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March 14, 2017

Sanford Guide releases stewardship solution

Stewardship Assist LogoAs the world’s most trusted source for guidance in the treatment of infectious diseases, The Sanford Guide has been a leader in promoting antimicrobial stewardship, providing clinicians with the tools they need to improve patient outcomes through wise use of antimicrobial agents. While The Sanford Guide has always provided outstanding content with accurate, concise, and reliable recommendations, disseminating locally-focused stewardship information to prescribers in a way that is convenient for them and simple for the stewardship team has presented a challenge for many stewardship programs. With this in mind, The Sanford Guide is pleased to announce the release of Stewardship Assist™, which leverages The Sanford Guide’s popular mobile and web platforms to provide stewardship messaging at the point of care.
 
Designed to allow stewardship teams to update and deploy their antibiograms and recommendations in minutes, Stewardship Assist™ empowers stewardship programs to provide information that is convenient, current, and local. Sanford Guide with Stewardship Assist™ allows Antimicrobial Stewardship Programs to:

  • Display institutional susceptibility/resistance data in a user-friendly antibiogram similar to the Sanford Guide Spectra of Activity.
  • Add localized stewardship recommendations for each organism/antibiotic interaction on the Spectra of Activity.
  • Develop separate antibiograms for different wards and facilities.
  • Display institution-specific stewardship recommendations at the top of Sanford Guide content pages.
  • Disseminate stewardship recommendations through web and mobile app platforms without the need for in-house development or IT support.
  • Reduce costs associated with medical error, inappropriate prescribing, and the need for pharmacy follow-up on targeted cases.

To schedule a demo or learn more about Sanford Guide with Stewardship Assist™, please visit http://www.sanfordguide.com/stewardship.

March 13, 2017

March ID Update

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New Treatment Guidelines

  • New IDSA clinical practice guidelines for the evaluation, diagnosis, and management of healthcare-associated ventriculitis and meningitis have been published (Clin Infect Dis 64:e34, 2017). The guidelines are available for download on the IDSA website.

Antimicrobial Stewardship

  • In late February the FDA expanded the indications for the biomarker procalcitonin (PCT) to include these uses:
    • As a marker of potential microbial invasion and progression to severe sepsis or septic shock in critically ill patients.
    • As an aid in determining the need for antibacterial therapy in patients with acute exacerbation of COPD and community-acquired pneumonia. The likelihood of invasive bacterial infection with a normal PCT level (≤0.25 ng/mL) is less than 5%. PCT levels do not increase unless colonizing bacteria like pneumoniae, H. influenzae, and M. catarrhalis are invading as opposed to colonizing the airway.
    • As an aid in determining the length of antibiotic therapy in both bacteria-induced sepsis/septic shock and community-acquired pneumonia.
    • Note that the FDA did not address the helpful role of PCT levels in hypotensive patients with possible septic shock. A normal PCT level excludes bacteremia as a cause in 95% of the patients. In short, PCT levels are useful in antibiotic stewardship programs. The combination of serum PCT levels and pathogen detection (virus and bacteria) with multiplex PCR platforms can eliminate uncertainty and thereby allow customization of antibacterial and/or antiviral therapy.

Practice Pearls

  • Currently there are colistin (polymyxin E)* dosing recommendations from three sources: 1) an international pharmacokinetics (PK) study group, using creatinine clearance (CrCl)-based dosing, 2) the European Medicines Agency (EMA), also CrCl-based (with broader divisions than the PK study group), and 3) the US FDA, which uses weight- and CrCl-based dosing as found in the official prescribing information. The Sanford Guide editors favor the approach of the PK study group as published  (Clin Infect Dis 2016 Dec 23 [Epub ahead of print]).
     
    In 2011 the PK study group published complex colistin dosing recommendations derived from an interim analysis of 105 critically ill patients (Antimicrob Agents Chemother 55:3284, 2011). The group has now updated these recommendations based on their final analysis of data from 214 patients. The result is a more clinician-friendly dosing approach designed to achieve an average steady-state colistin plasma concentration of 2 μg/mL. Patients are administered a loading dose (expressed as mg of colistin base activity) of 4 x body weight (using the lower of actual or ideal body weight) followed by a maintenance regimen beginning 12 hours later using a “look-up” table of daily dose based on CrCl (divided in 10 mL/min increments). The maintenance dose should be administered in two divided doses 12 hours apart. The group also provides dosing recommendations for patients receiving intermittent hemodialysis, SLED, and CRRT. Full details are provided on our colistin* page. Colistin dosing remains a challenge. We recommend use of polymyxin B rather than colistin with one importance exception: polymyxin B does not achieve adequate urine concentrations. Hence, colistin is required to treat multidrug-resistant gram-negative infections of the urinary tract.
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  • Eosinophilic pneumonia is a rare disease characterized by the accumulation of eosinophils in the lung. It may occur following exposure to certain drugs (especially antibiotics and NSAIDs), toxins, or radiation. Eosinophilic pneumonia is characterized by fever, diffuse bilateral pulmonary infiltrates, hypoxemia, and bronchoalveolar lavage with >25% eosinophils. Eosinophil production and migration into the lung is facilitated by release of interleukin 5 from T-helper 2 lymphocytes as well as eotaxin secretion from activated alveolar macrophages (Clin Infect Dis 50:e63, 2010). A recent systematic literature review identified 35 cases of presumed daptomycin-induced eosinophilic pneumonia. 83% of the patients were male, and mean age was 65.4 years. Clinical findings included dyspnea (94%), infiltrates/opacities on CT or chest X-ray (86%), peripheral eosinophilia (77%), and fever (57%). Daptomycin dose ranged from 4 to 10 mg/kg/day (adjusted for renal function). Mean duration of therapy before symptom onset was 2.8 weeks. Symptoms improved one to seven days after discontinuation of daptomycin; 66% of the patients were also prescribed corticosteroids. The mechanism of daptomycin-induced eosinophilic pneumonia is not known but may involve an inflammatory response triggered by binding of daptomycin to lung surfactant with subsequent accumulation in the alveolar space (Antimicrob Resist Infect Control 2016 Dec 12 [Epub ahead of print]).

Drug Shortages (US)

  • Antimicrobial drugs or vaccines in reduced supply or unavailable due to increased demand, manufacturing delays, product discontinuation by a specific manufacturer, or unspecified reasons:
    • [New on the list]: Rabies vaccine (RabAvert)
    • [Continue to be in reduced supply]
      • Aminoglycosides: Amikacin, Gentamicin injection, Tobramycin injection
      • Cephalosporins: Cefepime, Cefotetan, Cefotaxime (unavailable), Cefoxitin, Ceftazidime, Ceftriaxone, Cefuroxime injection
      • Fluoroquinolones: Ciprofloxacin oral suspension, Ofloxacin 0.3% ophthalmic solution
      • Penicillins: Amoxicillin/clavulanate 1000 mg/62.5 mg ER tablets, Ampicillin injection, Ampicillin/sulbactam, Oxacillin injection, Penicillin G benzathine, Penicillin G benzathine 900,000 units/Penicillin G procaine 300,000 units (Bicillin C-R 900/300), Penicillin G benzathine/Penicillin G procaine 1.2 million units (Bicillin C-R), Penicillin G procaine injection (unavailable), Piperacillin/tazobactam
      • Other antimicrobials: Clindamycin injection, Erythromycin lactobionate injection, Mupirocin calcium 2% cream, Mupirocin calcium 2% nasal ointment (unavailable), Vancomycin injection
      • Vaccines: Hepatitis A Virus Vaccine Inactivated, Meningococcal vaccines (various), Tetanus and Diphtheria Toxoids Adsorbed, Yellow Fever vaccine
    • [Shortage recently resolved]: None
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  • Antimicrobial drugs recently 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
February 15, 2017

February ID Update

The Sanford Guide ID Update features current developments in infectious diseases, curated by the Sanford Guide Editorial Board. Links marked with an asterisk (*) provide details to Web Edition subscribers, while all other links are universal. To receive monthly ID Updates by e-mail, subscribe now. We will not share your e-mail address, and you may unsubscribe at any time.
 

FEBRUARY 2017

Updated Treatment Guidelines

  • Updated guidelines for the treatment of Helicobacter pylori infection from the American College of Gastroenterology have been published (Am J Gastroenterol 112:212, 2017). The guidelines are available for download on the ACG website.

Practice Pearls

  • Carbapenem* antibiotics are known to rapidly decrease valproic acid (VPA) concentrations. Doripenem, ertapenem, imipenem, meropenem, and panipenem have all been implicated, but the precise mechanism of the interaction is not fully understood. The most important metabolite of VPA is the inactive glucuronide, and it has been suggested that the key step is inhibition by carbapenems of acylpeptide hydrolase, an enzyme that hydrolyzes VPA-glucuronide (VPA-G) back to the parent compound (resulting in enhanced VPA-G urinary excretion). Other possible mechanisms include carbapenem-induced inhibition of intestinal VPA absorption, increased synthesis of VPA-G, and inhibition of VPA efflux from erythrocytes. In a retrospective study, VPA concentrations were reduced approximately 60% within 24 hours; the magnitude of decrease in VPA concentration was higher with ertapenem and meropenem than with imipenem (Ther Drug Monit 38:587, 2016).
     
    The interaction between meropenem and VPA was further examined on a large scale using a retrospective analysis of VPA therapeutic drug monitoring records from neurosurgery inpatients at a hospital in China. 381 records from 301 patients treated with VPA with or without meropenem over a three-year period were collected. Two findings extend our knowledge of this interaction: 1) the occurrence of the interaction is independent of the daily dose of VPA and meropenem, suggesting that the decrease in VPA concentration cannot be reversed by simply increasing the VPA dose, and 2) discontinuation of meropenem for more than seven days is necessary for recovery of the VPA concentration (J Clin Pharm Ther 2017 Feb 1 [Epub ahead of print]).
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  • Clindamycin* is a lipophilic drug that may require dosage adjustment in obese patients, yet we have little to no pharmacokinetic or outcomes data in obesity (adult or pediatric) to guide us. Data from three separate prospective trials were recently combined to perform a clindamycin population pharmacokinetic analysis in 220 children, 76 of whom had a BMI ≥95th percentile for age. Total body weight was found to be the most appropriate weight for dosing in obese and non-obese children. Alternative measures of body composition (normal fat mass, fat free mass, and lean body weight) resulted in inferior model performance. Study limitations acknowledged by the authors include the use of multiple study designs and populations possibly introducing variability into the model, missing laboratory data for many study subjects, and possible misclassification of obesity status for some subjects (Antimicrob Agents Chemother 2017 Jan 30 [Epub ahead of print]).
  • In 2008, the U.S. Food and Drug Administration (FDA) notified fluoroquinolone manufacturers that a boxed warning in the product labeling concerning the increased risk of tendinitis and tendon rupture was necessary. Last year, the FDA announced it was requiring a stronger black box warning for all fluoroquinolones, 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. The side effects can involve the tendons, muscles, joints, nerves, and CNS. For patients with the aforementioned diseases, fluoroquinolones should be reserved for those who do not have alternative treatment options. The need for an upgraded warning was fueled in part by recent studies such as a nested, case-control analysis from the Taiwan National Health Insurance Research Database in which fluoroquinolone usage was associated with an approximately 2-fold increase in risk of aortic aneurysm and dissection within 60 days of exposure (JAMA Intern Med 175:1839, 2015).
     
    In light of this, a reader inquired as to whether the first-line status of fluoroquinolones for CAP in certain patient subgroups might be downgraded. In our response, we pointed out that the warning pertains to the use of fluoroquinolones for relatively minor infections, of which two (sinusitis and bronchitis) are often self-limited, viral in etiology, and for which the benefit of any antibiotic is marginal. Bacterial pneumonia is another matter, and for now a change in our recommendations is not anticipated. IDSA has a guidelines committee working on CAP recommendations and it will be interesting to see what comes from that. In addition, emerging data suggest that current treatment recommendations are based on a distorted perception of the cause of CAP (N Engl J Med 373:415, 2015; Clin Infect Dis 62:817, 2016). For now, the benefit of an antibiotic in CAP is well established and the use of a fluoroquinolone as a first-line agent in the older, more medically complicated adult remains reasonable.
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  • Metronidazole*, in clinical use for over 50 years, has an important role in the treatment of trichomoniasis, giardiasis, amebiasis, bacterial vaginosis, H. pylori, and various anaerobic bacterial infections. Why does metronidazole lack activity against aerobic bacteria?
     
    Metronidazole enters the bacterial cell via passive diffusion. It is then reduced in the cytoplasm to a short-lived nitroso free radical intermediate that binds nonspecifically to bacterial DNA. This results in inhibition of DNA synthesis and strand breakage, killing the cell. Aerobic bacterial cells lack electron-transfer proteins with sufficient negative redox potential to donate the necessary electrons to metronidazole. In anaerobes, there are electron-transfer proteins like flavodoxin and ferredoxin that have a redox potential lower than metronidazole, so they will give their electrons up and reduce the drug. Redox potential describes the tendency of a chemical species to accept or donate electrons from/to another species; positive potential is the tendency to accept electrons, negative potential is the tendency to donate electrons.
     
    Resistance to metronidazole among Bacteroides group species is rare, although a few case reports of multidrug-resistant B. fragilis have recently appeared (MMWR 62:694, 2013). However, there are at least two anaerobes in which metronidazole resistance is common. One is Propionibacterium acnesP. acnes is typically highly susceptible to clindamycin but resistant to metronidazole, which explains the superiority of topical clindamycin for mild-to-moderate acne. Topical metronidazole is useful for acne rosacea, however, presumably due to its antiinflammatory properties (Curr Med Res Opin 15:298, 1999).
     
    The other one is Clostridium tertiumC. tertium distinguishes itself among other members of the Clostridium genus as a non-toxin-producing, aerotolerant species. C. tertium is rarely associated with bacteremia. Patients are typically (but not always) neutropenic with injury to the gastrointestinal mucosa, and they frequently have a history of exposure to beta-lactam antibiotics (especially third-generation cephalosporins). C. tertium is commonly (but not always) resistant to clindamycin as well (Clin Infect Dis 32:975, 2001).

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]: None
    • [Continue to be in reduced supply]: Amikacin, Amoxicillin/clavulanate 1000 mg/62.5 mg ER tablets, Ampicillin injection, Ampicillin/sulbactam, Cefepime, Cefotetan, Cefoxitin, Ceftazidime, Ceftriaxone, Cefuroxime injection, Ciprofloxacin oral suspension, Clindamycin injection, Erythromycin lactobionate injection, Gentamicin injection, Hepatitis A Virus Vaccine Inactivated, 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), Penicillin G benzathine/Penicillin G procaine 1.2 million units (Bicillin C-R), Piperacillin/tazobactam, Tetanus and Diphtheria Toxoids Adsorbed, Tobramycin injection, Vancomycin injection, Yellow Fever vaccine
    • [Shortage recently resolved]: Tigecycline
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  • Antimicrobial drugs currently unavailable due to manufacturing delays or product discontinuation:
    • [New on the list]: None
    • [Continue to be unavailable]: Cefotaxime injection, Mupirocin calcium 2% nasal ointment, 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
February 7, 2017

Sanford Guide Partners with Health Care Volunteers International

Health Care Volunteers InternationalThe Sanford Guide is pleased to announce a newly expanded partnership with Healthcare Volunteers International (HCVI), a Washington, DC-based non-profit focused on patient care, capacity building, and educational projects in multiple developing countries. HCVI’s mission is to provide low-cost solutions, drive better outcomes, and expand care to individuals around the globe, so a partnership with The Sanford Guide seemed a perfect fit.

 

Over the past several years, The Sanford Guide has been providing print copies of The Sanford Guide to Antimicrobial Therapy to HCVI for their Infection Prevention and Control clinical training program in Phnom Penh, Cambodia. With HCVI’s recent development of a digitally-based medical library, the partnership expanded to include the full suite of Sanford Guide infectious disease content, provided through the Sanford Guide Web Edition. The resource will be available to students and clinicians at the National Pediatric Hospital, Cambodia, as well as other users of the HCVI Medical Library.

January 17, 2017

January 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.

 

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]).
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  • 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).

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  • 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).
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  • 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