- 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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Recent Feature Updates
- Found in the Tools menu, new tables include Pharmacologic Features of Antimicrobial Agents, Renal Impairment Dosing, Pediatric Dosing, and Use of Antimicrobials During Lactation.
- Activity Spectra information has been incorporated into antibacterial pages, along with links to pathogen information.
- 70 topics were updated in November's update! For Web Edition users, the date a page was last modified is shown under the page Title. For app users, the date is shown at the bottom of each page.
- Our Spectra of Activity tables have been redesigned and reclassified using more descriptive categories. Click the "Legend" button within the table for a complete description of the categories.
Drug Safety Communication
- The FDA is requiring the manufacturer of Viekira Pak and Technivie, two fixed-dose combination products for hepatitis C, to include new information about serious liver injury in their product labeling. At least 26 worldwide cases submitted to the FDA Adverse Event Reporting System since product approval are considered to be possibly or probably related to Viekira Pak or Technivie. Injury has generally occurred within 1-4 weeks of initiation of treatment. Click here to review the complete FDA communication.
Drug Shortage Updates
- Chloramphenicol sodium succinate injection: currently unavailable in the US. Company estimates release date of first quarter, 2016.
- Chloroquine tablets (250, 500 mg): currently unavailable in the US. Resupply date unknown.
- Meropenem injection: insufficient supply for usual ordering.
- Ofloxacin 0.3% otic solution: currently unavailable in the US. Estimated resupply date is August 2016.
- For more information, see http://www.ashp.org/menu/DrugShortages
New Drug Approvals
- Genvoya (elvitegravir 150 mg + cobicistat 150 mg + emtricitabine 200 mg + tenofovir alafenamide 10 mg) for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. This is the first fixed-dose combination of antiretroviral drugs approved by the FDA to include tenofovir alafenamide (TAF). TAF is a phosphonoamidate prodrug of tenofovir that has antiretroviral efficacy similar to tenofovir disoproxil fumarate at less than one-tenth the dose. The recommended dose of Genvoya is one tablet daily with food.
The QT interval represents the time in which ventricular myocytes are depolarized and repolarized. It is shortened in tachycardia and prolonged in bradycardia, so Bazett’s formula (QTc = QT divided by the square root of the RR) is often used to correct for heart rate (some clinicians favor other formulas). The QT interval should be <430 ms in healthy men and <450 ms in healthy women. Prolongation of the QT interval can lead to potentially life-threatening arrhythmias such as torsades de pointes (TdP) and ventricular fibrillation. The risk of TdP does not correlate in a linear fashion with QT prolongation, but an interval >500 ms is thought to significantly increase the risk.
Known risk factors for QT prolongation include inherited long QT syndrome, bradycardia, CHF, hypokalemia, hypomagnesemia, older age, female gender, and the co-administration of drugs that prolong repolarization. A variety of drugs have been implicated, including fluoroquinolones (FQs). The likely mechanism is blockade of a certain type of potassium channel, inhibiting efflux. An amino or methyl substituent at position 5 of the FQ bicyclic ring may increase the potential for QT prolongation; two drugs with such substituents (sparfloxacin and grepafloxacin) were removed from the US market.
A recent review summarizes data published in 1980-2014 on QT prolongation, episodes of TdP, and adverse cardiac events associated with FQs. Prospective healthy volunteer studies suggest that moxifloxacin (but not levofloxacin or ciprofloxacin) can slightly prolong the QT interval, although the studies are of short duration with small numbers of subjects. Prospective trials in sick patients suggest the same rank order of propensity among the FQs, but cardiac event rates are far too small to draw meaningful conclusions. Finally, in larger retrospective studies the rank order of propensity seems to be moxifloxacin>levofloxacin>ciprofloxacin although there are significant inconsistencies in the data. The authors of the review suggest that FQ choice should not be based on concern about cardiac arrhythmia except in patients thought to be at the highest risk (J Clin Pharmacol 55:1198, 2015).
Azole antifungals are typically included in the list of antimicrobial agents that prolong the QT interval. An interesting exception may be isavuconazole, which in healthy subjects shortened the QTc interval by 13.1 msec (2 hours postdose) with 200 mg daily x13 days and 24.6 msec (2 hours postdose) with 600 mg daily x13 days. In another study, 73 of 257 patients (32.2%) treated with isavuconazole for invasive mold infection had QTc shortening >30 msec from baseline, 17 (7.5%) had shortening >60 msec from baseline. Besides avoiding isavuconazole in patients with familial short QT syndrome, the clinical importance of these observations is unestablished (Clin Infect Dis 61:1558, 2015).
Voriconazole tablets do not contain measurable fluoride, but fluorine is organically bound to the drug. The drug contains three fluorine atoms and is 16.3% fluorine by weight. The first report of fluoride toxicity from voriconazole was published in 2011 (Clin Infect Dis 52:604, 2011). Wermers et al describe a 64-yo heart transplant patient receiving long-term voriconazole therapy (dose not specified) for Aspergillus pneumonia who developed periostitis and exostoses (exuberant growth of periosteal bone). She experienced painful bony growths on her fingers, wrists, elbows, leg, and feet after about six months of voriconazole. Lab findings identified high bone turnover markers and elevated plasma and bone fluoride concentrations. The patient denied all known sources of high fluoride intake. Transiliac crest bone biopsy showed osteomalacia with excessive accumulation of unmineralized bone (osteoid). The patient was switched to itraconazole with pain improvement within one month. Two months after discontinuation of voriconazole her alkaline phosphatase had decreased by 50%, and after three months her plasma fluoride concentration was 13.2 micromoles/L (her peak was 20.7, normal range 1-4).
The authors then evaluated plasma fluoride concentrations in ten adult transplant patients who received voriconazole (200 mg po bid) for at least six months compared to ten transplant recipients who were not treated with voriconazole. All voriconazole-treated patients had elevated plasma fluoride concentrations compared to none of the control patients (14.32 vs 2.54, p<.001). Alkaline phosphatase was also significantly higher in the voriconazole-treated patients (207 vs 86, p=.003). Renal function was not predictive of plasma fluoride concentrations, and serum voriconazole concentrations were not significantly correlated with fluoride concentrations. Five of the voriconazole-treated patients had evidence of periostitis, with multiple exostoses in two of them. Drug discontinuation resulted in improvement in bone pain and decreased alkaline phosphatase and fluoride concentrations within two months.
In a more recent retrospective study, 21 of 195 non-immunocompromised patients receiving voriconazole for E. rostratum epidural abscesses and meningitis associated with contaminated methylprednisolone injections developed periostitis, most commonly in the ulna and ribs. Alkaline phosphatase, blood fluoride concentrations, daily voriconazole dose, and cumulative dose were significantly elevated in patients with periostitis (compared to those without). Voriconazole dose reduction or discontinuation resulted in improvement of pain in 89% of patients (Clin Infect Dis 59:1237, 2014; Semin Respir Crit Care Med 36:786, 2015).
In a prospective cohort of former inpatients receiving outpatient parenteral antibiotics, 210 of 824 (25.5%) had eosinophilia; median days of therapy until onset of eosinophilia was 15. Use of vancomycin, a penicillin, rifampin, and linezolid was associated with a higher risk of eosinophilia, whereas metronidazole use was associated with reduced risk; cephalosporins and fluoroquinolones were not associated with increased risk. Sixty-four (30.5%) of the 210 patients with eosinophilia had a subsequent hypersensitivity reaction (rash in 32 patients, renal injury in 31, liver injury in 13). Patients with eosinophilia were more than four times as likely to have a rash and more than twice as likely to have renal injury as a patient without eosinophilia. Possible DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) occurred in seven patients, four of whom were receiving vancomycin, which is higher than the expected frequency of 1/1,000 to 1/10,000. Three of the seven cases met criteria for probable DRESS and were attributed to vancomycin by expert consultants. In summary, eosinophilia is a common occurrence in patients receiving outpatient parenteral antibiotics; it is of no clinical consequence in most patients but it increases the risk of rash and renal injury (J Allergy Clin Immunol 136:1288, 2015).
New or Updated Guidelines
- AHA/IDSA guidelines for the diagnosis and management of infective endocarditis in adults are available for download (http://circ.ahajournals.org). This is an update of the 2005 iteration (Circulation 132:1435, 2015).
- AHA guidelines for the diagnosis and management of infective endocarditis in childhood are available for download (http://circ.ahajournals.org). This is a update of the 2002 iteration (Circulation 132:1487, 2015).
Susceptibility of Neisseria gonorrhoeae has been progressively declining, limiting our treatment options. Solithromycin is a new fluoroketolide under development that has potent activity against N. gonorrhoeae, including strains resistant to Azithromycin, as well as various other sexually transmitted pathogens such as C. trachomatis and M. genitalium. Activity against resistant strains is due, at least in part, to the ability of Solithromycin to bind to a greater number of sites on the bacterial ribosome than earlier-generation macrolides. In this phase 2 trial, 28 patients received a single 1200 mg oral dose and 31 patients received 1000 mg. 46 patients had positive cultures for N. gonorrhoeae at enrollment (42 urogenital, 8 pharyngeal, 4 rectal). Following therapy, cultures for N. gonorrhoeae were negative from all sites of infection. In addition, about 87% of positive NAATs (nucleic acid amplification test) reverted to negative at follow-up testing. Chlamydial coinfection was present in 11 of the 59 patients; 2 were positive at follow-up. The most common side effect was dose-related mild GI toxicity (Clin Infect Dis 61:1043, 2015).
A clever new tool, the iChip, may help in the hunt for new antimicrobials. The iChip is a multichannel device that allows previously unculturable bacteria access to key nutrients and growth factors from their natural environment. A diluted soil sample is pipetted onto the iChip in the hope that a single bacterial cell will end up in each channel, the channels are covered on both sides with semipermeable membranes, and then the iChip is placed back in the soil. The membrane pores are large enough for nutrients to flow in but small enough to block the movement of any bacteria. Extracts from isolates that grow are then screened for antimicrobial activity. A promising candidate was recently obtained from a new species of β-proteobacteria, provisionally named Eleftheria terrae, found in a soil sample from Maine. Named Teixobactin, the compound (a depsipeptide) inhibits cell wall synthesis in a different manner from current antibiotics. Teixobactin is active against various Gram-positive bacteria such as S. aureus (including MRSA), S. pneumoniae, and VRE, and also M. tuberculosis. It lacks Gram-negative activity. The investigators who originally identified Teixobactin were unable to produce resistant mutants, which is highly encouraging (but preliminary). They speculate that because E. terrae is Gram-negative it has no need for an alternative pathway for cell wall synthesis to protect itself against Teixobactin (such a pathway could be borrowed by other bacteria). Teixobactin is years away from clinical trial and may never make it to market, but the iChip seems promising as a new tool for identifying potentially useful substances (J Antimicrob Chemother 70:2679, 2015, Nature 517:455, 2015).
Intraabdominal fungal infections are difficult to treat. Antifungal drugs vary in their ability to achieve useful peritoneal fluid concentrations after intravenous administration, and published data for a number of drugs including Micafungin are sparse or non-existent. In this study, ten critically ill patients with proven or suspected intraabdominal fungal infection were administered Micafungin 100 mg IV daily. Plasma and peritoneal fluid sampling occurred after the first dose and at steady state. Micafungin penetration into the peritoneal fluid was low to moderate; the median AUC0-24 peritoneal fluid/plasma ratio was approximately 0.3 at both sampling times. These data represent, at present, our best information about echinocandin distribution into peritoneal fluid (J Antimicrob Chemother 70:2854, 2015).
Para-aminosalicylic acid (PAS) is one of the last remaining drugs available for extensively drug-resistant (XDR) tuberculosis. PAS was synthesized in 1902 and first used in patients with pulmonary TB in the early 1940s. Many preparations were created to reduce GI intolerance; at one point more than 60 different preparations were available in the US, produced by more than 12 manufacturers. PAS had descended into obsolescence and was almost unobtainable by the time we became aware of the extent of MDR- and XDR-TB. The current delayed-release granule formation used in the US, Europe, and many other countries became available in 1994. This review suggests that for XDR-TB the currently recommended dose of 8-12 gm/day may not be adequate since the companion agents are relatively weak. Moreover, once-daily dosing appears to be as well tolerated as divided dosing, it would simplify the regimen for patients, and the high peak concentrations may confer advantages in terms of providing bactericidal activity and offering increased protection to companion drugs against resistance (Lancet Infect Dis 3:1091, 2015).
Drug Safety Communication
Dosing errors with Ceftazidime-avibactam (Avycaz) 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 (similar to other injectable beta-lactam/beta-lactamase inhibitor products). Revised labeling will list the sum. Click here to review the complete FDA communication.
A recent paper (Clin Infect Dis 61:1141, 2015) describes the successful use of oral Fosfomycin in two patients with acute prostatitis caused by multidrug-resistant E. coli. Prostatitis treatment with oral Fosfomycin is not a new idea, and it is also difficult to draw firm conclusions from two patients. Nevertheless, the report is intriguing because of the prolonged treatment approach: 3 grams daily for 12-16 weeks. It also gives us an opportunity to review a drug that is unfamiliar to many clinicians.
Fosfomycin, a phosphonic acid derivative, was first isolated from cultures of Streptomyces in 1969. It is FDA-approved only for single-dose treatment of uncomplicated cystitis due to susceptible strains of E. coli and E. faecalis. In vitro activity encompasses a fairly broad range of Gram-positive and Gram-negative bacteria (listed on our Fosfomycin page) but Acinetobacter, Listeria, and Bacteroides are resistant. The drug is not particularly active against Pseudomonas but it may be synergistic in combination with other drugs (Pharmacotherapy 34:845, 2014).
Fosfomycin irreversibly inactivates MurA (UDP-N-acetylglucosamine enolpyruvyl transferase), which catalyzes the first committed step in bacterial cell wall biosynthesis. No other clinically used drug targets this enzyme. Fosfomycin is bactericidal in urine, with concentrations reaching as high as 4400 mcg/ml in the first four hours following a 3 gm oral sachet, and the drug also achieves considerable intraprostatic concentrations. However, serum concentrations following oral therapy are generally insufficient to treat systemic infections. Resistance occurs in three ways: (1) amino acid substitutions in MurA, reducing drug binding; (2) decreased intracellular drug transport; and (3) a plasmid-encoded bacterial enzyme that inactivates the drug (Int J Infect Dis 15:e732, 2011).
The only form of Fosfomycin currently available in the US is a 5.6 gm single-dose sachet of fosfomycin tromethamine powder, equivalent to 3 gm of Fosfomycin. It is meant to be dissolved in 3-4 oz of water (not hot) and ingested immediately, with or without food. Concomitant use of metoclopramide (and presumably other prokinetic agents) lowers GI absorption and urinary concentrations. Fosfomycin disodium is available in some countries as an injectable product for systemic infections. Oral fosfomycin is well tolerated; the most common side effect is diarrhea. The two patients discussed in the CID paper tolerated the prolonged course well; the dose was increased to 3 gm twice daily in one patient but then returned to daily administration because of intolerable diarrhea.
- Voriconazole is notorious for interpatient pharmacokinetic variability due, in part, to its metabolism. The drug is metabolized primarily by CYP2C19 and less significantly by CYP2C9, CYP3A4, and flavin-containing monooxygenase. There are at least 20 variant CYP2C19 alleles in the population and, depending on which alleles they are carrying, individuals may be classified as ultrarapid metabolizers, extensive metabolizers (the “normal” phenotype), intermediate metabolizers, and poor metabolizers. The cited case report describes a hematopoietic stem cell transplant patient with aspergillosis and undetectable Voriconazole concentrations who failed therapy and was shown by cytochrome assay to be an ultrarapid metabolizer despite “normal” Voriconazole doses. It is important to fully appreciate the complex role of CYP2C19 in Voriconazole metabolism. For example, in a patient with normal CYP2C19 activity, an inhibitor of CYP3A4 would have little effect on Voriconazole concentrations; in contrast, a CYP3A4 inhibitor might markedly increase Voriconazole concentrations in a poor metabolizer because the CYP3A4 pathway becomes relatively more important. Depending on the situation, a patient suspected or shown to be an ultrarapid or poor Voriconazole metabolizer might be better off with Posaconazole or Isavuconazole. Posaconazole is not significantly metabolized by CYP enzymes whereas Isavuconazole is metabolized mainly by CYP3A4 (Diagn Microbiol Infect Dis 83:46, 2015).
Side effects we routinely associate with Metronidazole include nausea and metallic taste (torquegeusia). Other toxicities (not as common, sometimes forgotten) include neuropathy (peripheral, autonomic, optic), reversible cerebellar syndrome, aseptic meningitis, acute pancreatitis, and black urine (there is also the Metronidazole disulfiram-like reaction, see next pearl). Rarer still is Metronidazole-induced hepatotoxicity (typically associated with ethanol use), with only a few cases described in the literature. That number is more than doubled by this recent report of eight cases of acute liver failure associated with Metronidazole use in patients with Cockayne syndrome (CS). Three of the cases were fatal (interval between drug administration and death, 6-11 days). In addition, acute neurologic deficit was observed in two of the eight patients. CS is a rare genetic disorder characterized by microcephaly, impaired postnatal growth, and premature pathological aging (mean age at death, 8.4 years). The authors comment that no patient in their CS Natural History Study (over 100 patients) has received Metronidazole without adverse effects, suggesting a disorder-specific reaction related to the underlying pathology of CS (Pediatrics 136:e706, 2015).
The disulfiram reaction refers to the unpleasant signs and symptoms (blurred vision, nausea, vertigo, anxiety, and cardiovascular effects such as hypotension, tachycardia, and flushing of the face and neck) experienced by individuals ingesting ethanol after treatment with disulfiram. Acetaldehyde, produced by the initial oxidation of ethanol by hepatic alcohol dehydrogenase, is further oxidized by hepatic aldehyde dehydrogenase (ALDH). ALDH is inhibited by disulfiram, and thus the symptoms of the disulfiram reaction are attributed to acetaldehyde accumulation. Patients treated with Metronidazole may have a toxic response to ethanol and this is often referred to as a disulfiram-like reaction, presumably caused by ALDH inhibition.
Metronidazole was developed in 1959 and approved for the treatment of trichomoniasis in the early 1960s. The first Metronidazole disulfiram-like reaction was reported in 1964, and it was soon suggested that the drug might be useful for the treatment of alcoholism. Between 1982 and 1999, six more case reports involving eight patients were published. An assumption of all the reports seems to be that the Metronidazole disulfiram-like reaction is well documented and no further investigation of the underlying mechanism is required (Ann Pharmacother 34:255, 2000). However, recent studies have established that Metronidazole neither inhibits hepatic ALDH nor raises blood acetaldehyde concentrations (Int J Toxicol 26:423, 2007), leaving us without a proper explanation.
Could the Metronidazole disulfiram-like reaction be explained by monoamine oxidase (MAO) inhibition? An inhibitory effect of Metronidazole on bovine brain MAO has been shown (Inflamm Res 50 Suppl 2:S136, 2001). Another group found that Metronidazole (but not disulfiram) enhances rat brain serotonin levels with a parallel decrease in 5-HIAA (a serotonin breakdown product) and serotonin turnover, observations explained by MAO inhibition (Int J Toxicol 26:423, 2007). Moreover, ethanol increases the concentrations of serotonin metabolites in the urine and blood of humans, consistent with increased serotonin release in the nervous system (Biol Psychiatry 36:395, 1994). Given the similarity between the symptoms of a disulfiram reaction and those of the serotonin syndrome (the triad of altered conscious state, autonomic dysfunction, and neuromuscular excitability), it is therefore tempting to speculate that the ethanol intolerance produced by Metronidazole in some patients may in fact be due to enhanced serotonin concentrations in the CNS--a “serotonin syndrome” similar to the interaction between an MAO inhibitor and an SSRI.
This hypothesis fits with another known drug interaction. Psychosis secondary to concomitant use of Metronidazole and disulfiram is well documented but the mechanism is murky. One possible explanation is the toxic accumulation of dopamine by two independent pathways. A metabolite of disulfiram is known to inhibit the enzymatic conversion of dopamine to norepinephrine, and since dopamine is metabolized by MAO, the inhibition of MAO by Metronidazole would further increase dopamine concentrations (J Clin Psychopharmacol 33:136, 2013).
New or Updated Guidelines
- IDSA recommendations regarding the diagnosis and management of patients with native vertebral osteomyelitis are available for download (http://www.idsociety.org). These are new guidelines (Clin Infect Dis 61:e26, 2015).
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 US 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 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).