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Antimicrobial Agents and Chemotherapy, February 2007, p. 423-428, Vol. 51, No. 2
0066-4804/07/$08.00+0 doi:10.1128/AAC.01244-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.
Harvard Medical School, Boston, Massachusetts,1 Fenway Community Health, Boston, Massachusetts,2 Brown University School of Medicine, Providence, Rhode Island3
Received 4 October 2006/ Returned for modification 19 October 2006/ Accepted 10 November 2006
| ABSTRACT |
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| INTRODUCTION |
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CA-MRSA can be distinguished from classic hospital-associated MRSA based on genetic features, such as the presence of the staphylococcal cassette chromosome, mec type IV, and Panton-Valentine leukocidin production (2, 5, 7, 10, 17, 18, 20, 24). The antibiotic resistance profiles of community and hospital-associated MRSA also differ. Whereas hospital-associated MRSA usually has broad resistance to a number of diverse antibiotics, CA-MRSA has tended to have a narrower resistance profile and may often be sensitive to clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), and/or tetracyclines (2, 5, 10, 17, 20, 24). Guidelines for the treatment of CA-MRSA have been published, but data are limited regarding optimal outpatient antibiotic treatment regimens for MRSA SSTI (2, 3, 5, 10, 17, 19, 20, 24).
The purpose of this study was to examine the relationship between trends in choice of empirical antibiotic therapy for suspected S. aureus SSTI at an ambulatory care center and the likelihood of clinical resolution of these infections on the empirical antibiotic(s). We hypothesized that increasing usage of alternative antistaphylococcal drugs, such as TMP-SMX, would be associated with improved rates of clinical resolution among patients with suspected S. aureus SSTI.
| MATERIALS AND METHODS |
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As this was a retrospective chart review, a waiver for informed consent was obtained from the FCH Institutional Review Board.
Study population. The study population included all patients with at least one medical-clinic visit to FCH from 1 January 1998 through 31 December 2005 that was recorded in the clinic's electronic medical-record system (Centricity EMR; GE Healthcare). Patients with wound cultures positive for S. aureus were identified by querying the electronic medical-record database. Patients were included in the analysis of S. aureus skin and soft tissue infections only if they had a positive wound culture with antibiotic sensitivities available, as well as a clinic visit where they presented with signs and/or symptoms of skin or soft tissue infection. We also identified patients with other types of clinical cultures (e.g., urine, blood, or joint aspirates) positive for S. aureus to assess the spectrum of S. aureus infections seen among outpatients at FCH. Data from patients initially diagnosed at an outside hospital were included, provided these patients had a subsequent clinic visit at FCH and clinical cultures and antibiotic sensitivities were available. Cases diagnosed at outside hospitals without any supporting culture and sensitivity data in the record were excluded, as were cases in which only nasal cultures were obtained to detect asymptomatic staphylococcal carriage.
Clinical management. Wound cultures were obtained at the discretion of FCH clinicians when there was clinical suspicion that the patient was at risk for infection with an antibiotic-resistant organism. The choice of antibiotic and duration of antibiotic therapy were at the discretion of the patient's physician.
Definitions. The empirical antibiotic regimen was defined as the initial antibiotic regimen instituted prior to availability of culture and sensitivity data. Cases were considered to have clinically resolved only if the patient had a follow-up medical visit documenting the resolution of all symptoms and signs of the infection or if the infection was not listed as a current active problem and the documented physical findings did not include any persistent signs of the infection. Persons without any follow-up clinic visit were not counted as having clinical resolution of their infection. For individuals with multiple infection-related visits, recurrent MRSA skin or soft tissue infections were diagnosed if the patient presented to FCH with a new clinical infection more than 2 weeks after clinical resolution of a previous infection and/or clinical infections involving a noncontiguous anatomic site.
Highly active antiretroviral therapy (HAART) was defined as a medication regimen comprising at least three antiretroviral medications, including at least two nucleoside or nucleotide reverse transcriptase inhibitors.
Assessment of changes in health care providers' ordering of clinical cultures was done by first searching the electronic medical record for International Classification of Diseases 9 codes (680, 682, and 041.1) thought to be relevant to deep SSTI that were likely to yield specimens for culture and then checking the medical record for the presence of a wound culture report with antibiotic sensitivity results.
Although the exact number of persons at risk could not be precisely known, a crude adjustment for the size of the clinic patient population was done by dividing the number of yearly S. aureus infection cases by the number of visits by distinct patients during that year. This denominator included all medical, podiatry, and gynecology visits, excluding visits for intrauterine insemination and for mental health care.
Prespecified comparisons between patients with infections by MRSA and methicillin-susceptible S. aureus (MSSA) isolates included age, race, ZIP code of residence, HIV status, and HIV status within 1 year after diagnosis of an S. aureus SSTI.
Statistical analysis. Statistical analysis was performed using Stata version 9.2 (Statacorp, College Station, TX). All P values are two sided, and exact confidence limits were calculated for all odds ratios (OR). Tests of categorical variables were done using Fisher's exact test. Two sample t tests or the Wilcoxon rank-sum test were used to compare means or medians as appropriate. Linear trends were computed with the Mantel Score Test (12). A logistic regression model was constructed to assess the effects of antibiotic sensitivity, incision and drainage, and HIV status on the odds of clinical resolution. Likelihood ratio tests were used to compare regression models.
| RESULTS |
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S. aureus skin and soft tissue infections. A total of 232 distinct culture-confirmed MRSA clinical infections were identified in Fenway outpatients between 1 January 1998 and 31 December 2005. Of these, 227 were SSTI, including folliculitis, furuncles, carbuncles, abscesses, and unclassified infections (Fig. 1a). Of the other five MRSA infections, four were urinary tract infections and one was due to bacteremia in a patient with a prostatic abscess. The 227 MRSA SSTI occurred in 173 different patients, 40 of whom (23.1%) had a subsequent culture-confirmed MRSI SSTI during the study period. Overall, 54/227 (23.8%) MRSA SSTI cases occurred in patients with a previous culture-confirmed MRSA SSTI (Fig. 1b). There was a trend toward a higher proportion of recurrent cases from 2001, the first year with more than one MRSA SSTI case, through 2005 (P = 0.06 for trend). The mean number of distinct MRSA infections per year among patients infected with MRSA isolates was 1.1 (range, 1.0 to 1.3 mean infections per year from 1998 to 2005). Over the study period, a total of 179 culture-confirmed MSSA infections were identified in Fenway outpatients. Of these, 172 were SSTI, and they occurred in 165 different patients. The other seven MSSA infections comprised five urinary tract infections, one bacteremia, and one case of septic bursitis. No endovascular infections occurred in this study. Fourteen patients had at least one MRSA and at least one MSSA skin and soft tissue infection during the study. Altogether, 324 different patients experienced any skin or soft tissue infection due to S. aureus during the study period; 164 persons had an initial MRSA isolate infection, whereas 160 persons had an initial MSSA isolate infection.
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Antibiotic resistance profiles of MRSA isolates. Resistance to TMP-SMX was uncommon (Table 2). Of the 399 S. aureus SSTI, 386 had TMP-SMX sensitivities available, with only 10 isolates (2.6%) resistant. Of these 10 patients, 5 were HIV infected, and 3 of the HIV-infected patients were receiving prophylactic TMP-SMX. Nine isolates were MSSA, and one was MRSA. Only 1 (0.5%) of the 216 MRSA skin and soft tissue isolates with TMP-SMX sensitivities available was resistant to TMP-SMX. Inducible clindamycin resistance could not be assessed, as disk diffusion testing was not performed routinely (11). Notably, constitutive clindamycin resistance was present in nearly half (48.2%) of the MRSA isolates. Only a few (13/399) had tetracycline sensitivities available, since susceptibility to tetracycline was not routinely tested for at the clinical laboratory to which wound cultures were most often sent. Of these 13 isolates, 53.8% were resistant to tetracycline. Testing for resistance to doxycycline and minocycline was not routinely performed. Among MRSA isolates, resistance to ciprofloxacin (78.5%) or erythromycin (93.8%) was common, but the isolates were almost uniformly sensitive to chloramphenicol, gentamicin, rifampin, and vancomycin.
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Information regarding the duration of empirical antibiotic therapy was available for 183/203 (90.1%) antibiotic-treated SSTI cases. There was a trend toward longer duration of empirical treatment for cases receiving empirical TMP-SMX than for cases treated with other empirical antibiotics (mean, 11.0 ± 3.4 days for TMP-SMX versus 10.3 ± 3.5 days for other antibiotics; P = 0.06).
Additional clinical management of S. aureus skin and soft tissue infections. As MRSA became more widely recognized, clinicians tended to obtain clinical cultures of suspected S. aureus SSTI more frequently. The percentage of SSTI with a culture obtained increased significantly, from none in 1998 to nearly 73% in 2005 (P < 0.0001 for trend). In addition, the percentage of all S. aureus SSTI for which incision and drainage were performed also increased significantly, from 0 in 1998 to 45.1% in 2005 (P < 0.0001 for trend). The percentage of MRSA infections with incision and drainage performed similarly increased significantly, from 0 in 1998 to 56.1% in 2005 (P = 0.002 for trend).
Clinical outcomes on empirical antibiotic regimens. In order to determine whether these changes in empirical antibiotic regimens for S. aureus SSTI led to improved clinical outcomes, we determined the percentage of cases that resolved clinically on the empirical antibiotic(s) (Fig. 3). The percentage of cases with clinical resolution on the empirical oral regimen increased significantly for MRSA (P < 0.04 for trend) but did not change significantly for MSSA (P = 0.75 for trend). Although a higher percentage of recurrent cases than initial cases resolved on empirical therapy early in the study period, by 2005 this difference was not significant (65.6% of recurrent cases versus 60.5% of initial cases; P = 0.67).
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In the multivariate analysis, isolate sensitivity to empirical antibiotics remained significantly associated with clinical resolution on empirical therapy when incision and drainage and HIV status were controlled for (OR = 5.91; 95% confidence interval, 3.14 to 11.13). The association between HIV seropositivity and clinical resolution on empirical therapy was no longer statistically significant after isolate sensitivity to empirical antibiotics was controlled for (OR = 1.74; 95% confidence interval, 0.94 to 3.22).
Of the 203 MRSA SSTI cases treated with oral antibiotics, 104 (51.2%) occurred in patients who were known to be HIV+. Neither use of HAART (OR = 0.68; 95% confidence interval, 0.28 to 1.65), CD4 count (OR = 1.06 for each increase of 100; 95% confidence interval, 0.92 to 1.23), nor log viral load (OR = 1.10; 95% confidence interval, 0.91 to 1.33) was significantly associated with clinical resolution on empirical therapy. In the multivariate analysis, isolate sensitivity to empirical antibiotics remained significantly associated with clinical resolution on empirical therapy after incision and drainage, HIV status, use of HAART, log viral load, and CD4 count were controlled for (OR = 6.76; 95% confidence interval, 2.57 to 17.74).
Finally, we examined adverse reactions to TMP-SMX, the most commonly prescribed empirical antibiotic for MRSA SSTI by the end of the study period. Adverse reactions, including fever and rash deemed serious enough by the provider to discontinue TMP-SMX, occurred in 8/150 (5.3%) SSTI cases treated with empirical TMP-SMX.
| DISCUSSION |
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In the late 1990s, most MRSA cases were initially treated with oral beta-lactam antibiotics, to which MRSA isolates are insensitive. By 2005, with greater recognition of MRSA as a major cause of SSTI at FCH, clinicians tended to choose TMP-SMX for empirical treatment for suspected S. aureus SSTI. In parallel, a greater percentage of clinical S. aureus isolates were sensitive to the empirical antibiotic and a greater proportion of cases resolved clinically on the empirical antibiotic. The nonsignificant decrease in the proportion of MSSA cases that clinically resolved on empirical therapy over the study period was due to clinicians changing to beta-lactam antibiotics once wound culture data were available, not to a lack of susceptibility of MSSA to TMP-SMX (Table 2).
The increase in the frequency of obtaining clinical cultures for patients with skin and soft tissue infections likely reflects growing awareness by FCH clinicians of the high prevalence of MRSA among the patient population and the importance of antimicrobial susceptibility testing for these infections. It is also possible that the increase in clinical cultures was due to an increase in deep-seated infections from which culturable material could be collected. The classification of infections as deep seated or not was not always possible with certainty based on descriptions provided in the medical record. While the observation that the percentage of S. aureus skin and soft tissue infections undergoing incision and drainage significantly increased over the study period suggests a possible increased prevalence of deep-seated infections, such a change may simply reflect the evolution of clinical management of SSTI among FCH clinicians. A prospective study would be needed to answer this question definitively.
Awareness that MRSA is an important cause of community-onset SSTI has not spread to all centers, and patients may still receive monotherapy with agents lacking activity against MRSA, such as cephalexin or dicloxacillin (9, 18, 23). The clinical importance of inactive empirical therapy has not always been clear, as one group found no significant association between inactive empirical therapy and clinical outcomes (4). However, these researchers interviewed only a subset of their total MRSA cases, and outcomes were assessed via patient interviews, which may be less reliable than medical-record review. In the current study, information regarding the clinical response to therapy was available for the vast majority of patients in the sample. Furthermore, the prevalence of HIV was only 9% among persons over 18 in the study by Fridkin et al. compared to more than 40% of MRSA patients in our investigation (4). It is possible that treatment of S. aureus SSTI with the antibiotics showing the most in vitro efficacy has a more important role in immunocompromised individuals; however, the data from the present study do not support this hypothesis. While incision and drainage are likely to be important for resolution of deep S. aureus SSTI (3, 4), we found that use of active empirical therapy was significantly associated with improved odds of clinical resolution after incision and drainage were controlled for.
Our data suggest that TMP-SMX is an appropriate empirical oral antibiotic for the outpatient treatment of MRSA SSTI. FCH clinicians have tended to choose TMP-SMX for empirical therapy of MRSA SSTI because it is inexpensive, few isolates at FCH have shown in vitro resistance to it, and clinical response has been satisfactory.
The incidence of intolerance or adverse effects severe enough to discontinue TMP-SMX therapy was low, even though high doses were routinely prescribed (one or two double-strength tablets twice daily). Moreover, TMP-SMX resistance was uncommon, consistent with previous characterizations of community-acquired MRSA resistance patterns (2, 5, 10, 17-20, 24). The role for TMP-SMX in the treatment of MRSA infections has recently been reviewed in detail (6). Although data regarding antimicrobials for community-onset MRSA are limited (3, 6, 17, 19), Markowitz et al. found that TMP-SMX had clinical efficacy similar to that of vancomycin for treatment of nonendocarditis S. aureus infections, 47% of which were MRSA in their study (13). TMP-SMX may be an attractive option for outpatient treatment of MRSA SSTI due to its oral formulation and low cost (6, 8). Clinicians should bear in mind, however, that additional antibiotic coverage is necessary if infection with group A Streptococcus is suspected (17).
The high prevalence of clindamycin resistance in this study limits clindamycin's usefulness as empirical therapy for suspected MRSA SSTI at Fenway. Data regarding inducible clindamycin resistance in isolates that appeared sensitive to clindamycin would be useful, considering the high prevalence among MRSA isolates of erythromycin resistance (Table 2), which is associated with inducible clindamycin resistance (11). One limitation of this study is the absence of additional supporting laboratory data, such as pulsed field gel electrophoresis analysis to classify strains (16).
Furthermore, it is possible that the observed increase in clinical resolution of MRSA SSTI on empirical antibiotic therapy could be due to factors not directly related to antibiotic choice, such as changes in the virulence of MRSA strains, improved clinical management, earlier presentation or clinical recognition, or other factors not considered here. Although the mean duration of therapy was modestly increased among patients treated with empirical TMP-SMX, this difference was not statistically significant. Future investigations are needed to evaluate the relative importance of active oral antibiotic therapy and incision and drainage for community-onset MRSA SSTI. The relative efficacies of the oral antibiotics commonly used to treat MRSA SSTI should be compared in a prospective trial.
In summary, this study suggests that TMP-SMX represents an appropriate choice for outpatient empirical therapy of suspected S. aureus SSTI, especially when the prevalence of MRSA in the patient population is significant and resistance of local MRSA strains to clindamycin is common.
| ACKNOWLEDGMENTS |
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We gratefully acknowledge Chris Grasso for assistance with database queries and Alex Gonzalez for initial work on this project.
| FOOTNOTES |
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Published ahead of print on 20 November 2006. ![]()
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