Is Streptococcus pyogenes Resistant or Susceptible to Trimethoprim-Sulfamethoxazole?

Bowen, Asha C; Lilliebridge, Rachael A.; Tong, Steven Y. C.; Baird, Robert W.; Ward, Peter; McDonald, Malcolm; Currie, Bart J.; Carapetis, Jonathan R.

doi:10.1128/jcm.02195-12

Cited by 55 publications

(41 citation statements)

References 49 publications

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“…Studies reporting high resistance rates either used media known to have high concentrations of thymidine, which attenuates the antimicrobial effect of SXT, or did not provide details of the medium used. Today, Mueller-Hinton medium is used in trimethoprim and SXT susceptibility testing to ensure a low thymidine concentration (8). As suggested by others, SXT may be a valuable alternative for treatment of skin and soft tissue coinfections with S. pyogenes and methicillin-resistant Staphylococcus aureus, for which penicillin treatment is losing efficacy (8).…”

Section: Discussionmentioning

confidence: 99%

“…SXT may be an underestimated alternative to other antibiotics under certain circumstances, such as in the treatment of streptococcal skin and soft tissue coinfections with methicillin-resistant Staphylococcus aureus (MRSA) (8,9). However, a reevaluation of SXT for use in S. pyogenes infections requires clinical studies and more, reliable data on the spread of resistance.…”

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confidence: 99%

“…Today's knowledge of the pitfalls in SXT susceptibility testing has raised doubts about some of the early data and the widespread resistance of S. pyogenes to this combination drug (8). SXT may be an underestimated alternative to other antibiotics under certain circumstances, such as in the treatment of streptococcal skin and soft tissue coinfections with methicillin-resistant Staphylococcus aureus (MRSA) (8,9).…”

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confidence: 99%

“…Therefore, the development and spread of resistance of S. pyogenes to alternative antibiotics, such as erythromycin or clindamycin, is a matter of concern. The use of SXT for treatment of skin infections has been suggested for use in certain settings (8). Trimethoprim is among the most frequently used antimicrobial agents (22,23) and is commonly prescribed in rural areas of India (24), where high resistance rates to SXT have been reported (25,26).…”

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Factors That Cause Trimethoprim Resistance in Streptococcus pyogenes

Bergmann

Linden

Chhatwal

et al. 2014

Antimicrob Agents Chemother

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bThe use of trimethoprim in treatment of Streptococcus pyogenes infections has long been discouraged because it has been widely believed that this pathogen is resistant to this antibiotic. To gain more insight into the extent and molecular basis of trimethoprim resistance in S. pyogenes, we tested isolates from India and Germany and sought the factors that conferred the resistance. Resistant isolates were identified in tests for trimethoprim or trimethoprim-sulfamethoxazole (SXT) susceptibility. Resistant isolates were screened for the known horizontally transferable trimethoprim-insensitive dihydrofolate reductase (dfr) genes dfrG, dfrF, dfrA, dfrD, and dfrK. The nucleotide sequence of the intrinsic dfr gene was determined for resistant isolates lacking the horizontally transferable genes. Based on tentative criteria, 69 out of 268 isolates (25.7%) from India were resistant to trimethoprim. Occurring in 42 of the 69 resistant isolates (60.9%), dfrF appeared more frequently than dfrG (23 isolates; 33.3%) in India. The dfrF gene was also present in a collection of SXT-resistant isolates from Germany, in which it was the only detected trimethoprim resistance factor. The dfrF gene caused resistance in 4 out of 5 trimethoprim-resistant isolates from the German collection. An amino acid substitution in the intrinsic dihydrofolate reductase known from trimethoprim-resistant Streptococcus pneumoniae conferred resistance to S. pyogenes isolates of emm type 102.2, which lacked other aforementioned dfr genes. Trimethoprim may be more useful in treatment of S. pyogenes infections than previously thought. However, the factors described herein may lead to the rapid development and spread of resistance of S. pyogenes to this antibiotic agent.

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confidence: 99%

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Factors That Cause Trimethoprim Resistance in Streptococcus pyogenes

Bergmann

Linden

Chhatwal

et al. 2014

Antimicrob Agents Chemother

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“…e thank Gelfand et al (1) for their interest in our article on the in vitro susceptibility of Streptococcus pyogenes to trimethoprim-sulfamethoxazole (SXT) (2). We agree that the two cases outlined by Gelfand et al act as cautionary points for clinical practice, as there are currently no good clinical trial data to support the use of SXT for the treatment of S. pyogenes skin and soft tissue infections (SSTI).…”

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Reply to “Susceptibility of Streptococcus pyogenes to Trimethoprim-Sulfamethoxazole”

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b W e thank Gelfand et al.(1) for their interest in our article on the in vitro susceptibility of Streptococcus pyogenes to trimethoprim-sulfamethoxazole (SXT) (2). We agree that the two cases outlined by Gelfand et al. act as cautionary points for clinical practice, as there are currently no good clinical trial data to support the use of SXT for the treatment of S. pyogenes skin and soft tissue infections (SSTI). Our aim in publishing the in vitro data is to challenge the misconception that all S. pyogenes isolates are inherently resistant to SXT and hence open the way for clinical trials to more precisely determine the role for SXT in the treatment of S. pyogenes infections.In the two clinical scenarios presented by Gelfand et al., the absence of SXT susceptibility data for the S. pyogenes isolates is concerning. Other reasons for treatment failure that are not elucidated include incomplete adherence, poor absorption, and the reality that the conditions of both of these patients might have deteriorated regardless of the antibacterial used. One wonders why the authors prescribed SXT for these SSTI despite their understanding of the traditional teaching that S. pyogenes is largely resistant to SXT. Perhaps it was due to the need for a simple, palatable, oral antibacterial regimen that would treat undifferentiated SSTI, in the era of highly methicillin-resistant Staphylococcus aureus (MRSA) prevalence. We are in agreement with Gelfand et al. that human clinical studies are urgently needed to respond to this challenge.The results of our clinical trial comparing oral SXT with intramuscular benzathine penicillin for impetigo treatment will inform treatment decisions and generate confidence in the use of SXT for impetigo treatment in our region and possibly beyond. To date, with recruitment of 660 participants completed, despite twothirds of the participants presenting with severe impetigo, none have been hospitalized with invasive S. pyogenes infection due to presumed treatment failure. Although the numbers in our study are not large enough to detect a trend for bacteremia or other complications of inadequate treatment, we might have seen clinical outcomes similar to those Gelfand et al. have experienced if SXT really has no role in the treatment of impetigo. Spontaneous resolution of mild impetigo may occur; however, the natural history of impetigo, particularly when severe, is neither completely understood nor benign (3).We agree that the role of thymidine and its availability in the context of damaged host tissues (4) are unknown with respect to the treatment of SSTI with SXT. There are now numerous trials under way that involve the use of SXT for SSTI (http: //clinicaltrials.gov/), and the results are eagerly awaited to better define the clinical utility of SXT in such settings.Rather than claiming in vitro data being less relevant than clinical efficacy, we would argue that in vitro data should be used to inform the design of appropriate clinical trials to determine the clinical role for SXT, particularly in an...

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