virus exposure to include preconception counseling recommendations. This guidance also provides updated recommendations for testing pregnant women with possible Zika exposure (MMWR 65:315, 2016).

  • The Sanford Guide to Antimicrobial Therapy 2016 print edition is now available from the Sanford Guide Online Store. This latest edition features completely reclassified activity spectra printed in color, a new pediatric dosing table, a reworked renal dosing table, and many other updates.

Practice Pearls

  • Up to now our best data to guide acyclovir dosing in obesity has been from a small pharmacokinetic study of seven morbidly obese (MO) but otherwise healthy females presented only in abstract form (abstract #765, 31st ICAAC, 1991). The authors concluded that dosing by ideal body weight (IBW) is appropriate, but this recommendation has never been validated. In a recent prospective matched-pair study in oncology inpatients, a single 5 mg/kg dose of intravenous acyclovir was administered to seven MO patients (actual body weight ≥190% of IBW, mean BMI 45) and seven normal-weight patients (actual body weight 80-120% of IBW, mean BMI 22.5). The dose was based on IBW in the MO patients and actual body weight in the normal-weight patients, consistent with current recommendations. Acyclovir clearance was found to be significantly higher in the MO patients while AUC0-∞ and Cmax were significantly lower. Simple linear regression showed that clearance was more closely correlated to adjusted body weight [IBW + 0.4 x (actual body weight - IBW)] than IBW. Using patient-specific parameters in the MO patients, the use of adjusted body weight would result in drug exposure (AUC0-∞) similar to that observed in normal-weight patients. This study suggests that adjusted body weight is the appropriate dosing weight for acyclovir in patients who are morbidly obese (Antimicrob Agents Chemother 60:1830, 2016).
  • Another issue with acyclovir that occasionally comes up is how to laterally convert a patient from intravenous acyclovir to oral. There aren’t much clinical data to guide us—but one approach is to at least select an oral antiherpesvirus drug with systemic plasma acyclovir exposure (assessed using area under the plasma concentration vs. time curve) comparable to IV acyclovir. Oral acyclovir won’t cut it but valacyclovir might, and at least one paper is supportive. In an open-label, crossover study, 15 neutropenic cancer patients (mean age 40) were randomized to receive acyclovir 5 mg/kg IV q8h x7 doses followed 24 hours later by valacyclovir 1 gm PO q8h  x7 doses, or vice versa. Thirteen patients completed both treatment periods; two patients withdrew before oral valacyclovir administration due to adverse events unrelated to study medication (mucositis, progressive nausea). Mean AUC0-8 after PO valacyclovir was 76.3 (micromolar x h) compared to 64.2 after IV acyclovir (p=0.149). As expected, Cmax was higher after IV administration (34.0 micromolar compared to 26.6, p=0.044). The absolute bioavailability of acyclovir from valacyclovir was 60%, Tmax 2 hours with oral valacyclovir compared to 1 hour with IV acyclovir, and elimination half-life of acyclovir was the same with both treatments (about 2.5 hours). These data suggest that valacyclovir 1 gm PO q8h and acyclovir 5 mg/kg IV q8h produce comparable systemic plasma acyclovir exposure at steady state, at least in in neutropenic patients (J Antimicrob Chemother 47:855, 2001).
  • Clinicians often ask how do the two most commonly used forms of oral doxycycline, the hyclate and the monohydrate, compare? Doxycycline hyclate is a shortened version of the full name doxycycline hydrochloride hemiethanolate hemihydrate, whereas the monohydrate is doxycycline free base combined with a water molecule. As anti-infective agents they are equally effective. However, doxycycline hyclate is thought to have more gastrointestinal side effects than the monohydrate. The hyclate is quite acidic in solution (pH 2-3) and has been commonly associated with esophageal ulceration, particularly in patients who take doses at bedtime with little or no water. The monohydrate tends to dissolve slowly in the higher pH of the esophagus but rapidly in the stomach, so the risk of esophageal ulceration may be less than with the hyclate. On the other hand, the reduced bioavailability of the monohydrate at higher pH may be of concern in patients who are on long-term gastric acid suppression or have undergone gastrectomy or gastric bypass surgery. The monohydrate also tends to be a bit more expensive (Expert Opin Drug Saf 7:571, 2008).

MARCH 2016

Drug Shortage Updates

  • Antimcrobial 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, Ampicillin/sulbactam, Cefazolin, Cefepime, Cefotaxime, Cefotetan, Cefpodoxime, Ceftazidime, Ceftriaxone, Chloroquine tablets (250, 500 mg), Clindamycin, DTaP (Daptacel) vaccine, DTaP-IPV/Hib (Pentacel) vaccine, Haemophilus B conjugate vaccine, Imipenem-cilastatin, Meningococcal vaccines (various), Meropenem, Mupirocin calcium 2% cream, Neomycin and Polymyxin B sulfates and Dexamethasone ophthalmic ointment, Piperacillin-tazobactam, Poliovirus inactivated vaccine, Tigecycline, Tobramycin, Vancomycin, Yellow Fever vaccine

  • Antimicrobial drugs currently unavailable due to manufacturing delays or product discontinuation:
    • [New on the list] None

    • [Continue to be unavailable] Chloramphenicol sodium succinate injection, Ofloxacin 0.3% otic solution

  • Antimicrobial drugs discontinued: Peginterferon alfa-2b (February 2016; 50 mcg vials still available in limited quantities), Boceprevir (December 2015), Permethrin 1% topical lotion (September 2015)
  • For detailed information including estimated resupply dates, see http://www.ashp.org/menu/DrugShortages

New Drug Approvals

  • Odefsey (rilpivirine 25 mg + emtricitabine 200 mg + tenofovir alafenamide 25 mg) for the treatment of HIV-1 infection in patients ≥12 years of age with no antiretroviral treatment history and viral load ≤100,000, or to replace a stable ARV regimen in a patient with a viral load ≤50 x6 months, no history of treatment failure, and no known substitutions associated with resistance to any of the component drugs. Odefsey (pronounced oh-DEF-see) contains one NNRTI (RPV) + two NRTIs (FTC, TAF). The recommended dose is one tablet daily with food.

Pearls

  • It is well known that Candida parapsilosis has reduced susceptibility to echinocandins (caspofungin, micafungin, anidulafungin) relative to other species of Candida. What is thought to be the explanation for this?

    First, some background about C. parapsilosis. In 1928 Ashford reported the isolation from stool of a species of Monilia that did not ferment maltose. He called this strain Monilia parapsilosis to distinguish it from the more frequent isolate Monilia psilosis, which later became Candida albicans. C. parapsilosis was thought to be nonpathogenic until 1940 when it was blamed for a fatal case of endocarditis in an injection drug user. We now recognize C. parapsilosis as notorious for its ability to form biofilms on implanted devices. The detection of bloodstream infection with C. parapsilosis should raise a red flag regarding breaks in catheter care and infection control.

    The answer to the question posed above is a naturally-occurring change from amino acid proline to alanine at position 660 of FKS1p, the putative catalytic subunit of the fungal beta 1,3-glucan synthase complex. This subunit is the target of echinocandins and this amino acid change (P660A) results in about a 2-log reduction in the sensitivity of the enzyme to the drugs. P660A also occurs in sibling species C. metapsilosis and C. orthopsilosis but has not been observed in any other species. Amino acid position 660 is immediately distal to the hot spot 1 region of FKS1p (position 641-649) where spontaneously arising substitutions are associated with reduced susceptibility to echinocandins. A second hot spot region maps to amino acid positions 1345-1365 (Antimicrob Agents Chemother 52:2305, 2008; Fungal Genet Biol 47:117, 2010).

    In a recent study, the initial use of an echinocandin-based regimen did not negatively influence outcome in C. parapsilosis bloodstream infection (Clin Infect Dis 58:1413, 2014).

  • More than 80 drugs have been linked with esophageal injury. The elderly are at particular risk because of their frequent use of multiple medications, a greater likelihood of cardiac enlargement with concomitant mid-esophageal compression, pre-existing esophageal motility disorders, and decreased saliva production. Esophageal damage mostly occurs at the level of physiological narrowings (aortic arch level or above the lower esophageal sphincter) where drugs (especially large pills) may stick. Common presenting symptoms are sudden onset odynophagia, dysphagia, and retrosternal pain. Severity of injury ranges from mild inflammatory changes to severe ulceration, perforation or stricture formation.

    Drug-induced esophageal injury can be broadly classified into two groups. The first group includes drugs that cause transient, self-limited injury. Antibiotics are common offenders here, with the tetracyclines including doxycycline among the most well known. Drugs in this group tend to have an acid pH when dissolved, resulting in discrete ulcers that heal when the drug is removed without stricture formation. The second group of drugs are associated with persistent injury often accompanied by stricture. With these drugs (e.g. KCl, quinidine) the injury cannot be explained entirely by pH as it is often near neutral. Rather, the disorder may be the result of a drug that is hyperosmotic in solution ingested by a person with an esophageal motility disorder. Aspirin and NSAIDs are also important members of this group; the likely mechanism with them is disruption of the normal cytoprotective barrier in the esophageal mucosa often in the setting of pre-existing GERD (Dis Esophagus 22:633, 2009).

    Kadayifci et al describe five cases of severe esophageal ulceration due to doxycycline. All the patients were guilty of swallowing their doxycycline capsules with a small amount of water or immediately prior to bedtime, or both (Dis Esophagus 17:168, 2004). In the first case of apparent azithromycin-induced esophageal ulceration, the patient presented with a week of symptoms (heartburn, dysphagia, odynophagia) after finishing a course of azithromycin (500 mg qd x3). He denied smoking and drinking and was not receiving ASA or NSAIDs. Endoscopy revealed an extensive midesophageal ulcer; biopsies from the edge and center did not show cancer or an infectious etiology. The patient was treated with a liquid diet, PPI, and sucralfate and was asymptomatic in two weeks. Repeat upper endoscopy was normal (Cases J 3:48, 2010). Other reported antibiotic culprits are amoxicillin, ampicillin, clindamycin, cloxacillin, rifampin, and telithromycin (Can J Gastroenterol Hepatol Epub Sept 11, 2015; Endoscopy 37:740, 2005; Turk J Gastroenterol 17:113, 2006; World J Gastroenterol 20:10994, 2014).

    Patients prescribed likely offenders should be counseled to take them with plenty of water and not immediately before lying down at night. Liquid formulations may be preferable in the elderly, especially those with cardiomegaly or motility disorders.

  • Dapsone is a sulfone antimicrobial and antiinflammatory drug. It is useful for prophylaxis and treatment of Pneumocystis jirovecii pneumonia as well as leprosy and other skin diseases. In a 2004 retrospective study examining 138 cases of acquired methemoglobinemia at two tertiary care hospitals over 28 months, dapsone was the most common etiology (accounting for 42% of the cases). Methemoglobinemia has been associated with dapsone therapy at both therapeutic doses and in overdose situations, but during 1997-2011 the majority of reports involved therapeutic doses (Am J Ther 14:585, 2007).

    Hemoglobin can accept and transport oxygen only when the iron is in the +2 (ferrous) state. In methemoglobin (MetHb) the heme iron is in the +3 (ferric) state. Low levels of MetHb in the red blood cell are maintained (a) via reduction of MetHb using NADH- and NADPH-dependent enzyme systems, and (b) via the nonenzymatic antioxidants ascorbic acid and glutathione. The most striking physical finding in methemoglobinemia is discoloration of the skin and blood, which takes on a chocolate-brown color as blood MetHb concentrations (normally about 1%) rise. Venous blood samples are typically brown at levels of 10% or more. Headache, fatigue, tachycardia, and dizziness are observed at levels of 30-40%. More serious signs and symptoms including acidosis, arrhythmias, seizures, and coma are observed as levels approach 60%, and death ensues at MetHb concentrations of 70-80%. These MetHb thresholds are lower in patients with anemia, significant cardiac or pulmonary disease, or other hemoglobin abnormalities (Ann Pharmacother 45:1103, 2011).

    Dapsone undergoes reversible acetylation by hepatic N-acetyltransferase (NAT2) to the inactive metabolite monoacetyldapsone. In addition, CYP2C isoenzymes, with other CYP450 isoenzymes playing a minor role, generate dapsone hydroxylamine. Dapsone hydroxylamine is responsible for the development of methemoglobinemia by oxidizing the iron moiety of hemoglobin from +2 to +3. Risk factors for dapsone-induced methemoglobinemia include renal failure, coadministration of other drugs known to cause methemoglobinemia, slow NAT2 activity, and decreased glucose-6-phosphate dehydrogenase (G6PD) activity. G6PD is necessary for generation of NADPH (Drug Metab Dispos 28:865, 2000).

    Drug treatment of choice is methylene blue, which accelerates the enzymatic reduction of MetHb by NADPH-MetHb reductase. The dose is 1-2 mg/kg IV over five minutes. Methylene blue works within an hour and many patients only require a single dose.  If repeated dosing is necessary, note that excessive concentrations of methylene blue may result in a paradoxical worsening of methemoglobinemia. It should be used with caution in G6PD-deficient patients because it may induce hemolysis. A recent anecdotal report describes the apparently successful use of high dose IV ascorbic acid used instead of methylene blue because of local unavailability of the latter (Am J Emerg Med 32:684.e1, 2014).

FEBRUARY 2016

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] Ampicillin, Cefazolin, Cefpodoxime, DTaP (Daptacel) vaccine, Meningococcal polysaccharide vaccine (MPSV4), Mupirocin calcium 2% cream, Neomycin and Polymyxin B sulfates and Dexamethasone ophthalmic ointment, Poliovirus inactivated vaccine

    [Continued reduced supply] Amikacin, Ampicillin/sulbactam, Cefepime, Cefotetan, Cefotaxime, Ceftazidime, Ceftriaxone, Clindamycin, DTaP-IPV/Hib (Pentacel) vaccine, Haemophilus B conjugate vaccine, Imipenem-cilastatin, Meropenem, Piperacillin-tazobactam, Tigecycline, Tobramycin, Vancomycin, Yellow Fever vaccine

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

    [New on the list ] None

    [Continued unavailable] Chloramphenicol sodium succinate injection, Chloroquine tablets (250, 500 mg), Mupirocin calcium 2% nasal ointment (1 gm tubes), Ofloxacin 0.3% otic solution

  • Antimicrobial drugs discontinued: Peginterferon alfa-2b (February 2016), Boceprevir (December 2015), Permethrin 1% topical lotion (September 2015)

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

New Drug Approvals

  • Zepatier (elbasvir 50 mg + grazoprevir 100 mg) for the treatment of adults with chronic hepatitis C genotypes 1 or 4 infection (with or without ribavirin). Key points: this is the first HCV drug for which a resistance assay is recommended prior to treating genotype 1a infection, and also the first HCV drug given priority approval owing to its safety in ESRD/hemodialysis patients. The approved dose is one tablet once daily, with or without food.

New or Updated Treatment Guidelines

  • The Infectious Diseases Society of America 2016 clinical practice guideline for management of candidiasis is available on the IDSA website for download (http://www.idsociety.org). This is an update of the 2009 iteration. The guideline has been reviewed and endorsed by the American Academy of Pediatrics, the Pediatric Infectious Diseases Society, and the Mycoses Study Group (Clin Infect Dis 62:e1, 2016).

Pearls

  • Despite its long terminal half-life of 147-258 hours, the initially approved dose of dalbavancin for acute bacterial skin and skin structure infections (ABSSSI) in adults was 1000 mg on day 1 followed one week later by 500 mg. In a recent study, 698 adults with ABSSSI were randomized to receive dalbavancin as a single dose (1500 mg) or via the approved two-dose regimen. The primary study endpoint was a ≥20% reduction in the area of erythema at 48-72 hours. Dalbavancin administered as a single dose was found to be noninferior to the two-dose regimen after 48-72 hours, and clinical outcomes were also similar at day 14, day 28, and at day 14 in patients with MRSA in a baseline culture. Adverse event profiles of the two regimens were similar. Based on the results of this trial, the FDA has approved updated product labeling to include a single 1500 mg dose over 30 minutes for the treatment of ABSSSI in adults, including infections caused by MRSA (Clin Infect Dis 62:545, 2016).

  • Foscarnet is useful for acyclovir-resistant and ganciclovir-resistant herpesvirus infection because it does not require initial phosphorylation by a virus-encoded enzyme (resistance to nucleoside analogs is commonly due to diminished phosphorylation). Well-known adverse effects of foscarnet include nephrotoxicity, metabolic disturbances, and seizures. Genital ulceration is a less widely appreciated but nevertheless troublesome toxicity. Experienced by up to one-third of patients, common ulcer locations are the glans penis and periurethral area in men and the labia in women. Ulcers generally occur early in treatment (when induction dosing is used) and are likely the result of an irritant contact dermatitis, as foscarnet is mostly excreted unchanged in urine and aggressive hydration regimens increase the likelihood of urine coming in contact with skin. Patients should be instructed to wash thoroughly after urinating to minimize the occurrence of genital ulcers, but if ulcers occur the drug should be withheld until they heal (Acta Dermatoven APA 20:39, 2011; Clin Infect Dis 28:139, 1999).

  • Teeth discoloration is an unusual side effect of linezolid that was recently reported for the first time in an adult. A female in her mid-20s was treated for multidrug-resistant tuberculosis with a combination regimen that included linezolid, cycloserine, moxifloxacin, pyrazinamide and amikacin. Brown teeth discoloration was noted after eight weeks of oral linezolid (600 mg po daily). Dental cleaning removed the discoloration, the drug was continued, and the discoloration returned within four weeks. Dental cleaning was again performed, linezolid was discontinued, and this time the discoloration did not return (Clin Infect Dis 62:617, 2016). Five pediatric patients with this side effect have previously been described, all with MRSA infections treated with oral or intravenous linezolid 30 mg/kg/day (or 600 mg bid) with or without other agents. In all instances, teeth discoloration was observed after one week or more and was sometimes accompanied by tongue discoloration. Resolution occurred upon drug discontinuation, and dental cleaning was effective in all but one case. The mechanism of linezolid-induced teeth discoloration is not known (Clin Pediatr 54:809, 2015; Pediatr Infect Dis J 28:345, 2009; Pediatr Infect Dis J 32:1284, 2013; Pharmacotherapy 23:682, 2003).

  • A number of retrospective studies have suggested that combination therapy with piperacillin-tazobactam plus vancomycin may be associated with an increased incidence of acute kidney injury (Pharmacotherapy 34:653, 2014; Pharmacotherapy 34:662, 2014; Pharmacotherapy 34:670, 2014). This suspicion is substantiated in yet another report, a retrospective study of 228 noncritically ill patients in whom the odds of acute kidney injury were over five times higher during piperacillin-tazobactam plus vancomycin therapy compared to vancomycin alone. Study design and other factors limit our ability to draw firm conclusions, but this observation is intriguing and deserves prospective investigation. At the very least it provides further justification for narrowing antimicrobial therapy as soon as possible in patients who are started on the combination. The mechanism of enhanced nephrotoxicity with piperacillin-tazobactam plus vancomycin, if it is real, remains a matter of speculation (BMC Res Notes 8:579, 2015).