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Links marked with an asterisk (*) provide details to Sanford Guide Web Edition subscribers, while all other links are universal.
- Treatment guidelines for drug-susceptible tuberculosis* are available for download on the IDSA website. These guidelines were jointly sponsored by the American Thoracic Society (ATS), CDC, and IDSA and are endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association (Clin Infect Dis 2016 Aug 10 [Epub ahead of print]).
- 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]).
- IDSA has updated its clinical practice guidelines for the treatment of coccidioidomycosis*. The new guidelines, available for download on the IDSA website, replace the 2005 version (Clin Infect Dis 2016 July 27 [Epub ahead of print]).
- 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:
- Cobicistat* (MATE1)
- Dolutegravir* (OCT2)
- Pyrimethamine* (MATE1, MATE2K)
- Rilpivirine* (OCT2)
- Trimethoprim* (MATE2K)
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