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2017 Infectious Disease Update Archive

Dec 31st 2017

Table of Contents

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

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January 2017 Infectious Disease Update

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

February 2017 Infectious Disease Update

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]).
  • 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.
  • 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 acnes. P. 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 tertium. C. 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
    • 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

March 2017 Infectious Disease Update

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.
  • 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
    • 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)

April 2017 Infectious Disease Update

New Treatment Guidelines

  • New evidence-based American Association for Thoracic Surgery (AATS) consensus guidelines for the surgical treatment of infective endocarditis* have been developed. The guidelines focus on surgical treatment and perioperative issues: when to operate, how to prepare the patient for operation, how to operate, and other issues relevant to managing and following patients after surgery (J Thorac Cardiovasc Surg 2017 Jan 24 [Epub ahead of print]).

Updated Drug Approvals for Pediatric Patients

  • The FDA has approved sofosbuvir (Sovaldi)* and ledipasvir/sofosbuvir (Harvoni)* for treatment of hepatitis C virus in children and adolescents:
    • Sofosbuvir in combination with ribavirin is indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 35 kg with genotype 2 or 3 infection without cirrhosis or with mild cirrhosis.
    • Ledipasvir/sofosbuvir is indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 35 kg with genotype 1, 4, 5, or 6 infection without cirrhosis or with mild cirrhosis.

Antimicrobial Stewardship

  • Last month we summarized the recently expanded indications for procalcitonin (PCT). New data add to our understanding of the potential role of PCT in children. In a cohort of 532 prospectively enrolled children with strictly defined, radiographically confirmed community-acquired pneumonia (CAP), PCT concentrations <0.25 ng/mL were strongly associated with a decreased likelihood of detecting typical bacteria and decreased disease severity. PCT concentrations <0.1 ng/mL had a very high negative predictive value, effectively excluding typical bacterial CAP. These findings suggest that PCT may safely be incorporated into treatment algorithms for children with CAP to reduce antibiotic administration and duration (J Pediatric Infect Dis Soc 2017 Feb 3 [Epub ahead of print]).

Emerging Infection Updates

  • Human infections with an Asian lineage avian influenza A (H7N9) virus were first reported in China in March 2013. Since then, annual epidemics of sporadic human infections with Asian H7N9 viruses in China have been reported. During the first four epidemics, about 40% of people with confirmed infection died. China is currently experiencing its fifth epidemic of Asian H7N9 human infection, the largest annual epidemic to date. 460 human infections have been reported since October 1, 2016. The clinical characteristics and risk factors for human infections do not appear to have changed; most infections have been associated with poultry exposure and result in severe respiratory illness. 453 of the infections occurred in mainland China; six are associated with travel to mainland China from Hong Kong (four cases), Macao (one) and Taiwan (one), and one occurred in an asymptomatic poultry worker in Macao. Asian H7N9 viruses have not been detected in people or birds in the United States. Although some limited human-to-human spread continues to be identified, no sustained transmission has been observed. Of concern, ongoing genetic analysis of neuraminidase genes from fifth epidemic viruses indicates that approximately 7-9% of the viruses analyzed to date have known or suspected markers for reduced susceptibility to one or more neuraminidase inhibitors (which are currently recommended for treatment). CDC does not recommend delay or cancellation of trips to China, but travelers are advised to avoid contact with poultry (including poultry markets and farms), birds, and their droppings and to avoid eating undercooked poultry. Infected birds that appear healthy may still be able to transmit the virus to humans. Further information can be found at http://www.who.int/csr/don (MMWR 66:254, 2017).
  • Yellow fever is caused by an arbovirus (Flavivirus) that is transmitted to humans by the bites of infected Aedes and Haemogogus mosquitoes. Since December 2016 there has been an ongoing outbreak of yellow fever in Brazil. The first human cases were reported in the State of Minas Gerais in southeastern Brazil but many epizootic and human cases, mainly in rural areas, are under investigation in neighboring states. These are referred to as sylvatic, or jungle, cases: the virus is transmitted between non-human primates (such as monkeys) via mosquito species found in the forest canopy, and is sporadically transmitted by mosquitoes from non-human primates to human visiting or working in the jungle. As of early April, more than 1500 cases have been reported and yellow fever virus transmission continues to expand towards the Atlantic coast of Brazil in areas not previously deemed to be at risk. At present there is no evidence of human-to-human transmission through Aedes aegypti, the vector that could sustain urban transmission of yellow fever, but the outbreak is affecting areas close to major urban centers where the vaccine is not routinely administered. In response to this outbreak, the list of destinations for which yellow fever vaccination is recommended for travelers has been expanded. Because of the current shortage of yellow fever vaccine, travelers may need to contact a yellow fever vaccine provider well in advance of travel. Detailed information about the situation in Brazil including specific areas considered at risk for yellow fever transmission and vaccine recommendations can be found on at http://www.who.int/csr/don or http://www.cdc.gov/travel (N Engl J Med 2017 Mar 8 [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]: None
    • [Continue to be in reduced supply]:
      • Aminoglycosides: Amikacin injection, 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/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, Rabies vaccine (RabAvert), Tetanus and Diphtheria Toxoids Adsorbed, Yellow Fever vaccine
    • [Shortage recently resolved]: Ampicillin injection, Meningococcal vaccines (various)
  • Antimicrobial drugs newly discontinued: MenHibrix (February 2017)
  • Other discontinuations: 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

June 2017 Infectious Disease Update

New Drug Approval

  • Delafloxacin* (Baxdela), the first new fluoroquinolone antibiotic in many years, was approved by the US FDA in late June. It is indicated for the treatment of adults with acute bacterial skin and skin structure infections caused by designated susceptible bacteria, including MRSA. The recommended dosage is 300 mg IV q12h or 450 mg po q12h x5-14 days. Product availability: 450 mg tablets, injection.

Updated Treatment Guidelines

  • Updated clinical practice guidelines for the management of hepatitis B virus infection from the European Association for the Study of the Liver have been published (J Hepatol 67:370, 2017). These guidelines update the 2012 release and are available for download on the EASL website.

Antimicrobial Stewardship

  • We know that antibiotic stewardship programs reduce antibiotic use and hospital costs. According to the results of a 32-study meta-analysis, they also reduce the incidence of infection and colonization with multidrug-resistance gram-negative bacteria, ESBL-producing gram-negative bacteria, and MRSA, as well as the incidence of C. difficile infection, in hospital inpatients. No effect on the incidence of VRE, or fluoroquinolone-resistant and aminoglycoside-resistant gram-negative bacteria, was observed. Stewardship programs are more effective when implemented in hematology-oncology settings and with infection control strategies such as improved hand hygiene (Lancet Infect Dis 2017 June 16 [Epub ahead of print]).

Practice Pearls

  • According to the latest guidelines from the American Academy of Dermatology, systemic antibiotics are not to be used for mild acne vulgaris*. Systemic antibiotics are reasonable for moderate to severe cases, but only in combination with one or more topical agents. Doxycycline and minocycline are more effective than tetracycline, and azithromycin should only be used if a tetracycline is contraindicated. Other systemic drugs should be avoided due to resistance concerns (such as erythromycin) or lack of supportive data (Am Fam Phys 95:740, 2017; J Am Acad Dermatol 74:945, 2016).
  • Phenazopyridine, useful for the relief of pain, burning, and discomfort in patients with UTI, is a commonly used OTC drug that is not without toxicity. Adverse effects include gastrointestinal disturbances, discoloration of urine and skin, hepatitis, hemolytic anemia, methemoglobinemia, and acute tubular necrosis. Added to the list of phenazopyridine toxicities is a case report of biopsy-proven acute interstitial nephritis. The patient’s renal function improved after stopping the phenazopyridine, worsened when it was reintroduced, and improved again after drug discontinuation plus a brief tapering course of oral corticosteroids (Ren Fail 36:804, 2014).
  • Pyrazinamide, an excellent sterilizing agent, is the only antituberculous drug with bactericidal activity against M. tuberculosis in acidic environments. The currently recommended dose is 20-25 mg/kg/day. Using proposed therapeutic targets of Cmax >35 μg/mL and/or AUC of >363 μg x hr/mL, recent pharmacokinetic data suggest that this dose may be too low for most patients. Mathematical simulations suggest that a daily dose in the range of 30-40 mg/kg or more is needed to achieve the therapeutic target(s) in most patients (Antimicrob Agents Chemother 61:e02625, 2017).
  • Extracorporeal membrane oxygenation (ECMO) may result in increased extraction of highly lipophilic and protein-bound drugs, increased volume of distribution (Vd), and altered clearance. The best published pharmacokinetic data are in neonates, although the trials were largely conducted in the 1980s and 1990s. The most well-defined effect of ECMO in neonates is increased Vd, resulting in the need for higher initial doses of some drugs. In contrast, limited studies of poor quality suggest that Vd and clearance are typically unchanged in adults and thus, there are very few recommendations for dose adjustments in that patient population (Clin Ther 38:1976, 2016).
  • Syphilis during pregnancy* is the classic situation in which desensitization of a patient with evidence of IgE-mediated penicillin allergy is necessary. Repeated administration of subthreshold doses of penicillin is thought to provide sufficient antigenic determinant to bind IgE on the surface of basophils and mast cells without cross-linking, thus rendering them unresponsive to higher doses. Oral penicillin desensitization protocols are generally preferred, although GI absorption may be variable; parenteral administration offers the advantage of easier dosage control and the ability to quickly interrupt a dose if a reaction occurs. Allergic reactions, mostly mild, occur in at 1/3 or more of patients undergoing penicillin desensitization but are typically managed successfully with medications and a temporary pause of the desensitization protocol. Following desensitization, subsequent penicillin doses must be given without interruption; if enough doses are missed that the drug has been cleared from the system, or if penicillin is needed again in the future, then the desensitization procedure must be repeated (Ann Allergy Asthma Immunol 118:537, 2017).

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]: No new antimicrobial shortages
    • [Continue to be in reduced supply]:
      • Aminoglycosides: Amikacin injection, Gentamicin injection, Tobramycin injection
      • Cephalosporins: Cefepime, Cefotaxime injection (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/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 antibacterials: Clindamycin injection, Erythromycin lactobionate injection (unavailable), Metronidazole injection, Mupirocin calcium 2% cream, Mupirocin calcium 2% nasal ointment (unavailable), Vancomycin injection
      • Antifungal drugs: Fluconazole injection
      • Antiparasitic drugs: Albendazole tablets (unavailable)
      • Vaccines: Hepatitis A Virus Vaccine Inactivated (Vaqta), Hepatitis B vaccine recombinant, Tetanus and Diphtheria Toxoids Adsorbed, Yellow Fever vaccine
    • [Shortage recently resolved]: Rabies vaccine (RabAvert)
  • Antimicrobial drugs newly discontinued: No recent discontinuations
    • Recent discontinuations: MenHibrix (in February 2017), 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

Sanford Guide Digital Feature Highlights

  • Caring for a patient with fever who has just returned from abroad? Our page on Fever in Returning Travelers* can help!
  • Colistin* dosing. Check out our newly updated colistin dosing calculator*. This interactive tool provides dose recommendations in terms of colistin base activity (mg or IU) or colistimethate (mg or IU) using new clinician-friendly creatinine clearance level-based dosing algorithms (Clin Infect Dis 64:565, 2017) as well as current dose recommendations from the European Medicines Agency. Access the calculator from the Colistin page, from Tables and Tools >> Calculators, or using Search Site.

August 2017 Infectious Disease Update

New Drug Approvals

  • Mavyret*, a fixed-dose combination of glecaprevir 100 mg (NS3/4A protease inhibitor) and pibrentasvir 40 mg (NS5A inhibitor), for the treatment of adult patients with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infection without cirrhosis and with compensated cirrhosis (Child-Pugh A). The combination is also indicated for the treatment of adult patients with genotype 1 infection who have previously been treated with a regimen containing either an NS5A inhibitor or an NS3/4A protease inhibitor (but not both).
  • Vosevi*, a fixed-dose combination of sofosbuvir 400 mg (NS5B RNA polymerase inhibitor), velpatasvir 100 mg (NS5A inhibitor), and voxilaprevir 100 mg (NS3/4A protease inhibitor), for the treatment of adult patients with chronic HCV infection without cirrhosis or with compensated cirrhosis (Child-Pugh A) who have:
    • genotype 1, 2, 3, 4, 5, or 6 infection and have previously been treated with a regimen containing an NS5A inhibitor.
    • genotype 1a or 3 infection and have previously been treated with a regimen containing sofosbuvir without an NS5A inhibitor.

Treatment Guidelines

  • Brazilian guidelines for the diagnosis and treatment of cystic fibrosis have been published. The guidelines were prepared in partnership with several Brazilian medical societies and received contributions from multiple Brazilian professionals involved in the care of CF patients (J Bras Pneumol 43:219, 2017).
  • Brazilian guidelines for the clinical management of paracoccidioidomycosis have been published. These guidelines update the first Brazilian consensus on paracoccidioidomycosis by providing evidence-based recommendations for bedside management (Rev Soc Bras Med Trop 2017 July 20 [Epub ahead of print].

Antimicrobial Stewardship

  • A provocative analysis in BMJ calls into question our standard instruction to patients to complete the entire prescribed course of antibiotics in hopes of lessening or preventing antibiotic resistance (and treatment failure). There is value in a clear and simple message, but it deserves reassessment.In some pathogens such as M. tuberculosis, N. gonorrhoeae, and HIV, genetic mutations conferring resistance may arise spontaneously and be selected for during treatment if dosing is inadequate or monotherapy is employed (the authors term this “target selected resistance”). But for other problematic bacteria such as S. aureus, Enterococcus, Klebsiella, Acinetobacter, and Pseudomonas (all opportunistic microbes that are present in the human gut, on skin and mucus membranes, and in the environment), the predominant driver of resistance is “collateral selection.” When antibiotics are taken for any reason, the pressure leads to antibiotic-susceptible strains being replaced by resistant strains. The longer the antibiotics are taken, the greater the pressure. These resistant strains are often transmitted to asymptomatic persons, or the genetic material conferring resistance can be passed to other bacteria.Recommended durations of therapy are generally based on limited evidence and probably, in most cases, do not represent the minimum effective length. At the time they were set there was more concern about undertreating the patient than overusing the drug. Recent trials, however, have already led to shorter durations of therapy for some infections such as community-acquired pneumonia, nosocomial pneumonia, and pyelonephritis. The situation is complicated by newer drugs with different pharmacologic properties, such as longer half-lives, and it is also important to note that patients respond differently to the same antibiotic. A reasonable conclusion is this: we should continue to aggressively conduct research into administering the shortest course of antibiotics possible for all infections (BMJ 358:j3418, 2017).

New Sanford Guide Release

  • In July, the Sanford Guide to HIV/AIDS Therapy 2017 print edition was released in pocket-size and larger-print library editions. This latest guide includes the latest fixed-dose combination and once-daily formulations of ARV drugs, updated differential diagnosis of related syndromes and OIs, and more.

Practice Pearls

  • Optic neuropathy is a serious complication of ethambutol* therapy. At a dose of ≤15 mg/kg/day the risk is <1%, but higher ethambutol doses are associated with substantially increased risk. Other risk factors include age >65, hypertension, the presence of renal disease, and possibly the concomitant use of isoniazid. Visual symptoms develop in most patients within the first nine months of treatment, although they can occur much faster than that; patients experience loss of visual acuity and abnormal color vision, and also central or cecocentral scotoma. The best treatment is primary prevention, which means baseline followed by regular screening (e.g. monthly in high-risk patients). If detected early with prompt drug discontinuation, about 30-60% of patients will show improvement over a period of several months although few will have full recovery. Ethambutol, a metal chelator, impedes mycobacterial cell wall synthesis by inhibiting arabinosyltransferase; chelation of copper or zinc is thought to play an important role in the pathogenesis of optic neuropathy. Zinc or copper supplementation has not been shown to reduce the likelihood of optic neuropathy, however (Curr Opin Ophalmol 2017 Jul 28 [Epub ahead of print].
  • One of the most serious, although usually reversible, neurotoxic effects associated with metronidazole* is encephalopathy. The mechanism of metronidazole-induced encephalopathy, or its relationship to cumulative metronidazole dose or treatment duration, is not clear. It is interesting that the symptoms and brain MRI findings of metronidazole-induced encephalopathy can be similar to those of acute Wernicke’s encephalopathy, a neurologic disorder induced by thiamine deficiency. Given that metronidazole metabolites inhibit thiamine pyrophosphokinase, it is possible that the resulting thiamine antagonism plays a key role in the pathogenesis of metronidazole-induced encephalopathy. It is currently unknown if thiamine supplementation, particularly in thiamine-deficient patients, is a useful treatment strategy (J Neurol Sci 379:324, 2017).
  • Moxifloxacin* is an option for treatment of drug-susceptible tuberculosis when a first-line drug is not tolerated, or for isoniazid monoresistance. It is also being investigated in treatment-shortening regimens for drug-susceptible tuberculosis. We know that adequate antituberculous drug concentrations in the blood and at the infection site(s) are important for maximizing treatment outcomes. The optimal dose of moxifloxacin for tuberculosis has not been firmly established, for at least three reasons: one, drug exposure resulting from standard 400 mg once-daily dosing may not be optimal for efficacy, prevention of resistance, or achieving proposed PK/PD targets; two, the coadministration of rifamycin drugs (e.g rifampin, rifapentine) decreases moxifloxacin Cmax and AUC up to 31%; and three, moxifloxacin distributes heterogeneously in tissues and granulomatous lesions, contributing to substantial interpatient variability in pharmacokinetics. Higher-than-standard doses of moxifloxacin may be necessary to maximize treatment outcomes, but further research is necessary (J Clin Pharmacol 2017 July 24 [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]: No new antimicrobial shortages
    • [Continue to be in reduced supply]:
      • Aminoglycosides: Amikacin injection, Gentamicin injection, Tobramycin injection
      • Cephalosporins: Cefepime, Cefotaxime injection (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/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 antibacterials: Clindamycin injection, Erythromycin lactobionate injection (unavailable), Metronidazole injection, Mupirocin calcium 2% cream, Mupirocin calcium 2% nasal ointment (unavailable), Vancomycin injection
      • Antifungal drugs: Fluconazole injection
      • Antiparasitic drugs: Albendazole tablets (unavailable)
      • Vaccines: Hepatitis A Virus Vaccine Inactivated (Vaqta), Hepatitis B vaccine recombinant, Tetanus and Diphtheria Toxoids Adsorbed, Yellow Fever vaccine
  • [Shortage recently resolved]: Tigecycline injection
  • Antimicrobial drugs newly discontinued:
    • Recent discontinuations: MenHibrix (in February 2017), 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

September 2017 Infectious Disease Update

New Drug Approvals

  • Benznidazole* for the treatment of pediatric patients 2 to 12 years of age with Chagas disease* (American trypanosomiasis), a parasitic infection caused by Trypanosoma cruzi. Recommended dosage: 5-8 mg/kg/day (divided q12h) x60 days.
  • Vabomere (Meropenem + Vaborbactam)* for the treatment of patients ≥18 years of age with complicated urinary tract infection including pyelonephritis caused by E. coli, K. pneumoniae, and E. cloacae. Meropenem is a carbapenem and Vaborbactam is a cyclic boronic acid beta-lactamase inhibitor. Recommended dosage in normal renal function: 4 gm (Meropenem 2 gm/Vaborbactam 2 gm) IV q8h (each dose infused over 3 hr).

Updated Treatment Guidelines

  • The annual report from the Advisory Committee on Immunization Practices (ACIP) regarding the use of influenza* vaccines has been released (MMWR Recomm Rep 2017; 66 [No. RR-2]: 1–20). For the 2017–18 season, inactivated and recombinant influenza vaccine will be available in trivalent and quadrivalent formulations. Live attenuated influenza vaccine is not recommended due to concerns about its effectiveness against (H1N1)pdm09 viruses during the 2013–14 and 2015–16 seasons. No preferential recommendation is made for one vaccine product over another for persons for whom more than one licensed, recommended product is available. The full report is available on the CDC MMWR website.
  • Recommendations from the American Academy of Pediatrics (AAP) for routine use of the seasonal influenza vaccine and antiviral medications for the prevention and treatment of influenza in children have been published online (Pediatrics 2017 Sep 4 [Epub ahead of print]). The AAP recommends that pediatricians offer influenza vaccine to all children 6 months of age and older, as soon as the vaccine becomes available, in order to complete vaccination and provide protection before the flu season starts. The recommendations are available for download on the AAP website.
  • The Guidance for Non-HIV-Specialized Providers Caring for Persons with HIV Displaced by Disasters has been updated. Included are recommendations based on the current standard of care for persons with HIV infection and also specific guidance on management of HIV infection during pregnancy. In addition, the guidance includes an intake form clinicians can use when evaluating a patient with HIV, a collection of web-based resources for information on treatment and prevention of HIV, and a list of temporary regimen substitutions in case of supply shortages. The guidance is available for download on the AIDSinfo website.
  • Updated European guidelines for the management of genital herpes have been published online (Int J STD AIDS 2017 Jan 1 [Epub ahead of print]). The guidelines are available for download on the International Union against Sexually Transmitted Infections (IUSTI) website.
  • Updated guidelines for the diagnosis and empirical treatment of fever of unknown origin in adult neutropenic* patients from the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) have been published (Ann Hematol 2017 Aug 30 [Epub ahead of print]). These guidelines update the 2003 release and are available for download on the journal website.

Update on Miltefosine

  • CDC is no longer providing Miltefosine* for treatment of free-living amoeba infections (Acanthamoeba, Balamuthia, Naegleria). It is commercially available and must be obtained directly from Profounda, Inc. (www.profounda.com).

Practice Pearls

  • With the introduction of meropenem/vaborbactam* there are now five commercially available beta-lactamase inhibitors marketed in combination with a companion antibacterial agent (relebactam is not yet commercially available). Here is a chart of their activities versus the various classes of beta-lactamase enzyme. The letter in parentheses refers to the Ambler beta-lactamase class (the Ambler classification scheme is based on amino acid sequence homology).
TEM/SHV (A) CTX-M (A) KPC (A) MBL (B) AmpC (C) OXA (D)
Clavulanate Yes Yes No No No No
Sulbactam Yes Yes No No No No
Tazobactam Yes Yes No No No No
Avibactam Yes Yes Yes No Yes Yes
Vaborbactam Yes Yes Yes No Yes No
Relebactam Yes Yes Yes No Yes ?

NOTES:

  1. TEM and SHV are common beta-lactamases found in Gram-negative bacteria
  2. The CTX-M family is a type of extended-spectrum beta-lactamase (ESBL)
  3. KPC is Klebsiella pneumoniae carbapenemase
  4. MBL is metallo-beta-lactamase (e.g. IMP, VIM, NDM)
  5. AmpC is the inducible chromosomal beta-lactamase associated with certain Enterobacteriaceae (Serratia, Enterobacter, Aeromonas, Citrobacter, Hafnia, indole-positive Proteus, Morganella, Providencia)
  6. Some OXA enzymes may be inhibited by tazobactam or clavulanate
  7. References: Drugs 77:615, 2017 and Clin Microbiol Rev 23:160, 2010.
  • Inflammatory processes seem to play a role in a variety of psychiatric disorders, and recent data suggest that anti-inflammatory drugs may be useful adjunctive treatment for depression. Could the anti-inflammatory properties of minocycline* be useful in this regard? In a small (n=41), randomized, double-blind, placebo-controlled pilot trial in patients with treatment-resistant major depressive disorder, minocycline (100 mg qd x2 weeks, then 200 mg qd x10 weeks) was added to existing antidepressant treatment. A large, statistically significant decrease in Hamilton Depression Rating Scale was observed in the minocycline group. Clinical Global Impression score was significantly improved, and other measures showed improvement as well. Minocycline was well tolerated. These preliminary findings require confirmation in larger studies with longer follow-up periods (J Psychopharmacol 2017 Aug 1 [Epub ahead of print]).
  • Oral fosfomycin* is considered a firstline option for uncomplicated cystitis, although it appears to have inferior efficacy compared with other short course regimens. Despite being an “old” drug, our knowledge of its urinary pharmacokinetics is limited. A single 3 gram dose of fosfomycin was administered to 40 healthy females and urine samples were collected for a week. Peak urine concentration was 1982 mcg/mL with considerable intersubject variability (SD 1257). Mean urine Tmax was 7.5 hours, and mean urine half-life was 12.4 hours. High urinary output was correlated with low urine concentrations. It is possible that inadequate drug exposure (resulting from intersubject differences) explains treatment failure in some patients (Clin Microbiol Infect 2017 Aug 31 [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]: Cefpodoxime oral suspension
    • [Continue to be in reduced supply]:
      • Aminoglycosides: Amikacin injection, Gentamicin injection, Tobramycin injection
      • Cephalosporins: Cefepime, Cefotaxime injection (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/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 antibacterials: Clindamycin injection, Erythromycin lactobionate injection (unavailable), Metronidazole injection, Mupirocin calcium 2% cream, Mupirocin calcium 2% nasal ointment (unavailable), Vancomycin injection
      • Antifungal drugs: Fluconazole injection
      • Antiparasitic drugs: None
      • Vaccines: Hepatitis A Virus Vaccine Inactivated (Vaqta), Hepatitis B vaccine recombinant, Yellow Fever vaccine (unavailable)
    • [Shortage recently resolved]: Albendazole tablets, Tetanus and Diphtheria Toxoids Adsorbed
  • Antimicrobial drugs newly discontinued: No recent discontinuations
    • Recent discontinuations: MenHibrix (in February 2017), 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

October 2017 Infectious Disease Update

New Drug Approvals

  • Heplisav-B, a recombinant, adjuvanted two-dose hepatitis B vaccine, for prevention of infection caused by all known virus subtypes in adults ≥18 years of age. Regimen: two 0.5 mL doses IM, one month apart.
  • Letermovir* (Prevymis) for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients of an allogeneic stem cell transplant. The recommended dosage is 480 mg IV or orally once daily, initiated between day 0 and day 28 post-transplant and continued through day 100. Product availability: tablets (240 mg, 480 mg), injection.

New Treatment Guidelines

  • New clinical practice guidelines for the management of chronic pain in patients living with HIV from the HIV Medicine Association (HIVMA) of the Infectious Diseases Society of America (IDSA) have been published (Clin Infect Dis 65:e1, 2017). The guidelines are available for download on the IDSA website.

Updated Treatment Guidelines

  • The HHS Panel on Antiretroviral Guidelines for Adults and Adolescents has released an updated version of the Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. The guidelines are available for download on the AIDSinfo website.
  • The Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States have also been updated and are available for download on the AIDSinfo website.

Practice Pearls

  • Tetracycline is generally avoided in young children younger than eight years of age in part because of the risk of teeth staining. However, there are important pharmacologic differences among the members of the tetracycline class so generalizations may be inaccurate. In a retrospective study of 39 children (mean age 0-7.9 years) who received empiric doxycycline therapy (10 mg/kg/day x2-3 days then 5 mg/kg/day, mean treatment duration 12.5 days), no tetracycline-like staining or enamel hypoplasia of developing teeth was detected. Two previous studies likewise found no evidence of teeth discoloration following doxycycline treatment (J Antimicrob Chemother 72:2887, 2017).
  • Ciprofloxacin and fluconazole are commonly used for prophylaxis and treatment of infections in patients with hematological malignancies. They are both known for prolonging the QTc interval, a risk factor for the development of potentially lethal ventricular tachyarrhythmias, but how perilous is the combination? In a prospective observational study of 170 patients treated with both drugs, the prevalence of QTc-prolongation (>450 ms in males, >470 ms in females) was low (4.7%, mean prolongation 10.7 ms) and in no patient did the QTc interval exceed 500 ms. No patients experienced complications related to QTc interval prolongation and there were no cases of Torsade de pointes. These data suggest that the QTc-prolonging effect of concomitant ciprofloxacin and fluconazole may not be clinically relevant, and routine ECG monitoring of such patients is probably not necessary (Br J Clin Pharmacol 2017 Oct 22 [Epub ahead of print]).
  • It is relatively unusual for a beta-lactam antibiotic to affect CYP450 enzymes. Nafcillin induces CYP2C9 and CYP3A4, presumably explaining its ability to decrease the hypoprothrombinemic effect of warfarin. Similarly, dicloxacillin has been reported to decrease INR in warfarin-treated patients but the mechanism is unestablished. In a study performed in 12 healthy volunteers using a 5-drug pharmacokinetic cocktail, dicloxacillin (1 gm three times daily x10 days) was found to induce CYP2C9, CYP2C19, and CYP3A4. Details of the mechanism were further investigated in vitro using cryopreserved human liver cells. It is reasonable to be cautious when prescribing dicloxacillin to patients receiving narrow therapeutic index drugs metabolized by these CYP enzymes (Br J Clin Pharmacol 2017 Nov 4 [Epub ahead of print]).
  • The pharmacokinetics of many drugs in patients with cystic fibrosis (CF) are altered relative to healthy persons. Commonly observed changes include enhanced renal clearance, enhanced hepatic clearance, and variation in volume of distribution. In a prospective study of ceftaroline in seven patients with CF (mean age 20.3 years), the mean half-life was 1.1 hours, considerably shorter than the expected half-life of ceftaroline in the non-CF population (2.7 hours). 15 mg/kg (maximum 600 mg) IV q8h resulted in a mean Cmax of 22.7 µg/mL, which was adequate to achieve >60% time above an MIC of 1 µg/mL (the typical MIC90 of ceftaroline vs. MRSA). In comparison, 600 mg IV q12h in the non-CF population results in a Cmax of 21.3 µg/mL. These data provide evidence of accelerated clearance of ceftaroline in CF patients and support an increased dosage regimen (J Cyst Fibros 2017 Nov 2 [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]: Doxycycline hyclate injection, Moxifloxacin injection
    • [Continue to be in reduced supply]:
      • Aminoglycosides: Amikacin injection, Gentamicin injection, Tobramycin injection
      • Cephalosporins: Cefepime, Cefotaxime injection (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/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 antibacterials: Clindamycin injection, Erythromycin lactobionate injection (unavailable), Metronidazole injection, Mupirocin calcium 2% cream, Mupirocin calcium 2% nasal ointment (unavailable), Vancomycin injection
      • Antifungal drugs: Fluconazole injection
      • Antiparasitic drugs: None
      • Vaccines: Hepatitis A Virus Vaccine Inactivated (Vaqta), Hepatitis B vaccine recombinant, Yellow Fever vaccine (unavailable)
    • [Shortage recently resolved]: Cefpodoxime oral suspension
  • Antimicrobial drugs newly discontinued: None
    • Recent discontinuations: Terbinafine granules (in May 2017), MenHibrix (in February 2017), 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)
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