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

  • 80+ topics were updated in June. 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.

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 tabletsSusp (100 mg/5 mL,
    200 mg/5 mL)
    1 gm SD susp2 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

May 2016

Drug Safety Communications

  • The US Food and Drug Administration (FDA) is evaluating a Danish study (JAMA 315:58, 2016) that concludes there is a possible increased risk of miscarriage with the use of oral fluconazole for yeast infections. In this nationwide cohort study, the use of oral fluconazole in pregnancy (7 through 22 weeks gestation) was associated with a statistically significant increased risk of spontaneous abortion compared with the risk among unexposed women and women with topical azole exposure in pregnancy. Most of the oral fluconazole use appeared to be one or two doses of 150 mg. The FDA advises cautious prescribing of fluconazole in pregnancy pending completion of their review of this study and other data.
  • The FDA is advising that the serious side effects associated with fluoroquinolones generally outweigh the benefits for patients with acute sinusitis, acute bronchitis, and uncomplicated UTI who have other treatment options. A safety review has shown that systemic fluoroquinolones are associated with disabling and potentially permanent serious side effects involving the tendons, muscles, joints, nerves, and CNS that can occur together. All fluoroquinolone drug labeling will be updated to reflect this information. The full Drug Safety Communication may be viewed here.

  • In 2013 the FDA approved label changes for oral ketoconazole tablets to reflect the risk of liver damage, adrenal gland dysfunction, and drug interactions, and to remove the indications for treatment of skin and nail fungal infections. However, a recent safety review demonstrates that ketoconazole continues to be used for these infections, and since the label changes in 2013 there has been one patient death due to liver failure associated with oral ketoconazole use for nail infection. The FDA continues to recommend that oral ketoconazole not be used as first-line treatment for any fungal infection. Topical ketoconazole applied to the skin or nails has not been associated with liver damage, adrenal problems, or drug interactions. The full Drug Safety Communication may be viewed here.

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] Gentamicin injection, Ofloxacin 0.3% ophthalmic solution
    • [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, 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, Piperacillin-tazobactam, Poliovirus inactivated vaccine, Tigecycline, Tobramycin, Vancomycin injection, Yellow Fever vaccine
    • [Shortage resolved]: Cefazolin, Cefuroxime injection
  • Antimicrobial drugs currently unavailable due to manufacturing delays or product discontinuation:

    • [New on the list] Penicillin G procaine injection
    • [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

  • Otovel (ciprofloxacin 0.3% + fluocinolone acetonide 0.025% otic solution) for the treatment of acute otitis media with tympanostomy tubes in patients (aged ≥6 months) due to S. aureus, S. pneumoniae, H. influenzae, M. catarrhalis, and P. aeruginosa). The product is available in 0.25 mL single-dose vials and the recommended dose is instillation of the contents of one vial into the affected ear canal twice daily for seven days.

New or Updated Treatment Guidelines

  • The HHS Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission has updated its guidelines with 1) revisions to its appendix and table on the safety and toxicity of individual ARVs in pregnancy, 2) revisions to the abacavir, didanosine, and etravirine sections to include new data and FDA label updates, and 3) removal of the amprenavir, delavirdine, and zalcitabine sections as they are no longer available in the United States. The updated guidelines may be downloaded here.

  • In March, a number of key changes were made by the Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children to update the Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. The updated guidelines may be downloaded here.

  • New recommendations from the World Health Organization aim to speed up detection and improve treatment outcomes for MDR-TB through use of a novel rapid diagnostic test and a shorter, cheaper treatment regimen. Click here for details.

Practice Pearls

  • A reader wrote to inquire about our spectrum of activity rating for ceftazidime-avibactam vs. Burkholderia cepacia. We have rated the activity of ceftazidime-avibactam as + (green), which means it is potentially an alternative agent but still considered second line. A recommended agent would be rated ++ (blue).

    These ratings are often a source of uncertainty because microbes (such as B. cepacia complex, Acinetobacter, and Pseudomonas) may have variable susceptibility based on their mechanism of resistance. The addition of avibactam can overcome ceftazidime resistance if it is due to AmpC cephalosporinases, ESBLs, or serine based carbapenemases, but it cannot nullify the effect of metallocarbapenemases. In addition, the activity of avibactam would have no influence on resistance due to non-enzymatic mechanisms of resistance such as porin closure (reduced permeability) or efflux pumps.

    The Sanford Guide editors constantly debate how best to rate a drug’s likelihood of effectiveness for empiric therapy. Ceftazidime-avibactam should certainly be rated variable if the clinical likelihood is high that the pathogen is Burkholderia (e.g., a cystic fibrosis patient) and if the patient is critically ill. On the other hand, if the pretest probability of isolating Burkholderia is low and the patient is not seriously ill, the exclusion of ceftazime-avibactam from consideration might be the wrong conclusion as a large percentage of the isolates will likely prove susceptible.

    It remains a significant challenge to convey all the pertinent clinical issues in the cells of our spectrum of activity table.

  • The various dosage forms of of nitrofurantoin, a drug available since 1953, can be confusing. Here is a brief summary of the three forms:

    1) Microcrystalline suspension (25 mg/5 ml). Adult daily dose 50-100 mg q6h, pediatric dose (age >28 days) 5-7 mg/kg/day (divided q6h). Available generically; the brand name product is Furadantin.

    2) Macrocrystalline capsules (25, 50, and 100 mg). Adult daily dose 50-100 mg q6h, pediatric dose (age >28 days) 5-7 mg/kg/day (divided q6h). Available generically; the brand name product is Macrodantin.

    3) Macrocrystalline/monohydrate capsules (100 mg). 25% of each capsule is macrocrystalline nitrofurantoin; the remaining 75% is nitrofurantoin monohydrate contained in a powder blend which, upon exposure to GI fluids, forms a gel matrix that releases nitrofurantoin over time. Daily adult and pediatric dose (>12 years) is 100 mg q12h. Available generically; the brand name product is Macrobid.

    The macrocrystalline form of nitrofurantoin causes less nausea than the microcrystalline form. All forms of nitrofurantoin should be taken with food for enhanced absorption. Food may also improve tolerance in some patients.

    How does nitrofurantoin work? Enzymes reduce nitrofurantoin to highly reactive intermediates that are responsible for the drug's ability to damage DNA. Bacteria reduce nitrofurantoin more rapidly than mammalian cells do, accounting for the selective antimicrobial action of the compound. Bacteria that are susceptible to the drug rarely become resistant during therapy, a notable advantage of nitrofurantoin. The antibacterial activity of nitrofurantoin is reduced in alkaline urine. 

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).