- 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 Pregnancy Risk & Lactation Safety.
- Activity spectra data has been reincorporated into antibacterial drug pages, along with links to pathogen pages. We continue working to improve performance of the antibacterial activity spectra table, especially on older mobile devices. Filtering feature allows you to view activity for selected groups of pathogens and/or antibacterial agents.
- 50+ topics were updated in January. 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.
Drug Safety Communication
Oral Posaconazole is available as 100 mg delayed-release tablets and as 40 mg/mL oral suspension. It is important to appreciate that the two formulations cannot be directly substituted for each other but instead require a change in dose. The delayed-release tablets generally provide higher plasma drug exposures than the oral suspension under both fed and fasted conditions. Since approval of the delayed-release tablets in November 2013, the FDA has received eleven reports of the wrong oral formulation being prescribed or dispensed; one case resulted in death and another resulted in hospitalization. Changes in the outer carton of the product and drug labeling have been made to address this issue.
Drug Shortage Updates
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] Amikacin, Ampicillin/sulbactam, Cefepime, Ceftazidime, Ceftriaxone, Clindamycin, DTaP-IPV/Hib (Pentacel) vaccine, Hib vaccine, Imipenem-cilastatin, Piperacillin-tazobactam, Tobramycin, Vancomycin, yellow fever vaccine
[Still on the list] Cefotaxime, Cefotetan, Meropenem, Tigecycline
Antimicrobial drugs currently unavailable due to manufacturing delays or product discontinuation:
[New on the list] Mupirocin calcium 2% nasal ointment (1 gm tubes)
[Still on the list] Chloramphenicol sodium succinate injection, Chloroquine tablets (250, 500 mg), Ofloxacin 0.3% otic solution
Antimicrobial drugs no longer available: Boceprevir (December 2015), Permethrin 1% topical lotion (September 2015)
- For detailed information including estimated resupply dates, see http://www.ashp.org/menu/DrugShortages
New or Updated Treatment Guidelines
- AASLD guidelines for treatment of chronic hepatitis B are available at (http://www.aasld.org). These guidelines are based on the GRADE approach and focus on nine clinical questions related to the care of specific patient populations (Hepatology 63:261, 2016).
- Zika Virus. The CDC issued interim Guidelines on January 22, 2016: MMWR 65:30, 2016.
A convenient way to keep the new direct acting antiviral agents for hepatitis C straight is by recognizing the meaning of their suffix:
"-asvir" means NS5A inhibitor. NS5A (nonstructural protein 5A) is essential for viral genome replication and virus assembly. Approved NS5A inhibitors are daclatasvir, ledipasvir, and ombitasvir.
"-buvir" means NS5B RNA polymerase inhibitor. There are two types: nucleoside/nucleotide inhibitors (sofosbuvir) and non-nucleoside inhibitors (dasabuvir).
"-previr" means NS3/4A protease inhibitor. First generation drugs were boceprevir and telaprevir. Second generation drugs are simeprevir and paritaprevir.
Molecular tests for C. difficile, such as PCR, became available in 2009. PCR targets toxin genes and is more sensitive than toxin enzyme immunoassays. Most institutions report a 50-100% increase in rate of C. difficile infection (CDI) after switching from toxin to molecular testing. But do patients who are PCR-positive but negative by toxin immunoassay actually have CDI, or are they perhaps only colonized with C. difficile with another reason for symptoms?1416 patients at a single academic medical center with a diarrheal stool sample submitted for testing at least 72 hours after admission were studied prospectively. Samples were tested by immunoassay and PCR and thus grouped as Tox+/PCR+, Tox-/PCR+, or Tox-/PCR-. Of the 293 patients (21%) who were PCR+, 55.3% were Tox-. Patients who were Tox-/PCR+ had significantly less diarrhea at the time of testing, faster resolution of diarrhea, and fewer CDI-related complications or deaths compared to Tox+/PCR+ patients. In addition, the presentation and outcomes of Tox-/PCR+ patients were no different than those of Tox-/PCR- patients. These findings suggest that relying exclusively on PCR for diagnosing C. difficile may result in overdiagnosis, unnecessary treatment, and increased health care costs (JAMA Intern Med 175:1792, 2015).
Do antibiotics reduce the efficacy of oral contraceptives (OCs)? The possible existence of this interaction first came to light in 1971 when an increased incidence of intermenstrual breakthrough bleeding was observed in 38 of 51 women treated concomitantly with OCs and rifampin. Soon after this report, rifampin was implicated in five unplanned pregnancies among 88 women with TB taking OCs. Another 62 women suffered from menstrual irregularities (Obstet Gynecol 98 (5 Pt 1):853, 2001).
There is no evidence that any antibiotic directly affects steroid receptor function or serves as a physiologic antagonist of the components of an OC. Thus the interaction, if it exists, is believed to be pharmacokinetic in nature. Ethinyl estradiol (EE) undergoes aromatic 2-hydroxylation in the liver, catalyzed by CYP3A4; this metabolite is further methylated and glucuronidated before renal and fecal excretion. EE is also directly glucuronidated and sulfated; these conjugates are secreted in the bile and may be hydrolyzed by gut flora to liberate the parent compound which can then be reabsorbed (enterohepatic circulation). Progestins (with the possible exception of levonorgestrel) are not directly conjugated, but rather are extensively metabolized to inactive metabolites prior to conjugation. Thus we have two possible mechanisms for the interaction: CYP3A4 induction resulting in enhanced estrogen and progestin metabolism, and interference with enterohepatic circulation of EE by the killing of gut flora (all antibiotics, in theory).
Taken together, the available pharmacokinetic studies suggest that, except for rifamycins, antibiotics do not significantly affect the plasma concentration of EE (or levonorgestrel) although large interindividual variation is observed. Further comment:
a) The existence or absence of the interaction (outside of OCs combined with potent CYP3A4 inducers like rifampin) still cannot be established scientifically. The interaction (if it exists) is likely rare, thus the available studies utilizing small numbers of patients are unlikely to pick it up. Anecdotal case reports provide insufficient evidence.
b) We generally fail to consider differences in antibiotics. For example, some antibiotics (such as erythromycin and clarithromycin) are 3A4 inhibitors and thus should increase circulating EE concentrations. Antibiotics also have variable effects on intestinal flora and gut motility.
c) The effect of an infection itself on OC failure is not well studied. Vomiting or diarrhea may reduce OC absorption, or women who are sick may be more likely to miss OC doses. Perhaps sick women are less likely to have sexual intercourse (thus masking an effect). And what about the effect of proinflammatory cytokines released during infection acting as inhibitors of drug metabolism by downregulating enzymes?
In summary: except in the case of OCs combined with rifampin or other 3A4 inducers, the OC-antibiotic interaction may not exist, but it has not been scientifically debunked either. It may be a rare event observed only in predisposed women (hard to define) taking certain OCs and certain antibiotics. It remains prudent to advise patients of the possibility of an interaction and suggest the use of nonhormonal contraceptive methods during and for at least seven days (preferably the rest of the cycle) after the antibiotic is finished (Pharm Times March 2010; 76 (published online)).
Chagas’ disease (American trypanosomiasis) is caused by the parasite Trypanosoma cruzi, which is transmitted to animals and people by insect vectors that are found only in the Americas (mainly, in rural areas of Latin America where poverty is widespread). It is estimated that six to seven million people in Mexico, Central America, and South America have Chagas’ disease. Cardiomyopathy develops in about 25% of infected patients (usually only after two to four decades). Chronic Chagas’ cardiomyopathy is associated with malignant arrhythmias, conduction disturbances, heart failure, and pulmonary and system embolism. Annual mortality is about 4% among patients followed in outpatient clinics. The role of the parasite in chronic cardiomyopathy is controversial, and the value of trypanocidal therapy is unclear.
In the recently published Benznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial, 2854 patients with established Chagas’ cardiomyopathy were randomized to receive benznidazole or placebo for 40-80 days. The benznidazole dose was initially 5 mg/kg po q24h x60 days, later modified to 300 mg po q24h x40-80 days. Primary study outcome was first occurrence of death, resuscitated cardiac arrest, insertion of a pacemaker or ICD, sustained ventricular tachycardia, cardiac transplantation, new heart failure, stroke or TIA, or a thromboembolic event. Benznidazole significantly reduced serum parasite detection as assessed by conversion to negative PCR results (a secondary outcome), but unfortunately the drug did not significantly reduce cardiac clinical progression through five years of follow-up. Rates of conversion to negative PCR results varied by geographic location but this did not correspond to a difference in the rates of clinical outcomes. Disease severity did not impact the effect of benznidazole on clinical outcomes or rates of conversion to negative PCR results (N Engl J Med 373:1295, 2015).
Drug Shortage Updates
- [new] Cefotaxime injection: insufficient supply for usual ordering.
- [new] Cefotetan injection: insufficient supply for usual ordering.
- [new] Tigecycline injection: insufficient supply for usual ordering.
- [continued] Chloramphenicol sodium succinate injection: currently unavailable in the US. Company estimates release date of first quarter, 2016.
- [continued] Chloroquine tablets (250, 500 mg): currently unavailable in the US. Resupply date unknown.
- [continued] Meropenem injection: insufficient supply for usual ordering.
- [continued] 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
- Otiprio (ciprofloxacin 6% otic suspension) for the treatment of pediatric patients with bilateral otitis media with effusion undergoing tympanostomy tube placement. Otiprio is administered as a single 0.1 mL (6 mg) intratympanic dose into each affected ear following suctioning of the middle ear effusion. It is a sustained-exposure formulation that utilizes a thermosensitive gel and drug microparticles to facilitate single-dose treatment.
A brief history and review of isoniazid (INH). INH, which stands for IsoNicotinic acid Hydrazide (there is no “H” in isoniazid), was discovered serendipitously. In 1938, someone at Johns Hopkins noticed that sulfanilamide had activity in mice infected with M. tuberculosis. The German investigator Domagk determined by 1942 that thiosemicarbazone intermediates used in sulfonamide synthesis had even better activity. Ten years later (1952) at the Squibb institute in New Jersey, Yale was using INH as an intermediate to synthesize a thiosemicarbazone, decided to test the INH in mice infected with M. tuberculosis, and discovered that it was more active than what he was trying to make in the first place. Almost simultaneously, Schnitzer at Hoffman-LaRoche in Nutley, NJ also discovered INH by expanding on a 1948 report that the B vitamin nicotinamide has mild antituberculous activity. Schnitzer was a German refugee who was interned at Buchenwald concentration camp before escaping Nazi Germany in 1939 with assistance from the Society for the Protection of Scientists (Mol Interv 6:124, 2006).
INH is one of the structurally simplest drugs ever made. A prodrug, it is thought to work by inhibiting mycolic acid synthesis in the mycobacterial cell wall. The activating enzyme is the mycobacterial catalase-peroxidase KatG. KatG generates an isonicotinyl radical from INH that binds to NAD and forms an adduct which inhibits the fatty acid enoyl-acyl carrier protein reductase InhA. There are probably other targets besides InhA. Resistance to INH in clinical isolates of M. tuberculosis is most commonly associated with point mutations in the katG gene that result in an enzyme with reduced ability to activate the drug. Another common mechanism of resistance is overexpression of InhA, overwhelming the drug with target (Annu Rev Microbiol 61:35, 2007).
INH is metabolized in the liver primarily by N-acetyltransferase 2 (NAT2), an enzyme that exhibits genetic polymorphism. Patients can be classified as slow, intermediate, or rapid acetylators. Rapid acetylators may be at greater risk for treatment failure whereas slow acetylators experience more toxicity such as hepatotoxicity or peripheral neuropathy. NAT2 genotype-guided dosing may result in improved outcomes (Clin Pharmacol Ther 98:387, 2015).
Many important drug interactions are mediate by drug uptake or efflux transporters. P-glycoprotein (PGP) is an ATP-dependent efflux transporter that is expressed at the apical surface of intestinal epithelial cells, liver bile ductules, and proximal renal tubular cells. It is also found in the adrenal gland, the placenta, and at the apical surface of endothelial cells lining the capillaries of the brain. These endothelial cells form a continuous monolayer, the blood-brain barrier (BBB). PGP is oriented to transport substrates into the blood, thus acting as an essential part of the BBB.
A primary role of PGP is protection of sensitive tissues from the toxic effects of xenobiotics and endogenous metabolites. PGP transports hundreds of structurally unrelated, typically lipid-soluble compounds. It transports many drugs that are also CYP3A4 substrates. PGP and 3A4 therefore act as barriers to intestinal absorption of drugs. Some drugs will be transported out of the enterocyte by PGP and eliminated without absorption whereas others will be inactivated by intestinal 3A4. By modulating the number of drug molecules in the enterocyte and helping to prevent saturation of 3A4, PGP increases the efficiency of first-pass drug metabolism. The content of PGP increases from proximal to distal intestine whereas 3A4 does the opposite, thus where there is a lot of 3A4 for metabolism there isn't as much PGP, and vice versa.
A good example of a clinically relevant drug interaction involving PGP is the interaction between digoxin (a PGP substrate) and clarithromycin. PGP impairs the bioavailability of digoxin and also contributes to its renal and biliary secretion. Coadministration with clarithromycin, a PGP inhibitor, has been shown to increase digoxin AUC (1.2-1.7 fold) and serum concentrations (Clin Pharmacokinet 46:1039, 2007; Essays Biochem 50:161, 2011).
Resistance to echinocandins among Candida species is generally uncommon. An exception is C. glabrata, in which resistance seems to be rising. The mechanism appears to be spontaneously arising mutations in two “hot spot” regions of the FKS genes encoding 1,3-beta-glucan synthase, the target enzyme of echinocandins. Of concern is that many of these isolates exhibit cross-resistance to azoles.
Certain species of Candida are associated with naturally-occurring polymorphisms in FKS genes that render them less susceptible to echinocandins (but still generally treatable): the C. parapsilosis family (C. parapsilosis and sibling species C. orthopsilosis and C. metapsilosis) and C. guilliermondii.
Also an issue is drug tolerance, a paradoxical effect of decreased antifungal activity at higher echinocandin concentrations. It may be both species-specific and drug-specific. One proposed mechanism (there are others) is compensatory upregulation of cell wall chitin synthesis by the fungus, reducing its susceptibility to echinocandins. This phenomenon may not result in clinical failure, but it does stabilize fungal cells in the presence of drug and may in time result in higher-level FKS mutations.
Risk factors for the emergence of resistance include prolonged and/or repeated exposure to echinocandins. Fungal cells living in biofilms contribute to the problem because drug penetration in the presence of biofilms tends to be irregular. It is interesting that there has been no documented horizontal transfer of resistant strains, perhaps because FKS mutations result in cells that are less fit (Clin Infect Dis 61 Suppl 6:S612, 2015).
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).