Infectious Disease Alert Updates
By Carol A. Kemper, MD, FACP
Dr. Kemper reports no financial relationships relevant to this field of study.
Colistin Resistance in Action
SOURCE: Rojas LJ, Salim M, Cobert E, et al. Colistin resistance in carbapenem-resistant Klebsiella pneumoniae: Laboratory detection and impact on mortality. Clin Infect Dis 2017:64;711-718.
Colistin has become an important “last resort” agent for patients infected with increasingly drug-resistant gram negatives, especially carbapenem-resistant Enterobacteriaceae. This study examined colistin resistance in isolates from patients infected or colonized with carbapenem-resistant Klebsiella pneumoniae (CRKP) from December 2011 to October 2014, comparing the results from broth macrodilution (performed in a research labor-atory) to those of standard clinical laboratory Etest, as well as to the results of polymyxin resistance testing. Only the first isolate from an individual patient was included in the assessment. Time to 30-day all-cause in-hospital mortality was determined.
A total of 246 patients with CRKP were identified. Of these, 22% had received prior treatment with colistin. Isolates were cultured from urine (59%), blood (18%), respiratory secretions (11%), wound (5%), or other (7%). Gene testing revealed that CRKP resistance was mediated by bla-KPC-3 (50%) and bla-KPC-2 (46%). Colistin resistance was identified for 31 (12.5%) of the isolates by broth macrodilution compared with 9% for the clinical laboratory, based on Etest. In comparison, 10% of the isolates tested were resistant to polymyxin B. Based on these results, the clinical laboratory underestimated colistin resistance for ~ 35% of isolates.
A variety of strain types were observed for both colistin-sensitive and colistin-resistant groups, suggesting that chromosomally mediated colistin resistance arises de novo. None of the isolates were found to be carrying MCR-1 or MCR-2 colistin resistance genes.
Kaplan-Meier confirmed that the 30-day all-cause mortality was significantly greater for patients with CRKP isolates resistant to colistin, regardless of whether the patients were actively infected or colonized (adjusted hazard ratio, 3.48; P < 0.001).
One of the difficulties infectious disease specialists have faced is the lack of interpretative standards for colistin resistance, and a lack of good clinical and PK/PD data for establishing breakpoints. A working group affiliated with the CLSI has been working to establish better data. For example, colistin breakpoints have been established for Acinetobacter spp. and Pseudomonas aeruginosa (≤ 2 micrograms/mL is considered susceptible). Based on epidemiological data, inferences can be made to support a similar cut-off value for Enterobacteriaceae. The CLSI has recommended that any Enterobacteriaceae isolate with an MIC to colistin of 4 micrograms/mL or higher should be tested for MCR genes.
PK-tailored High-dose Colistin May Not Be Beneficial
SOURCE: Benattar YD, Omar M, Zusman O, et al. The effectiveness and safety of high-dose colistin: Prospective cohort study. Clin Infect Dis 2016:63:1605-1612.
One of the difficulties in the use of colistin is understanding the optimal dose for patients with life-threatening infection with multidrug-resistant organisms. Not only is it difficult to interpret susceptibility data, but sufficient pharmacokinetic data are not available. These Israeli investigators examined the use of different dosing schemas of colistin in two prospective cohort studies performed between 2006 and 2009 and 2012 and 2015 at two different facilities. Pharmaco-directed therapy, using higher doses of colistin, aimed at maintaining the drug level above a breakpoint of 2 mg/L (see above article) was compared with standard dosing. High-dose colistin consisted of a loading dose of 9 MIU followed by 4.5 MIU twice daily, with daily renal-dose adjustment as needed to maintain at least 80% of the target dose. Mortality and toxicity were compared between those receiving higher-dose colistin vs. standard dosing in adult patients with carbapenem-resistant infection requiring colistin.
A total of 529 patients were included in the analysis, including 144 treated with high-dose colistin and 385 receiving standard dosing. Not including the loading dose, the median daily dose in the high-dose group was 9 MIU compared with 4 MIU in the standard dosing group. After adjustment in multivariate analysis and for propensity scoring, no significant difference in 28-day mortality was observed between the two groups. In looking at overall mortality, there were 50 (34.7%) deaths in the high-dose group compared with 165 (42.9%) in the standard-dose group (P = NS). However, the adjusted odds ratio for mortality was 1.07 (95% confidence interval, 0.63-1.83) for high-dose colistin, suggesting a possible trend in favor of standard dosing. Patients in the high-dose group were more likely to have pneumoniae from Acinetobacter baumannii, while the most frequent infection in the standard dose group was Klebsiella pneumoniae bacteremia. Mortality in patients with bacteremia was significant in both groups: 14/32 (43%) of bacteremic patients receiving high-dose colistin died vs. 91/175 (52%) of those in the standard dosing group.
Not unexpectedly, toxicity was greater in patients receiving high-dose colistin compared with standard dosing. Almost twice as many patients developed increased serum creatinine in the high-dose group. Three times the increase in creatinine was observed in 16.7% of high-dose vs. 8.8% of standard-dose group. Seizures occurred in 4.9% of those receiving high-dose colistin compared with 1% in the standard dosing group.
‘Dragon’s Blood’ Yields Possible Antibacterial
SOURCE: Bishop BM, Juba ML, Russo PS, et al. Discovery of novel antimicrobial peptides from Varanus komodoensis (Komodo dragon) by large-scale analyses and de-novo-assisted sequencing using electron-transfer dissociation mass spectrometry. J Proteome Res 2017;16:1470-1482.
The search is on for new antimicrobials that may prove useful against increasingly resistant organisms. Such bioprospecting is focused on the discovery of new products from biological and natural resources, as well as systematically reviewing centuries-old homeopathic products and drugs shelved years ago. Amphibians and reptiles are widely recognized for their ability to resist infection, despite a constant risk of wounds and wound infection. For example, different species of frogs secrete various antimicrobial peptides from their skin that have a broad range of activity against bacteria and fungi, and a couple have made their way into preliminary clinical trials as potential topical antimicrobials for humans. Thus far, more than 800 such organisms have been isolated from different species, including frogs, toads, spiders, scorpions, and fish.
These authors have turned their attention to crocodiles and lizards, such as the Komodo dragon, which lives on a series of islands in Indonesia. The Komodo is thought to kill its prey with the use of strong scissor-like teeth that inflict a bacterial-laden wound, resulting in fatal infection, much the same as the big cats (or your own cat) do. And yet, the Komodo itself seems resistant to these wound infections.
The first task was finding a cooperative Komodo willing to donate a blood specimen — a zookeeper managed to collect four tablespoons of blood from the tail of a 100-pound Komodo at a zoological park in Florida for use. Using mass spectrometry, 48 potentially useful cationic peptides were isolated from blood — referred to as CAMPS (for cationic antimicrobial peptides). Eight of these have been synthesized and tested in vitro against laboratory strains of S. aureus and Pseudomonas aeruginosa. All eight had activity against pseudomonas, while seven had activity against S. aureus. Researchers are still working on the other 40 compounds.
While researching this article, it was interesting to learn that the traditional Chinese remedy “Dragon’s blood” has nothing to do with Komodo or other dragons. Dragon’s blood is a bright red plant resin, acquired from the rattan palms in Indonesia or certain trees native to the Canary Islands, Morocco, and South America. Used for centuries as a cure-all for wound infections, stomach upset, mouth ulcers, and postpartum bleeding, it still can be found in use in commercial sculpting gels and night creams. It also has been found in furniture varnish and adds color to string instruments. This resin is a complex product containing phenols, flavonoids, sterols, etc., which also have been examined for their potential antimicrobial and antioxidant properties.
Colistin Resistance in Action; PK-tailored High-dose Colistin May Not Be Beneficial; ‘Dragon’s Blood’ Yields Possible Antibacterial
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