Guide to the Sanford Guide
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- ID Update™ is the Sanford Guide infectious diseases news page.
- Each month, we summarize new or updated practice guidelines, recent clinical trials, new reviews, relevant drug safety notices, new drug approvals, new dosage forms, new treatment indications and other current developments.
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New Drug Approvals
- Daclatasvir (Daklinza), indicated (in combination with Sofosbuvir) for the treatment of adults with genotype 3 chronic hepatitis C infection. The recommended dose of Daclatasvir is 60 mg once daily, with or without food.
- Technivie (Ombitasvir, Paritaprevir, Ritonavir), a fixed-dose combination product indicated (in combination with Ribavirin) for the treatment of adults with genotype 4 chronic hepatitis C infection without cirrhosis. The recommended dose of Technivie is two tablets once daily, with food.
New Rules for Pregnancy and Lactation Labeling
- The FDA has amended its regulations concerning the "Pregnancy," "Labor and delivery," and "Nursing mothers" subsections of the "Use in Specific Populations" section of product labeling. Pregnancy categories A, B, C, D, and X have been removed. Below is a summary of the labeling changes (ref: FDA.gov). Drugs approved after June 30 will use the new format immediately, while drugs approved after June 30, 2001 will be phased in gradually.
- In April the European Commission (EC) granted a marketing authorization for Delamanid for treatment of pulmonary MDR-TB in adults (in combination with other drugs). Delamanid is a dihydroimidazooxazole prodrug that works by inhibiting mycolic acid synthesis. It has potent activity in vitro vs. M. tuberculosis (including MDR and XDR strains) but MICs are more variable for nontuberculous mycobacteria. It has shown efficacy in animal models of drug-susceptible TB; human data are limited but it improves the rate of sputum culture conversion in patients with MDR-TB when added to an existing optimized regimen. The recommended dose of Delamanid is 100 mg po bid x24 weeks. Dose-related QT prolongation (linked to the drug's major metabolite) may be problematic, particularly in patients with other risk factors for QT prolongation. The drug does not affect transporters or CYP enzymes but it is a CYP3A4 substrate. Future clinical studies will help to clarify the role of Delamanid in the management of MDR- and XDR-TB (Drug Des Devel Ther 9:677, 2015).
- The drug interaction between Nafcillin and warfarin was first described in 1984. Case reports consistently show decreased INR resulting in a two- to four-fold increase in the warfarin dose requirement. This effect on INR is evident within a week of starting nafcillin, and the warfarin dose decreases to pre-Nafcillin levels about 1-4 weeks after Nafcillin is discontinued. The mechanism is not fully understood, but induction of CYP3A4 and CYP2C9 by Nafcillin is suggested (S-warfarin is a 2C9 substrate and R-warfarin is metabolized by multiple enzymes including 3A4). Similarly, in a retrospective cohort study from Denmark an association between Dicloxacillin treatment and decreased INR in patients receiving warfarin (or phenprocoumon, another vitamin K antagonist) was observed. Mean decrease in INR was 0.62 in patients receiving warfarin and 0.31 in those receiving phenprocoumon. The authors propose activation of the pregnane X receptor by Dicloxacillin, resulting in induction of CYP3A4 and probably CYP2C9 (JAMA 314:296, 2015).
- Candida glabrata (once known as Torulopsis glabrata) is a commensal colonist of the human GI tract and the second most commonly identified yeast pathogen in superficial and invasive infection (behind C. albicans). It is more closely related to Saccharomyces cerevisiae than to C. albicans. Four unique features of C. glabrata are 1) haploidy (it is asexual), 2) the inability to form pseudohyphae (thus the neutrophil response it induces is less vigorous), 3) the ability of some strains to grow only anaerobically (possibly resulting in lab underidentification), and 4) reduced susceptibility (both intrinsic and acquired) to all azoles, notably Fluconazole. The molecular basis for intrinsic resistance is unclear but may involve reduced affinity of lanosterol demethylase (the azole target enzyme, encoded by the ERG11 gene) or enhanced ability to upregulate ERG11 expression following azole exposure. The mechanism of acquired resistance involves upregulation of the genes CDR1 and CDR2, which encode ABC (ATP-binding cassette) multidrug efflux transporters. In contrast to azoles, echinocandins such as Micafungin maintain robust activity against C. glabrata although echinocandin resistance has been on the increase. The mechanism appears to be point mutations in the genes encoding 1,3-beta-glucan synthase, the target enzyme of echinocandins. These mutations are likely selected for by prior exposure (Mycoses 58:445, 2015).
Updated ACIP Recommendations for the 2015-2016 Influenza Season
- The Advisory Committee on Immunization Practices (ACIP) 2015-16 recommendations for prevention and control of seasonal influenza were published in the MMWR on August 7 and can be found here. Updated information for the upcoming season includes 1) antigenic composition of U.S. seasonal influenza vaccines, 2) information on vaccine product availability, 3) an updated algorithm for determining the appropriate number of doses for children aged 6 months through 8 years, and 4) recommendations for the use of live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) when either is available, including removal of the 2014–15 preferential recommendation for LAIV for healthy children aged 2 through 8 years (MMWR 64:818, 2015).
- In May the FDA approved Moxifloxacin for the treatment of pneumonic and septicemic plague in adults. The drug is also approved for prevention of plague. Levofloxacin was approved for prevention and treatment of plague in adults and pediatric patients ≥6 months of age in 2012.
- Kounis syndrome, first described in 1991, is acute coronary syndrome accompanying mast cell activation from an allergic reaction. It is also known as allergic angina or allergic MI. There are three types. In type 1, the allergic episode induces coronary vasospasm in patients with normal coronary arteries; type 2 occurs in patients with preexisting atheromatous coronary artery disease in whom the allergic episode results in plaque rupture; type 3 includes coronary artery stent thrombosis secondary to the allergic episode. Kounis syndrome is potentially life-threatening without prompt diagnosis and proper treatment. Dozens of case reports of Kounis syndrome caused by beta-lactams have been published; the most commonly implicated beta-lactam is Amoxicillin. More recently, the first reported cases of Kounis syndrome due to Ceftriaxone and Metronidazole have appeared (Ann Saudi Med 34:250, 2014; BMC Res Notes 8:97, 2015; Int J Cardiol 179:222, 2015).
- A single IM injection of Benzathine Penicillin G is recommended for primary, secondary, and early latent syphilis whereas three weekly doses are used for late latent and syphilis of unknown duration. Oral Amoxicillin plus Probenecid has served as an alternative in some countries despite a lack of published safety and efficacy data. In a retrospective cohort study from Japan, 286 HIV-1-infected patients with early or late syphilis were administered Amoxicillin 3 gm/day + Probenecid (most commonly 750 mg/day). 95.5% of patients were treated successfully based on a ≥4-fold decrement in RPR titer (achieved within 12 months in 96.3% of the success group). Two and four weeks of treatment were similarly effective for early syphilis, but two weeks tended to be less effective for late syphilis. The oral regimen was generally well tolerated (Clin Infect Dis 61:177, 2015).
- Purple urine bag syndrome (PUBS) is described in a a 79-yo bedridden female with an indwelling urinary catheter. PUBS is a condition occasionally observed in chronically catheterized patients with alkaline urine. The proposed chemistry begins with conversion of dietary tryptophan to indole, which is absorbed and transported by the portal circulation to the liver. The liver conjugates the indole to indoxyl sulfate and excretes it into the urine. Phosphatase/sulfatase enzymes produced by certain bacteria (such as Providencia, E. coli, Proteus sp., K. pneumoniae, M. morganii, and P. aeruginosa) convert the indoxyl sulfate to indoxyl, which under alkaline conditions is converted to indigo (blue) and indirubin (red). Indigo and indirubin mixed together produce the purple color (Emerg Med J 32:347, 2015).
- Crystalluria (microscopic or macroscopic) is a rare adverse effect associated with Amoxicillin. Risk factors include high doses, dehydration, and low pH. Amoxicillin crystalluria may be asymptomatic but it can also cause hematuria or acute renal failure. This report describes a 62-yo woman with left-sided S. agalactiae endocarditis who was treated with IV Amoxicillin (200 mg/kg/day) plus Gentamicin (3 mg/kg/day). Cloudy urine with a thin granular appearance containing large typically aggregated needle-shaped crystals were observed on day 4. The patient developed acute renal failure (probably multifactorial) but eventually recovered. Crystalluria has also been reported with Ampicillin (Lancet 385:2296, 2015).
- Elderly patients with herpes zoster infection and poor renal function are especially vulnerable to Acyclovir-induced neurotoxicity, which may be mistaken for herpes encephalitis. Toxic accumulation of 9-CMMG, a renally-eliminated Acyclovir metabolite, is thought to be the culprit (Am J Med 128:692, 2015).
- In adult volunteers with BMI of 22.1-63.5 kg/m2 (total body weight 50.1-179.5 kg), decreased Cmax and AUC of Ceftaroline were observed with increasing body size. However, MIC target attainment data suggest that no adjustment of Ceftaroline dose based on body weight is necessary, at least for pathogens for which the MIC is ≤1 µg/mL. We view this recommendation as preliminary and await confirmation in obese patients, particularly those with BMI>40 (Antimicrob Agents Chemother 59:3956, 2015).
- Isavuconazole is a recently approved second-generation triazole antifungal agent. The drug has activity against various clinically important yeasts and molds including Candida spp, Cryptococcus spp., and Aspergillus; activity vs. Mucorales is variable. Attractive features include good oral bioavailability, no need for a cyclodextrin IV vehicle (the prodrug is water soluble), and predictable linear pharmacokinetics. Full characterization of Isavuconazole awaits the results of clinical trials (Ann Pharmacother 49:825, 2015).
212 subjects with history of immediate penicillin hypersensitivity and a positive skin test to at least one penicillin reagent underwent skin testing with Aztreonam, Imipenem, Meropenem, and Ertapenem. No subject displayed a positive skin test result to any of the four drugs; in addition, 211 accepted and tolerated drug challenges. These data support the belief that cross-reactivity between penicillins and both Aztreonam and carbapenems is very rare. This study is also the first to formally assess cross-reactivity between Penicillin and Ertapenem (J Allergy Clin Immunol 135:972, 2015).
Nitrofurantoin-induced pulmonary toxicity has been characterized as acute, subacute, and chronic. Risk increases with age and is higher in women than in men. The acute reaction (most common, occurring in 1 of 5,000 patients) is characterized by fever, shortness of breath, cough and peripheral eosinophilia, usually within days to a few weeks of drug initiation. Chronic toxicity is typically associated with cough and slowly progressive dyspnea manifesting months to years after initiating therapy. Treatment of acute toxicity involves prompt drug discontinuation plus various supportive measures. A case is presented and discussed (J Infect Public Health 8:309, 2015).
- CDC has updated its 2010 STD treatment guidelines. Click here.
Drug Safety Communication
- Dosing errors with Ceftolozane-tazobactam (Zerbaxa) have occurred due to confusion about drug strength displayed on the vial and carton labels. Initial labeling listed the quantity of the active components separately, but the product is dosed based on the sum of the components. Revised labeling will list the sum. Click here to view the complete FDA communication.
- Benznidazole is the preferred agent for Chagas disease (American trypanosomiasis). Thirty patients receiving the drug at a US clinic experienced an alarming frequency of Benznidazole side effects. See our Benznidazole page for details (Clin Infect Dis 60:1237, 2015).
- Our pharmacokinetic knowledge of Benznidazole is limited. Could poor tolerance be related to supratherapeutic drug concentrations? The first published PK modeling study of Benznidazole in adults suggests that 5 mg/kg/day divided q12h may be excessive (Antimicrob Agents Chemother 59:3342, 2015).
- Previous case reports have linked fluoroquinolones, particularly Moxifloxacin, to uveitis. In a pharmacoepidemiologic case-control study conducted in a cohort of older men, Moxifloxacin demonstrated the highest risk, followed by Ciprofloxacin. Levofloxacin use was not significantly associated with uveitis. Most cases occurred with the first prescription of Moxifloxacin or Levofloxacin (JAMA Ophthalmol 133:81, 2015).
- Physiologic changes resulting from acute thermal injury can dramatically affect drug volume of distribution, clearance, and other pharmacokinetic/pharmacodynamic parameters. This review summarizes what we know about the PK/PD of antibacterial and antifungal agents in the burn population (J Burn Care Res 36:e72, 2015).
- A bipolar patient stable on divalproex acutely developed manic symptoms with decreased valproate concentrations during treatment with Ertapenem. This drug interaction isn't as commonly associated with Ertapenem as it is with other carbapenems. The mechanism seems to be inhibition of acylpeptide hydrolase, an enzyme that hydrolyzes the inactive valproic acid glucuronide back to the parent compound (J Clin Psychopharmacol 35:348, 2015).
- Voriconazole is an inhibitor of (and substrate for) CYP2C9, CYP2C19, and CYP3A4. Autoinduction of Voriconazole metabolism, resulting in subtherapeutic concentrations, has also been sporadically reported in adults receiving high mg/kg doses or prolonged treatment courses. The mechanism is unknown. This report describes possible Voriconazole autoinduction in a 10-year-old girl with aplastic anemia and invasive pulmonary aspergillosis (Pharmacotherapy 35:e20, 2015).
- We have a new time-saver. Try the Child-Pugh Score calculator in our Tools menu.
- Getting to know a microbe: Actinomyces. Actinomycosis is an endogenous infection. Twenty-five species of Actinomyces have been identified in humans, half in the past 15 years. Actinomyces spp. tend to be susceptible to Penicillin G, multiple other beta-lactams, and Clindamycin; Metronidazole is intrinsically resistant (Clin Microbiol Rev 28:419, 2015).
- Prolonged infusion of beta-lactam antibiotics is increasing in popularity. There are practical issues to consider: 1) a loading dose may be necessary, 2) drug stability at room temperature can be a limiting factor, 3) the dead space in infusion tubing may be a significant percentage of the drug dose if a small infusion volume is used, and 4) drug-drug incompatibilities can be problematic (Int J Antimicrob Agents 45:461, 2015).
- The mechanism of action of an integrase strand transfer inhibitor (INSTI) involves binding to magnesium at the active site of the integrase enzyme. This renders INSTIs susceptible to chelation-mediated drug interactions with multivalent metal cations. The recommendation for Dolutegravir (DTG) has been to avoid concomitant administration and instead administer the DTG 2 hours before or 6 hours after an antacid or mineral supplement. The data in this paper suggest that DTG can be co-administered with calcium or iron supplements as long as they are taken with a meal (J Clin Pharmacol 55:490, 2015).
- In a randomized, placebo-controlled trial in 785 hospitalized patients with community-acquired pneumonia (CAP), seven days of oral prednisone (50 mg qd) shortened time to clinical stability by 1.4 days. Time to hospital discharge and duration of IV antibiotics were reduced by 1 day without an increase in complications associated with CAP. These findings were independent of PSI class. Hyperglycemia from prednisone should be anticipated (Lancet 385:1511, 2015).
- A marked increase in clinical failures in recent years is challenging the status of Metronidazole as drug of choice for mild-to-moderate C. difficile infection, whereas oral Vancomycin remains superior for the treatment for severe infection. Fecal microbiota transplantation has emerged as a safe and highly effective strategy for treatment of recurrence (N Engl J Med 372:1539, 2015).
- We've reorganized the Tools menu to make it more intuitive and user-friendly!
- Desensitization protocols for Ceftaroline and Valganciclovir have been added to our collection. Look in Tools, Adverse Effects & Allergy.
Approved by the FDA
- for adults with invasive aspergillosis or mucormycosis. Isavuconazonium is the prodrug of isavuconazole, a triazole antifungal. The dose is 200 mg (isavuconazole) IV or po q8h x6 doses, then 200 mg IV or po q24h.
- Extracorporeal membrane oxygenation (ECMO) may influence antibiotic pharmacokinetics. Data in critically ill patients receiving beta-lactams are scant. In a case-control study, ECMO therapy did not significantly influence volume of distribution, half-life, or clearance of Meropenem or Piperacillin-tazobactam (Int J Antimicrob Agents 45:278, 2015.
- Getting to know a microbe: Cryptococcus gattii. Cryptococcosis caused by C. gattii occurs in both immunocompromised and immunocompetent patients. Meningoencephalitis is the most severe clinical manifestation. Treatment involves aggressive management of increased intracranial pressure plus antifungal therapy with Amphotericin B plus Flucytosine. The role of adjunctive dexamethasone is unclear Lancet Infect Dis 15:348, 2015.
- Drug-resistant microbes can spread widely and with alarming speed. Treatment options may be limited or nonexistent, infection control can be a challenge, and infections are associated with increased mortality and economic costs. Carbapenemase-producing Gram-negative bacilli, such as those harboring KPC or NDM beta-lactamases, have recently emerged and are reviewed (Mayo Clin Proc 90:395, 2015.
- This RCT performed at four US centers located in areas of CA-MRSA endemicity compared Clindamycin (300 mg po tid) and TMP-SMX (two single-strength tablets po bid) for the treatment of uncomplicated skin infections (cellulitis, abscesses >5 cm, or both). All abscesses underwent incision and drainage. No significant differences in efficacy or adverse effects were found (N Engl J Med 372:1093, 2015).
- Within endemic areas for schistosomiasis, children bear the heaviest burden of infection. In 2010 the WHO updated their treatment recommendations for preschool-aged children. This paper discusses current barriers and knowledge gaps in pediatric schistosomiasis control. A pediatric formulation of Praziquantel about to enter clinical trials will be helpful (Pediatrics 135:537, 2015.
For New Users
- Try our handy calculators in the Tools menu. You'll find one for BMI, BSA, CrCl, IBW, MELD score, and unit conversions. There is also a calculator for colistin dosing. The CrCl calculator automatically uses Cockcroft-Gault or Salazar-Corcoran depending on patient body weight.
New Drug Approvals
- Ceftazidime-avibactam (Avycaz) for adults with complicated intra-abdominal infections (in combination with metronidazole) and complicated UTIs including pyelonephritis. The drug received a priority review based on phase II and in vitro data, and as such should be reserved for patients who have limited or no alternative treatment options. The recommended dose in normal renal function is 2.5 gm (ceftazidime 2 gm + avibactam 0.5 gm) IV q8h.
- Dutrebis (lamivudine 150 mg + raltegravir 300 mg) in combination with other antiretrovirals for the treatment of HIV-1 infection. The dose is one tablet twice daily, with or without food. At this time it will be available only in select non-US markets on a country-by-country basis.
- Evotaz (atazanavir 300 mg + cobicistat 150 mg) in combination with other antiretrovirals for the treatment of HIV-1 infection. The dose is one tablet daily with food.
- Prezcobix (darunavir 800 mg + cobicistat 150 mg) in combination with other antiretrovirals for the treatment of HIV-1 infection. The dose is one tablet daily with food.
- High-dose daily rifapentine. In this dose-ranging study, high dose daily rifapentine (10, 15, or 20 mg/kg) substituted for rifampin in the intensive phase (first eight weeks) of pulmonary TB treatment was associated with improved antimycobacterial activity. Daily rifapentine was well tolerated and antimycobacterial activity was strongly correlated with rifapentine exposure (AUC) (Am J Respir Crit Care Med 191:333, 2015).
- Combination therapy for invasive aspergillosis. Hematologic malignancy or hematopoietic stem cell transplant patients with suspected or documented invasive aspergillosis (IA) were randomized to voriconazole with or without anidulafungin. 6-week all-cause mortality was significantly lower in the subgroup in whom the IA diagnosis was established by radiographic findings and positive galactomannan. The observed reduction in overall mortality was not statistically significant, however (Ann Intern Med 162:81, 2015).
- Update on Ebola virus disease. The mainstay of therapy for Ebola virus disease is early recognition, effective isolation, and optimal supportive care. The best known emerging treatment is ZMapp, a combination of three humanized monoclonal antibodies expressed in tobacco plants. Brincidofovir, favipiravir, and a few other drugs are also being investigated. Vaccine trials are underway (BMJ 349:g7348, 2014).
- Review of telavancin. Telavancin is a bactericidal lipoglycopeptide that inhibits bacterial cell wall synthesis and also disrupts cell membrane barrier functions. Limited published data suggest a role in the treatment of bacteremic Staph. aureus infection but additional clinical experience is needed. Nephrotoxicity can be an issue (Clin Infect Dis 60:787, 2015).
- Getting to know a microbe: Clostridium difficile. The incidence and severity of C. difficile infection (CDI) have increased since 2000. Metronidazole 500 mg po tid x10-14 days is recommended for mild-moderate CDI, vancomycin 125 mg po qid x10-14 days (or fidaxomicin 200 mg po bid x10 days if risk of recurrence significant) for more severe disease. Vancomycin 500 mg po qid with or without vancomycin 500 mg po qid, plus metronidazole 500 mg IV q8h, is recommended for severe, complicated CDI (JAMA 313:398, 2015).
- Daptomycin in pediatrics. Daptomycin is not licensed by the FDA or the EMA for use in pediatric patients. The important gaps in our pharmacokinetic and clinical knowledge of the drug in this patient population are summarized (J Antimicrob Chemother 70:643, 2015).
New Drug Approvals
- Ceftolozane-tazobactam (Zerbaxa): indicated for treatment of adults with complicated intra-abdominal infections (in combination with metronidazoIe) and complicated urinary tract infections. It is the fourth new antibacterial drug approved in 2014. The recommended dose is 1.5 gm IV q8h.
- Finafloxacin 0.3% otic suspension (Xtoro): indicated for the treatment of acute otitis externa caused by P. aeruginosa and Staph. aureus in patients age 1 year and older. The recommended dose is 4 drops into the affected ear q12h x7 days.
- Peramivir (Rapivab): an IV neuraminidase inhibitor indicated for the treatment of acute uncomplicated influenza in patients age 18 years and older who have been symptomatic for no more than two days. The recommended dose is 600 mg IV x1.
- Viekira Pak: indicated (with or without ribavirin) for treatment of adults with genotype 1 chronic HCV, including patients with compensated cirrhosis. The product consists of ombitasvir/paritaprevir/ritonavir fixed-dose tablets copackaged with dasabuvir tablets. The recommended dose is two ombitasvir/paritaprevir/ritonavir tablets every morning and one dasabuvir tablet in the morning and evening.
- Clavulanic acid, the first commercially-available beta-lactamase inhibitor, was identified in 1972. Sulbactam emerged in 1978, followed by tazobactam in 1984. New beta-lactamase inhibitors such as avibactam, relebactam, and others are under investigation as companion agents to existing antibiotics. Their future is promising yet uncertain (Ann Pharmacother 49:86, 2015).
- Getting to know a microbe: Kingella kingae. The Gram-negative coccobacillus K. kingae has emerged as an important cause of pediatric bacteremia and bone/joint infection. It is the "K" in HACEK, the acronym for a group of fastidious Gram-negative organisms responsible for about 6% of all cases of endocarditis in the general population. K. kingae tends to be highly susceptible to antibiotics; ceftriaxone is a good choice (Clin Microbiol Rev 28:54, 2015).
- The incidence of traveler's diarrhea (TD) during a 2-week trip is 10-40%. Most cases are caused by bacterial enteropathogens. Antibiotic chemoprophylaxis for TD is not generally recommended. Bismuth or loperamide is usually effective for treatment of mild TD, whereas for moderate to severe TD a fluoroquinolone is typically the best choice. Azithromycin is preferred in areas where Campylobacter is common (JAMA 313:71, 2015).
- Antifungal drugs in pregnancy. Anidulafungin, micafungin, and posaconazole have been approved by the FDA since the last published review of this subject. Additional data regarding other azoles and polyenes have also recently emerged (J Antimicrob Chemother 70:14, 2015).
- Non-anti-infective uses of antimicrobial agents include chronic inflammatory pulmonary and dermatologic disorders, chronic periodontitis, GI dysmotility, rheumatoid arthritis, and malignancy. Most of these uses are not FDA-approved, and the quality of supportive literature varies widely (Mayo Clin Proc 90:109, 2015).
Updated Practice Guidelines
- Revised AASLD/IDSA/IAS-USA hepatitis C treatment guidelines are available. Interferon is no longer recommended for most situations. The direct-acting antiviral (DAA) era is upon us. Click here.
- A Working Party formed by the British Society for Antimicrobial Chemotherapy, British Heart Rhythm Society, British Cardiovascular Society, British Heart Valve Society, and British Society for Echocardiography has developed guidelines relating to the diagnosis, treatment and prevention of implantable cardiac electronic device infection in the UK (J Antimicrob Chemother 70:325, 2015).