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August 23, 2016

August ID Update

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

New Guidelines

Updated Guidelines

    • CDC has updated its interim guidance for U.S. health care providers caring for infants born to mothers with possible Zika virus infection* during pregnancy (MMWR Morb Mortal Wkly Rep 2016 Aug 19 [Epub ahead of print]).

 

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)

 

July 27, 2016

July ID Update

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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 30, 2016

Collaboration with the Republic of Georgia

The Sanford Guide is pleased to announce the development of a Georgian language adaptation of The Sanford Guide to Hepatitis Therapy in collaboration with the Georgian National Center for Disease Control and Public Health. The new title, to be released on digital platforms on World Hepatitis Day in July, will be an integral element in a new public health initiative to eradicate Hepatitis C in Georgia.

 

Jeb and Dianne Sanford recently traveled to Tbilisi, Georgia to discuss the collaboration and co-host a Sanford Guide Round Table Symposium on antimicrobial therapy and the infectious disease situation in Georgia. Dr. David Sergeenko, Georgian Minister of Health summarized the discussion by saying “Thank you very much…I believe this collaboration will make our health care better, giving new opportunities to our medical doctors.”

June 21, 2016

June ID Update

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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