January ID Update

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Updated Treatment Guidelines

  • Updated guidelines for the prevention, detection, and management of surgical site infections* from the American College of Surgeons (ACS) and the Surgical Infection Society (SIS) have been published (J Am Coll Surg 224:59, 2017). The guidelines are available for download on the JACS website.
  • Current SIS recommendations regarding the management of patients with intra-abdominal infection are also available (Surg Infect 18:1, 2017). The guidelines were last updated in 2010.

Practice Pearls

    • The impressive final results of a trial designed to assess the efficacy of the rVSV-ZEBOV vaccine for prevention of Ebola virus disease* (EVD) are now available. The trial, conducted in Guinea, used the ring vaccination approach inspired by the surveillance-containment strategy that resulted in eradication of smallpox. After confirmation of a case of EVD, clusters of contacts and contacts of contacts were identified. Clusters were randomly assigned to immediate vaccination or vaccination delayed by 21 days. Vaccination was a single IM dose (2 x 107 plaque-forming units) administered in the deltoid muscle. Randomized assignment was eventually discontinued on the recommendation of an independent data and safety board because of interim analysis findings, and thereafter all clusters received immediate vaccination (including children). Immediate vaccination resulted in complete protection against subsequent onset of EVD ten days later or more. Headache, fatigue, and muscle pain were the most commonly reported adverse events across all age groups. The rVSV-ZEBOV vaccine is a recombinant, replication-competent, vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of a Zaire Ebolavirus (Lancet 2016 Dec 23 [Epub ahead of print]).

 

    • A classic question: does concomitant treatment with an anti-infective agent enhance the pharmacologic effects of warfarin?First, some background. Warfarin is a racemic mixture of R-warfarin (half-life 37-89 hours) and S-warfarin (half-life 21-43 hours). R-warfarin is metabolized by CYP1A2, 2C19, and 3A4 whereas S-warfarin is metabolized by CYP2C9. The S enantiomer is five times as active as the R enantiomer. Therefore, anti-infectives that inhibit CYP2C9 would be expected to have the greatest impact on warfarin metabolism and INR. Here is a complete (hopefully) list of anti-infectives that inhibit CYP2C9:
      • Antibacterials: metronidazole, oritavancin (weakly), TMP/SMX (specifically SMX)
      • Antifungals: fluconazole, voriconazole
      • Antiretrovirals: delavirdine, efavirenz, etravirine

      There are at least five reasons why an anti-infective might enhance the effects of warfarin (listed in no particular order):

      1) Protein-binding displacement. The notion that a highly protein bound anti-infective might displace warfarin from its binding sites was one of the earliest explanations offered. However, we know that protein displacement results in an increased free fraction of unbound warfarin but also increased warfarin clearance since more is available to its metabolic enzymes. Thus, any increase in warfarin effect should be transient.

      2) Direct inhibition of clotting factor formation by the anti-infective. For years we all recited the specific cephalosporins containing an N-methylthiotetrazole (MTT) side chain at position 3 of the cephalosporin nucleus because of its known association with bleeding. MTT is a heterocyclic leaving group that inhibits the gamma-carboxylation of glutamic acid, a vitamin K-dependent reaction required for the formation of clotting factors. Thankfully, most of the MTT-containing cephalosporins (cefotetan, cefoperazone, cefmetazole, cefamandole, moxalactam) are gone from the market (at least the US market).

      3) Impairment of vitamin K production by gut flora. This is a commonly invoked explanation with a striking lack of supportive data. We know that the typical diet contains about 300-500 mcg/day of vitamin K, and it has been estimated that a chronic change in intake of about 250 mcg/day would be required to alter one’s response to warfarin. But we have not quantified the contribution of vitamin K production by gut flora, nor do we know the reduction that might be expected from anti-infective therapy (or the extent to which it would vary depending on the drug).

      4) Alteration in dietary vitamin K intake as a consequence of infection. In other words, sick people may eat less leafy green vegetables.

      5) Reduced warfarin metabolism resulting from the infection itself, i.e. proinflammatory cytokines released during infection acting as inhibitors of drug metabolism by downregulating enzymes such as CYP2C9 (Clin Pharmacol Ther 85:434, 2009). Thus an anti-infective that appears to inhibit warfarin metabolism is simply acting as a marker for the true culprit, and the disappearance of the interaction is due to resolution of the infection, not withdrawal of the drug.

      The fifth listed reason may be most likely with a possible (lesser) contribution from the third and fourth reasons. Many anti-infectives have been associated with elevated INR in patients taking warfarin, but it is important to note that case reports from infected patients make up the bulk of the positive interaction data whereas controlled, prospective, randomized trials in healthy subjects usually fail to demonstrate the interaction. An interesting observational case-control and case-crossover study of warfarin users using US Medicaid data was published in 2008. Exposure to all seven antimicrobials examined in the study (ciprofloxacin, levofloxacin, gatifloxacin, TMP/SMX, fluconazole, amoxicillin, cephalexin) was associated with GI bleeding. But here’s the best part. After adjusting the risk for confounders including the use of cephalexin as a reference group, only the odds ratios for TMP/SMX and fluconazole were still significantly elevated (predictable since they are both 2C9 inhibitors). Because cephalexin (they could have used amoxicillin) is a drug known to be devoid of effect on warfarin metabolism, this study is the first to control for infection in assessing the interaction. Obviously it’s not the best way to control for infection but it is ethically challenging to have a group of infected warfarin-treated patients who are not administered anti-infective treatment (Clin Pharmacol Ther 84:581, 2008).

      In summary, the interaction of warfarin with anti-infectives, except for known inhibitors of CYP2C9, may be more a disease-drug (infection-warfarin) interaction than anything else (Pharmacy Times June:27, 2009).

 

    • Trimethoprim (TMP), which is structurally related to the potassium-sparing diuretic amiloride, interferes with sodium reabsorption by the kidney. Hyperkalemia secondary to TMP-SMX is well known, but hyponatremia is less commonly appreciated. In a retrospective single-center review of hospitalized patients who received high-dose TMP-SMX* (defined as TMP ≥8 mg/kg/day for ≥3 consecutive days), the incidence of hyponatremia (defined as serum sodium <136 mEq/L) was 72.3% (55 of 76 patients). Patients with comorbid conditions and those receiving other drugs that lower serum sodium concentrations were excluded from the cohort. Mean starting sodium concentration was 138.4 mEq/L, and mean sodium concentration at nadir was 131.6 mEq/L. Mean time to nadir development was 5.5 days. 43.6% of the patients had sodium concentrations <130 mEq/L at nadir, and the lowest concentration observed was 117 mEq/L. Male patients and African-American patients had a higher overall incidence of hyponatremia, and lower serum sodium concentrations were associated with longer duration of TMP-SMX therapy and higher cumulative doses. 32.9% of patients in the cohort also developed hyperkalemia (more commonly in those receiving concomitant corticosteroids). In those patients who had serum sodium concentrations measured within 1-3 weeks after discontinuation of TMP-SMX, hyponatremia had resolved in 57.9% (38 of 58 patients). Although most patients in this retrospective review had pneumonia, the observed incidence of hyponatremia was higher than that described in other pneumonia studies (Am J Med 129:1322, 2016).

 

  • Central nervous system toxicity is the second most common toxicity of fluoroquinolones* (gastrointestinal toxicity is most common) but the vast majority of reports are in adult patients (reflecting the typical usage of the drugs). Only two case reports of levofloxacin neurotoxicity in pediatric patients have been published. In the first case, a previously healthy 13-year-old girl was treated with oral levofloxacin for acute bronchitis and developed delirium two hours after her first dose. The drug was immediately discontinued and she recovered gradually over the next four days (Med J Armed Forces India 69:404, 2013). More recently, a 2-year-old girl with neuroblastoma was begun on levofloxacin prophylaxis prior to stem cell transplantation. Drug administration late in the evening was consistently associated with agitation, confusion, and hallucinations. Altering the time of administration to earlier in the evening resulted in disappearance of symptoms, while incidental rechallenge with a dose late in the evening led to symptom recurrence (J Clin Psychopharmacol 36:737, 2016).CNS side effects of fluoroquinolones are poorly understood. Symptoms range from headache, dizziness, and insomnia to delirium, psychosis, and seizures. Among the fluoroquinolones the relative potential for CNS toxicity seems to be:Norfloxacin > ciprofloxacin > ofloxacin > gemifloxacin > levofloxacin > moxifloxacinOne proposed mechanism is inhibition of the binding of GABA (gamma-aminobutyric acid), an inhibitory neurotransmitter, to its receptors (the same mechanism associated with beta-lactam neurotoxicity). The drugs may also activate excitatory N-methyl-D-aspartate receptors. Coadministration of fluoroquinolones with certain NSAIDs may potentiate seizure risk, and the ability of some fluoroquinolones to inhibit CYP450 enzymes can result in toxic concentrations of certain epileptogenic drugs. As fluoroquinolone usage in pediatrics increases, it is important for clinicians caring for younger patients to be aware of this potential toxicity (Clin Infect Dis 41(suppl 2):S144, 2005; Br J Clin Pharmacol 72:381, 2011). &npsb

Drug Shortages (US)

  • 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]: Hepatitis A Virus Vaccine Inactivated, Tetanus and Diphtheria Toxoids Adsorbed
    • [Continue to be in reduced supply]: Amikacin, Ampicillin injection, Ampicillin/sulbactam, Cefepime, Cefotetan, Cefoxitin, Ceftazidime, Ceftriaxone, Cefuroxime injection, Ciprofloxacin oral suspension, Clindamycin injection, Erythromycin lactobionate injection, Gentamicin injection, Meningococcal vaccines (various), Mupirocin calcium 2% cream, Ofloxacin 0.3% ophthalmic solution, Oxacillin injection, Penicillin G benzathine, Penicillin G benzathine 900,000 units/Penicillin G procaine 300,000 units (Bicillin C-R 900/300), Piperacillin/tazobactam, Tigecycline, Tobramycin injection, Vancomycin injection, Yellow Fever vaccine
    • [Shortage recently resolved]: Ceftazidime/avibactam injection, Chloroquine tablets (250, 500 mg), Diphtheria, Tetanus Toxoid, and Acellular Pertussis vaccine (DTaP), Diphtheria, Tetanus Toxoid, and Acellular Pertussis and Inactivated Poliovirus and Haemophilus B Conjugate Vaccine (DTaP-IPV/HiB), Haemophilus B conjugate vaccine, Poliovirus vaccine inactivated
  • Antimicrobial drugs currently unavailable due to manufacturing delays or product discontinuation:
    • [New on the list]: Amoxicillin/clavulanate 1000 mg/62.5 mg ER tablets
    • [Continue to be unavailable]: Cefotaxime injection, Mupirocin calcium 2% nasal ointment, Penicillin G benzathine/Penicillin G procaine 1.2 million units (Bicillin C-R), Penicillin G procaine injection
  • Antimicrobial drugs discontinued: Elvitegravir (Vitekta, in December 2016), 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