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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