Mrsa Skin And Soft Tissue Infections

The American Journal of Surgery 194 (2007) 606 – 610

Presentation

Increasing incidence of methicillin-resistant Staphylococcus aureus skin and soft-tissue infections: reconsideration of empiric antimicrobial therapy Samir S. Awad, M.D.*, Saleem I. Elhabash, M.B.B.S., Liz Lee, M.D., Buckmister Farrow, M.D., David H. Berger, M.D. Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Michael E. DeBakey Veterans Affairs Hospital, MED VAMC, OCL (112), 2002 Holcombe Blvd, Houston, TX 77030, USA Manuscript received May 25, 2007; revised manuscript July 9, 2007 Presented at the 31st Annual Surgical Symposium of the Association of VA Surgeons, Little Rock, AR, May 10 –12, 2007

Abstract Background: Community-acquired methicillin-resistant Staphylococcus aureus (MRSA) rates are at an all time high. MRSA rates as high as 60% have been reported in patients presenting with skin and soft-tissue infections (SSTIs). Our objectives were to (1) examine the incidence of MRSA over a 7-year period in surgical patients with SSTIs, (2) examine the choice of empiric antibiotic therapy, and (3) evaluate the vancomycin minimum inhibitory concentration (MIC) in MRSA isolates. Methods: The medical records of all patients who underwent operative debridement of SSTIs from 2000 to 2006 were retrospectively reviewed. Demographic data such as age, race, and gender as well as co-morbid risk factors were collected. Preoperative American Society of Anesthesiologists (ASA) score, temperature, WBC, creatinine, HgbA1c, albumin, and empiric antimicrobial of choice were also included. Microbiology of all operative cultures was recorded. Available vancomycin MIC data were collected. All data are presented as mean ⫾ standard error of the mean. A chi-square test was used for statistical analysis. Results: From 2000 to 2006, 288 patients with operative debridement for SSTIs were identified. The mean age was 54 ⫾ 11 years. Fifty-two percent of patients had diabetes mellitus, 55% were tobacco users, 34% alcohol users, and 23% had hepatitis C. The mean temperature at presentation was 99.2° ⫾ 1.5°F. The mean white blood cell count was 13.8 ⫾ .9. The mean HgbA1c was 8.6 ⫾ 2.5. The mean body mass index was 30.1 ⫾ 8. Sixty-seven percent of patients had an ASA ⱖ 3. There was a significant increase in MRSA SSTIs in 2006 (77%) compared with 2000 (34%, P ⬍ .001). Correspondingly, there was a significant increase in empiric administration of vancomycin in 2006 (93%) compared with 2000 (18%, P ⬍ .001). The examination of vancomycin MIC shows a shift for MRSA isolates over this time period (MIC ⱕ ⫽ .5 ␮g/mL, 62%, MIC ⫽ 1 ␮g/mL, 7%, and MIC ⫽ 2 ␮g/mL, 31%). Conclusion: Our study shows a significant and ongoing increase in the incidence of MRSA in patients with SSTIs. Empiric coverage with an MRSA antimicrobial should be used as first-line therapy. However, given the observed increase in vancomycin MIC, alternative MRSA antimicrobials should be considered. © 2007 Published by Excerpta Medica Inc. Keywords: MRSA; Skin and soft-tissue infections; Minimum inhibitory concentration; Vancomycin

Methicillin-resistant Staphylococcus aureus (MRSA) infections are increasing at an alarming rate and in some regions of the United States have become epidemic. Since the first description of MRSA in 1961, the initial pathogens de* Corresponding author. Tel.: ⫹1-713-794-7765; fax: ⫹1-713-794-7352. E-mail address: [email protected] 0002-9610/07/$ – see front matter © 2007 Published by Excerpta Medica Inc. doi:10.1016/j.amjsurg.2007.07.016

scribed were associated with patients in the health care setting and considered to be hospital-acquired infections (HA-MRSA). These MRSA infections were thought to be related to previous antibiotic exposure, prolonged hospital stay, and patient comorbidities [1,2]. Data reported to the National Nosocomial Infection Surveillance System from 1995 to 2004 have shown a significant increase in the preva-

S.S. Awad et al. / The American Journal of Surgery 194 (2007) 606 – 610 Table 1 Demographic and comorbidity data Parameter

Percentage or Mean ⫾ SD

Age Male White Black Hispanic Smoking Diabetes mellitus Alcoholics Hepatitis C

54 ⫾ 11 93% 56% 35% 9% 55% 52% 34% 23%

SD ⫽ standard deviation.

lence of MRSA as a proportion of health care–acquired S aureus infections among intensive care unit patients, with 2004 rates approaching 65%. In the early 1990s, a different MRSA pathogen was identified from patients presenting from the community (CA-MRSA). Although initially thought to be associated with spread from the hospitals to the community, several studies have now revealed a number of genetic and epidemiological differences between HA-MRSA and CAMRSA [3]. CA-MRSA has been associated with a number of different syndromes affecting skin and soft tissues (furuncles, impetigo, and cellulitis), bloodstream (bacteremia, endocarditis, and line sepsis), lungs (pneumonia and empyema), bones and joints (osteomyelitis and septic arthritis), and urinary tract (pyelonephritis). Naimi et al [3] have shown that soft-tissue infections are the predominant site of CAMRSA and account for 74% of all CA-MRSA infections. In a prospective cohort study of MRSA infections in San Diego (1990 –2004), 65% of cases were CA-MRSA with skin and soft tissue (skin and soft-tissue infections [SSTIs]) as the major site of infection in 95% of cases [1]. In another study by Fagan et al [4], CA-MRSA was isolated from up to 86% of patients who presented with necrotizing SSTIs and necrotizing fasciitis. Current intravenous treatment for MRSA infection is typically vancomycin. Estimates are that, in 2001, approximately 1.8 million courses and 30 million doses of vancomycin were used in the United States [5]. Recently, vancomycin has been shown to be less effective with reports of increasing minimum inhibitory concentration (MIC) to vancomycin in MRSA isolates [6,7]. Given, the reported high prevalence of MRSA as a cause of SSTIs and the increasing reports of MIC, our objectives were to (1) examine the incidence of MRSA over a 7-year period in surgical patients with SSTIs, (2) examine choice of empiric antibiotic therapy, and (3) evaluate vancomycin MIC in MRSA isolates. Methods The medical records of consecutive patients undergoing operative debridement for complicated skin and soft tissue infections at the Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, were reviewed from 2000 to 2006. For each patient, the medical record was queried for information regarding demographic data such as age, race, and sex as well as comorbid conditions such as diabetes

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mellitus, hypertension, hepatitis C, coronary artery disease, chronic obstructive pulmonary disease, smoking, and alcohol use. In addition, vital signs on presentation to the hospital, body mass index (BMI), American Society of Anesthesiologists (ASA) score, and preoperative laboratory values including albumin, white blood cell count, electrolytes were also recorded. Aerobic and anaerobic microbiological cultures obtained from the initial operative debridement were tabulated. Culture sensitivities and vancomycin MIC (minimum inhibitory concentration) in cases of MRSA infection were identified. Descriptive statistics were used to summarize the characteristics of the patients and the prevalence of MRSA infection among patients with skin and soft-tissue infections. Statistical analysis was performed by using SPSS software (version 12; SPSS Inc, Chicago, IL). All data are presented as mean ⫾ standard deviation. Univariate analysis was performed by using a chi-square test. Multivariate analysis was performed to further explore factors associated with MRSA SSTIs. Results Patient characteristics From 2000 to 2006, 288 patients with SSTIs that required operative debridement were identified. The mean age was 54 ⫾ 11 years. White race was the most common (56%); 93% of patients were males, 55% of patients were smokers, 52% were diabetics with an HgA1C mean of 8.6 ⫾ 2.5, 34% alcohol users, and 23% were seropositive for hepatitis C (Table 1). The mean temperature on initial presentation was 99.2° ⫾ 1.5°F. The mean BMI was 30.1 ⫾ 8. Preoperative laboratory values showed a mean creatinine of 1.2 ⫾ .7, blood urea nitrogen of 16 ⫾ 12, blood glucose of 163 ⫾ 19, and white blood cell count 13.8 ⫾ 14.6. The American Society of Anesthesiologists score was greater than or equal to 3 in 67% percent of the patients, showing the acuity of this patient population (Table 2). Microbiology The most common microorganism retrieved from intraoperative cultures was S aureus, 70% of which were MRSA. Interestingly, Streptococcus species accounted only for 15% of the microbes isolated (Fig. 1). Sixty-seven perTable 2 Vital signs, laboratory values on presentation, and ASA Parameter

Percentage or Mean ⫾ SD

Temperature Body mass index WBC count HA1C for diabetics Creatinine Glucose Blood urea nitrogen ASA 1 2 ⱖ3

99.2 ⫾ 1.5 F 30.1 ⫾ 8 13.8 ⫾ 14.6 8.6 ⫾ 2.5 1.2 ⫾ 0.7 163 ⫾ 119 16 ⫾ 12

SD ⫽ standard deviation.

2% 31% 67%

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S.S. Awad et al. / The American Journal of Surgery 194 (2007) 606 – 610

Fig. 1. Type of bacteria recovered from operative debridement.

cent of the cultures showed monomicrobial etiology, and MRSA was also the predominant microorganism isolated from such cultures (68%). The frequency of MRSA isolation increased significantly during the study period (2000 ⫽ 34% and 2006 ⫽ 77%, P ⬍ .001; Fig. 2). Twenty-five percent of the patients in this study had received prior antibiotics by the emergency department or primary care physician as definitive therapy without incision and drainage for their skin and soft-tissue infection the week before admission. However, this did not correlate with the isolation of MRSA by uni or multivariate analysis. A review of MRSA antimicrobial susceptibility over the 7-year period showed a constant susceptibility rate to vancomycin at 100%, trimethoprim-sulfamethaxazole (98%), and tetracycline (78%); a significant decrease in susceptibility to quinolones (61%); and a fluctuating susceptibility to clindamycin with a significant decrease in 2003-2004 (63%). Of note, 15% and 4% of MRSA isolates were susceptible to erythromycin in 2000 and 2006, respectively, with a 17% average susceptibility (Fig. 3). Empiric antimicrobial therapy was adequate in 86% of patients, with vancomycin being the most commonly used antibiotic. Furthermore, the frequency of empiric administration of vancomycin increased significantly from 2000 (18%) to 2006 (93%) (Fig. 4). An examination of vancomycin MIC showed a shift for MRSA isolates over this time period, with 38% of the isolates having an MIC ⱖ1 (Table 3). Comments MRSA has emerged as the most common identifiable cause of SSTIs [8]. Our findings are consistent with the

Fig. 2. Incidence of MRSA isolated from patients presenting with an SSTI over 7 years.

Fig. 3. MRSA susceptibility to various antimicrobials.

dramatic trend of increasing reports of outbreaks and increased prevalence of MRSA in the last few years [1,2]. A number of differences have been shown between CAMRSA and HA-MRSA based on commonly associated infections, virulence factors, pulse-field gel electrophoresis and antimicrobial susceptibility pattern. CA-MRSA has been implicated more frequently in causing SSTIs, necrotizing fasciitis, and hemorrhagic necrotizing pneumonia, whereas HA-MRSA is associated with nosocomial pneumonia, catheter-related urinary tract infections, and bloodstream infections [9,10]. S aureus has the capacity to produce a wide array of virulence factors, some of which are responsible for specific clinical syndromes. The ability of new CA-MRSA strains to colonize hosts in the community and cause clinical syndromes is mediated by a unique combination of traditional and newly described virulence factors. A method used to classify MRSA strains is the staphylococcal chromosomal cassette (SCC). The SCC contains the genes that cause resistance; the mecA gene encodes for methicillin resistance. CA-MRSA most commonly carries the mecA gene on type 4 (SCC) in contrast with type 2 in HA-MRSA [11,12]. CA-MRSA is characterized by the production of different types of toxins; of special importance, the panton valentine leukocidin, a cytotoxin virulence factor that causes cell lysis of human leuckocytes, is associated with SSTIs and necrotizing pneumonia [3,13]. Antimicrobial susceptibility pattern can be used to classify MRSA strains. HA-MRSA isolates have been more resistant to antibiotics than CA-MRSA, likely because of a smaller SCC, which renders CA-MRSA less capable of carrying antimicrobial resistance genes [3]. Although we did not perform genetic analysis on our isolates, a review of the antimicrobial susceptibility from the years of 2000 to

Fig. 4. Vancomycin usage relative to MRSA isolated from SSTIs.

S.S. Awad et al. / The American Journal of Surgery 194 (2007) 606 – 610

2006 showed a pattern consistent with those reported for CA-MRSA with slight differences that may be explained by the geographic location (Fig. 5) [3,14]. Observation of the antimicrobial susceptibility over 7 years showed constant MRSA susceptibility to trimethoprim-sulfamethaxazole, fluctuation in the susceptibility to clindamycin, and a significant decrease in quinolones susceptibility. This emerging resistance can be attributed to the selective pressure in choosing these antibiotics when faced with SSTIs. The 17% erythromycin susceptibility among our MRSA isolates is higher than those recently reported [15]. This should be interpreted with caution because many CA-MRSA isolates appear resistant to erythromycin but sensitive to clindamycin. However, up to 80% of these isolates carry an inducible gene that also confers resistance to clindamycin. Simple laboratory testing using the erythromycin-clindamycin “Dzone” test can separate strains that have the genetic potential to become resistant during therapy from those that are fully susceptible to clindamycin [16,17]. Because our study and recently published reports emphasize the high impact of MRSA in SSTIs, special attention should be paid by physicians when faced with patients presenting with such infections. In areas with a high prevalence of CA-MRSA infection, empiric treatment with ßlactam agents may no longer be appropriate. For minor SSTIs that do not require debridement and excision in the operating room, incision and drainage alone may suffice, but this is not routinely practiced. Antibiotics in this setting should be reserved for patients with significant comorbidities or immunosuppression or patients who have recurrent infections. For severe SSTIs, especially for patients who show signs of systemic toxicity, surgical debridement is the key to achieving source control along with the administration of intravenous antimicrobials. Of the Food and Drug Administration (FDA)-approved antimicrobials for MRSA, vancomycin has been the most commonly used and is the one with which most clinicians are familiar. Our study over the 7-year period also showed a dramatic increase in the empiric administration of vancomycin that was probably attributable to the increasing awareness of MRSA in the cultures of SSTIs. The overuse of vancomycin has led to the first reports of MRSA strains with complete resistance to vancomycin (VRSA) in Japan, Britain, and the United States. Because of these isolated case reports of VRSA, the Centers for Disease Control has recommended the monitoring of MRSA MIC [18,19]. VRSA has a vancomycin MIC ⱖ32 ␮g/mL compared with the intermediate resistant isolates, which have an MIC of 4 to 8. Our experience confirms an increase in MIC for vancomycin over the last 7 years, which has also been reported by recently published studies [6,7]. Increasing the dose of vancomycin to 15 mg/kg per

Table 3 Vancomycin MIC MIC, 2006

(%)

MIC ⱕ0.5 ␮g/mL MIC ⫽ 1 ␮g/mL MIC ⫽ 2 ␮g/mL

62% 7% 31%

In 2003 100% of MRSA isolates from SSTI had an MIC ⱕ0.5 ␮g/mL.

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Fig. 5. MRSA susceptibility pattern for HA-MRSA and CA-MRSA.

dose has been advocated for isolates with increased MIC [20]. However, recent reports using this increased dosing strategy have shown up to a 76% treatment failure rate for MRSA infections with increased MIC [21]. Increased dosing of vancomycin may also be detrimental given the potential for nephrotoxicity and ototoxicity. Accordingly, vancomycin may be a suboptimal antimicrobial choice when faced with SSTIs. Newer antimicrobials alternatives have been recommended for the treatment of MRSA SSTIs. These include the FDAapproved agents linezolid, daptomycin, and tigecycline. Other agents under FDA review include dalbavancin. Linezolid is a novel oxazilidinone agent that binds to the 50S ribosomal subunit and has been shown to have activity against antibiotic resistant gram-positive organisms. In 1 study, linezolid has been shown to be superior to vancomycin in the treatment of MRSA SSTIs, with a 71% clinical cure rate compared with 55.1% for vancomycin in the modified intent to treat group [22]. Daptomycin is a cyclic lipopeptide antibiotic with a bactericidal activity against a broad range of gram-positive organisms including MRSA [23]. In a head-to-head comparison with vancomycin, daptomycin was shown to be noninferior in the treatment of SSTIs [24]. Furthermore, another study by Fowler et al [25] concluded that daptomycin is not inferior to vancomycin in the treatment of patients with MRSA bacteremia and reported the high failure rate in patients treated with vancomycin. Tigecycline belongs to the glycylcyclines group and is a chemically altered tetracycline with broader-spectrum activity and the ability to overcome most of the resistance mechanisms to tetracycline. Tigecycline was shown to be noninferior to vancomycin plus aztreonam in complicated SSTIs with comparable cure rates of 78.1% and 75.8%, respectively [9]. Dalbavancin is a semisynthitic glycopeptide analog with a similar mechanism of action to that of vancomycin; it shows a potent in vitro activity against MRSA and is still currently under review [26]. In conclusion, our study shows a significant and ongoing increase in the incidence of MRSA in patients with SSTI. Empiric coverage with an MRSA antimicrobial should be used as first-line therapy in patients with severe SSTIs who undergo operative debridement. However, given the observed increase in vancomycin MIC and the ineffectiveness of increasing vancomycin dosage, alternative MRSA antimicrobials should be considered.

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References [1] Crum NF, Lee RU, Thornton SA, et al. Fifteen year study of the changing epidemiology of methicillin-resistant Staphylococcus aureus. Am J Med 2006;119:943–51. [2] Public Health Dispatch: Outbreaks of Community-Associated Methicillin-Resistant Staphylococcus Aureus Skin Infections–Los Angeles County, California 2002–2003; Available at: www.cdc.gov. MMWR Weekly February 7, 2003/ 52(05);88. [3] Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003;290:2976 – 84. [4] Fagan SP, Berger DH, Rahwan K, et al. Spider bites presenting with methicillin-resistant Staphylococcus aureus soft tissue infection require early aggressive treatment. Surg Infect (Larchmt) 2004;5: 321–2. [5] Kirst HA, Thompson DG, Nicas TI. Usage of vancomycin (in kilograms) in the United States, France, Italy, Germany, United Kingdom, and the Netherlands. Antimicrob Agents Chemother 1998;42: 1303– 4. [6] Wang G, Hindler JF, Ward KW, Bruckner DA. Increased vancomycin MICs for Staphylococcus aureus clinical isolates from a university hospital during a 5-year period. J Clin Microbiol 2006;44:3883– 6. [7] Kralovic SM, Danco LH, Roselle GA. Laboratory reporting of Staphylococcus aureus with reduced susceptibility to vancomycin in United States Department of Veterans Affairs Facilities. Emerg Infect Dis 2002;8:402–7. [8] Rennie RP, Jones RN, Mutinick AH, et al. Occurrence and antimicrobial susceptibility patterns of pathogen isolated from skin and soft tissue infections: report from the SENTRY antimicrobial surveillance program (United States and Canada, 2000). Diagn Microbial Infect Dis 2003;45:287–93. [9] Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The efficacy and safety of tigacycline in the treatment of skin and skin-structure infections: results of 2 double blind phase 3. Clin Infect Dis 2005; 41(suppl 5):S341–53. [10] Weber JT. Community-associated methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2005;41(suppl):S269 –72. [11] Kazakova SV, Hageman JC, Matava M, et al. A clone of methicillinresistant Staphylococcus aureus among professional football players. N Engl J Med 2005;352:468 –75. [12] Ito T, Katayama Y, Asada K. Structural comparison of three types of staphylococcal cassette chromosome mec integrated in the chromosome in methicillin-resistant Staphylococcus aureus in Australia. Antimicrob Agents Chemother 2001;45:1323–36.

[13] King MD, Humphrey BJ, Wang YF. Emergence of community acquired methicillin-resistant staphylococcus aureus USA 300 Clone as the prdominant cause of skin and soft-tissue infections. Ann Intern Med 2006;144:309 –17. [14] Ruhe JJ, Smith N, Bradsher RW, Menon A. Staphylococcl aureus skin and soft-tissue infections: impact of antimicrobial therapy on outcome. Clin Infect Dis 2007;44:777– 84. [15] Frazee BW, Lynn J, Charlebois ED, et al. High prevalence of methicillin-resistant in emergency department skin and soft tissue infection. Ann Emerg Med 2005;45:311–20. [16] Fiebelkorn KR, Crawford SA, McElmeel ML, et al. Practical disk diffusion method for detection of inducible clindamycin resistance in Staphylococcus aureus and coagulase-negative staphylococci. J Clin Microbiol 2003;41:4740 – 4. [17] Rybak MJ, LaPlante KL. Community-acquired methicillin-resistant Staphylococcus aureus: a review. Pharmacotherapy 2005;25:74 – 85. [18] CDC. Staphylococcus aureus resistant to vancomycin. Available at: www.cdc.gov. MMRW Weekly July 5, 2002/ 51;565–7. [19] CDC. Reduced susceptibility of Staphylococcus aureus to vancomycin– Japan, 1996. MMWR Morb Mortal Wkly Rep 1997;46:624 – 4. [20] Hidayat LK, Hsu DI, Quist R, et al. High-dose vancomycin for methicillin-resistant Staphylococcus aureus infections. Arch Intern Med 2006;166:2138 – 44. [21] Howden BP, Ward PB, Charles PGP, et al. Treatment outcomes for serious infections caused by methicillin-resistant Staphylococcus aureus with reduced vancomycin susceptibility. Clin Infect Dis 2004; 38:521– 8. [22] Weigelt J, Itani K, Stevens D, Linezolid versus vancomycin in treatment of complicated skin and soft tissue infection. Antimicrob Agents Chemother 2004;188:760 – 6. [23] Martone WJ, Lamp KC. Efficacy of daptomycin in complicated skin and skin-structure infections due to methicillin-sensitive and -resistant Staphylooccus aureus: results from the core registry. Cur Med Res Opin 2006;22:2337– 43. [24] Arbeit RD, Maki D, Tally FP, et al. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis 2004;38:1673– 81. [25] Fowler VG, Boucher HW, Corey R, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006;355:653– 65. [26] Drew RH. Emerging options for treatment of invasive, multidrugresistant Staphylococcus aureus infections. Pharmacotherapy 2007; 27:227– 49.