A Closer Look At The Recent Literature On Infectious Diseases And Antibiotics

Warren S. Joseph DPM FIDSA

As I mentioned in a previous post, there are a number of journals I follow to stay abreast of developments in the infectious disease, microbiology and antibiotic world (see http://bit.ly/iLJb6k ). 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://aac.asm.org/ ). Just to give a taste of how relevant this publication can be to those of us treating lower extremity infections, there are at least five papers in the September 2011 issue that present useful information.

Richter and colleagues looked at the results of a nationwide S. aureus surveillance program, collecting clinical isolates from 43 medical centers throughout the United States during 2009.1 Hospitals each submitted 100 consecutive isolates to a reference laboratory for in depth testing including polymerase chain reaction (PCR) to determine the exact strain and presence or absence of Panton-Valentine leukocidin (PVL) production along with microbroth dilution testing to determine susceptibility to a broad range of antibiotics. They tested 4,210 isolates. The so-called “community associated” strains, genotype USA300 and USA100, constituted almost 40 percent of all isolates, methicillin resistant Staph aureus (MRSA) and methicillin susceptible Staph aureus (MSSA).

The USA300 was the most commonly found single strain of MRSA at 50.6 percent of isolates and was by far the most commonly isolated from wound and abscess specimens.1 Therefore, USA300 continues to be the type of MRSA 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 percent; levofloxacin (Levaquin, Janssen Pharmaceuticals), 49.1 percent; clindamycin, 7.6 percent; tetracycline, 3.3 percent; trimethoprim/sulfamethoxazole (Bactrim), 0.8 percent; daptomycin (Cubicin, Cubist Pharmaceuticals) 0.4 percent; ceftaroline (Teflaro, Forest Laboratories) and linezolid (Zyvox, Pfizer), 0 percent.

I have been an unabashed fan of the work by David Nicolau, PharmD, FCCP, FIDSA and his Center for Anti-Infective Research and Development at Hartford Hospital in Hartford, Conn. 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.2 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 authors describe the micro-D technique in detail in the paper.2 One basically inserts a catheter into the tissue in question and continuously perfuses the catheters with lactated Ringer’s solution. Clinicians then collect dialysate samples from the catheters and measure antibiotic levels. In this study, researchers placed the catheters in uninfected thigh tissue and within 10 cm of the infected foot wound in nine patients. The patients achieved steady state on IV linezolid and clinicians collected serum samples 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.”2 There was fairly wide variation between patients. This 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.

In a study out of Spain, Gomez and co-workers evaluated 161 hip and knee prosthetic joint infections that had failed on previous therapies.3 Therapies included teicoplanin, ciprofloxacin (Cipro) or TMP/SMX with rifampin. Researchers switched these patients 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 present in 22 while MRSA was present in six cases. The mean duration of therapy was 80.2 days (range 21 to 180). At two years of follow-up, the remission rate was 69.4 percent. A large amount of purulent drainage at the initiation of the therapy was a predictor of failure. Three patients developed thrombocytopenia and three developed anemia but the linezolid did not have to be discontinued in any of these cases.

While this study is perhaps not directly applicable to daily practice, it is worth reading for a number of reasons.3 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 study, 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 (see http://bit.ly/n63sxY ), it is possible that one should consider rifampin as adjunctive therapy when treating bone and joint infections caused by resistant Staph.

A Look At Recent Research On Fungal Infections

Usually fungal articles in AAC deal with systemic infections. It is rather uncommon to find articles about tinea pedis and onychomycosis. There were actually two this month. Both are brief reports.

In a brief in vitro study, researchers tested 150 clinical isolates of dermatophytes for fungicidal and fungistatic activity using sertaconazole (Ertaczo, Ortho Dermatologics).4 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 and colleagues reported pharmacokinetic data from a phase 2 clinical trial.5 Patients received with oral posaconazole (Noxafil, Merck) (100, 200, 400 mg) once daily for 24 weeks or 400 qd for 12 weeks. Researchers collected drug concentrations from both nail clippings and plasma from the 118 patients who completed treatment. In the hallux, researchers detected posaconazole as early as two 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 persisted at the distal end of the nail plate.”5 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. Merck bought Schering-Plough and priorities in drug portfolios change. I am currently uncertain about the fate of this drug’s future development.

Editor’s note: This blog was originally published at http://www.leinfections.com/antibiotics/literature-update-%E2%80%93-anti... and has been adapted with permission from Warren Joseph, DPM, FIDSA, and Data Trace Publishing Company. For more information about the Handbook of Lower Extremity Infections, visit www.leinfections.com/ .

References

1. Richter SS, Heilmann KP, Dohrn CL, et al. Activity of ceftaroline and epidemiologic trends in S. aureus isolates collected from 43 medical centers in the United States in 2009. Antimicrob Agents Chemother. 2011; 55(9):4154-60.

2. Wiskirchen DE, Shepard A, Kuti JL, Nicolau DP. Determination of tissue penetration and pharmacokinetics of linezolid in patients with diabetic foot infection using in vivo microdialysis. Antimicrob Agents Chemother. 2011; 55(9):4170-5.

3. Gomez J, Canovas E, Banos V, et al. Linezolid plus rifampin as a salvage therapy in prosthetic join infections treated without removing the implant. Antimicrob Agents Chemother. 2011; 55(9):4308-10.

4. Carrillo-Muñoz AJ, Tur-Tur C, Cardenes DC, et al. Sertaconazole nitrate shows fungicidal and fungistatic activities against T. rubrum, t. mentagrophytes and E. floccosum, causative agents of tinea pedis. Antimicrob Agents Chemother. 2011; 55(9):4420-1.

5. Krishna G, Ma L, Martinho M, 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. Antimicrob Agents Chemother. 2011; 55(9):4424-6.

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