Literature Update – Antimicrobial Agents and Chemotherapy, Sept, 2011
As I have mentioned in a previous post there are a number of journals I follow to stay abreast of developments in the ID, microbiology and antibiotic world. For updates on the latest in antibiotic development from pre-clinical through clinical testing no journal beats the American Society of Microbiology’s Antimicrobial Agents and Chemotherapy (http://asm.org/). Just to give a taste of how relevant this publication can be to those of us treating lower extremity infections, in the current September 2011 issue of AAC there at least 5 papers that present useful information. In this “Literature Update” I will list these manuscripts, give the PubMed link to their Abstracts, and give a summary of what the authors reported.
Richter SS, et.al. Activity of ceftaroline and epidemiologic trends in S. aureus isolates collected from 43 medical centers in the United States in 2009. (http://www.ncbi.nlm.nih.gov/pubmed?term=Richter%20SS%20ceftaroline). The authors looked at the results of a nationwide S. aureus surveillance program collecting clinical isolates from 43 medical centers throughout the US during 2009. Hospitals each submitted 100 consecutive isolates to a reference laboratory for in depth testing including PCR to determine the exact strain and presence of absence of Panton-Valentine leukocidin (PVL) production along with microbroth dilution testing to determine susceptibility to a broad range of antibiotics. 4,210 isolates were tested. The so-called “Community associated” strains, genotype USA300 and USA100, constituted almost 40% of all isolates (MRSA and MSSA) with the USA300 being the most commonly found single strain of MRSA at 50.6% of isolates. As one would expect it was, by far, the most commonly isolated from wound and abscess specimens and therefore continues to be the type of most importance to those of us treating the lower extremity. Turning to the question of antibiotic susceptibility for the USA300 strains resistance rates were as follows: erythromycin, 90.9%; levofloxacin, 49.1%; clindamycin, 7.6%; tetracycline, 3.3%; trimethoprim/sulfa, 0.8%; daptomycin 0.4%; ceftaroline and linezolid, 0%.
Wiskirchen DE, et.al. Determination of tissue penetration and pharmacokinetics of linezolid in patients with diabetic foot infection using in vivo microdialysis. (http://www.ncbi.nlm.nih.gov/pubmed/21709078). I have been an unabashed fan of the work by David Nicolau and his Center for Anti-infective Research and Development at Hartford Hospital. In particular, their work in the area of microdialysis (“micro-D”) to determine tissue penetration in both bone and soft tissue has been, in my mind, groundbreaking. It is a standardized proven methodology for determining antibiotic levels in different tissues, something that has been sorely lacking. In this paper they turn their catheters on to the study of linezolid levels in infected diabetic foot wounds. The micro-D technique is described in detail in the paper but basically a catheter is inserted into the tissue in question and the catheters are continuously perfused with Lactated Ringer’s. Dialysate samples are then collected from the catheters and antibiotic levels are measured. In this study the catheters were placed in uninfected thigh tissue and within 10cm of the infected foot wound. 9 patients were evaluated. The patients were brought to steady state on IV linezolid and serum samples were collected at the same time as catheter samples to compare the two. Again, the results of this elegant study should be read in their entirety but the conclusion was that “…linezolid penetrated equally well into both healthy thigh tissue and infected wound tissue as demonstrated by the tissue penetration ratios (AUCtissue/AUCplasma) of 1.42 in thigh tissue and 1.27 in wound tissue.” There was fairly wide variation between patients which is not at all surprising considering the normal differences we see in this population. Interestingly, these numbers where higher than an earlier study done in normal volunteers.
Gomez J, et.al. Linezolid plus rifampin as a salvage therapy in prosthetic join infections treated without removing the implant. (http://www.ncbi.nlm.nih.gov/pubmed/21690277) In this study out of Spain the authors evaluated 161 hip and knee prosthetic joint infections which had failed on previous therapies (teicoplanin, ciprofloxacin or TMP/SMX with rifampin). These patients were switched to linezolid plus rifampin, 600 mg po q12h plus 300 mg po q12h, without removing the implant. Cultures were positive in 28 cases. Interestingly, methicillin resistant S. epidermidis was found in 22 while MRSA was found in 6 cases. The mean duration of therapy was 80.2 days (range 21-180). At 2 years of follow-up the remission rate was 69.4%. A large amount of purulent drainage at the initiation of the therapy was a predictor of failure. 3 patients developed thrombocytopenia and 3 developed anemia but the linezolid did not have to be discontinued in any of these cases. This study, although perhaps not directly applicable to daily practice is worth reading for a number of reasons. With all of the publicity given to MRSA we sometimes forget the role coagulase negative Staph can cause in prosthetic joint infections. Also, there has been concern for giving prolonged courses of linezolid because of the risk for myelosuppression. As this, the linezolid package insert, and other studies have demonstrated it certainly can be an issue but it rarely causes a need for discontinuation of therapy. Upon discontinuation the changes are reversible. Finally, as I have discussed in a previous post, it is possible that rifampin should be considered as adjunctive therapy when treating bone and joint infections caused by resistant Staph.
Usually fungal articles in AAC deal with systemic infections. It is rather uncommon to find articles about tinea pedis and onychomycosis. This month there were actually 2! Both are brief reports.
Carrillo-Muñoz AJ, et.al. Sertaconazole nitrate shows fungicidal and fungistatic activities against T. rubrum, t. mentagrophytes and E. floccosum, causative agents of tinea pedis. (http://www.ncbi.nlm.nih.gov/pubmed/21746955) In this brief in vitro study 150 clinical isolates of dermatophytes were tested for fungicidal and fungistatic activity using sertaconazole (Ertaczo). The testing showed fungicidal activity against all three organisms with better activity against T. rubrum and E. floccosum than against T. mentagrophytes. According to the authors this result was important since, prior to this study; the only fungicidal data for this drug was limited to two strains of T. mentagrophytes. Their conclusion was that, although the clinical advantage of fungicidal over fungistatic activity for tinea pedis products remains unclear, “these dual fungicidal and fungistatic activities of sertaconazole are consistent with its efficacy against tinea pedis in randomized, placebo-controlled clinical trials”.
Krishna G, et.al. Determination of posaconazole levels in toenails of adults with onychomycosis following oral treatment with four regimens of posaconazole for 12 or 24 weeks. (http://www.ncbi.nlm.nih.gov/pubmed/21746944) In this pharmacokinetic data reporting from a phase 2 clinical trial, patients were treated with oral posaconazole (100, 200, 400mg) once daily for 24 weeks or 400 qd for 12 weeks. Drug concentrations from both nail clippings and plasma were collected. 118 patients completed treatment. In the hallux posaconazole was detected as early as 2 weeks in the 200 and 400 mg dose groups. The levels were dose related and continued to rise even after discontinuation of the drug. Plasma levels reached steady state and stayed there, declining once the drug was stopped. The authors opined that posaconazole remained high in the nail after treatment was discontinued “…probably because posaconazole accumulated in the nail matrix via systemic absorption during treatment. As the nail plate grew out, posaconazole was incorporated into the nail plate moving away from the nail fold, where it persisited at the distal end of the nail plate.” You may now ask yourself “Why have I never heard about this drug?” Posaconazole was being developed by Schering-Plough for possible oral use in onychomycosis. SP was bought by Merck and priorities in drug portfolios change. I am currently uncertain about the fate of this drug’s future development.