Microbiologic evaluation of skin wounds: alarming trend toward antibiotic resistance in an inpatient dermatology service during a 10-year period

REPORTS

Microbiologic evaluation of skin wounds: Alarming trend toward antibiotic resistance in an inpatient dermatology service during a 10-year period Isabel C. Valencia, MD,a Robert S. Kirsner, MD,a,b and Francisco A. Kerdel, MDa Miami, Florida Background: Increasing resistance to commonly used antibiotics has been seen for patients with superficial skin wounds and leg ulcers. Objectives: We sought to evaluate bacterial isolates from leg ulcers and superficial wounds for resistance to commonly used antibiotics and to compare current data with previous data. Methods: We performed a chart review for patients admitted to a tertiary care dermatology inpatient unit from January to December 2001. Comparison was made with 2 previous surveys of the same inpatient service from 1992 and 1996. Results: Bacterial isolates were cultured from 148 patients, 84% (72 of 86) with leg ulcers and 38% (76 of 202) with superficial wounds. Staphylococcus aureus and Pseudomonas aeruginosa were the most common bacterial isolates in both groups. For patients with leg ulcers, S aureus grew in 67% of isolates (48/72) of which 75% (36/48) were methicillin-resistant (MRSA). Of leg ulcers, 35% (25/72) grew P aeruginosa, which was resistant to quinolones in 56% of cultures (14/25). For patients with superficial wounds, S aureus was isolated in 75% (57/76) and 44% were MRSA (25/57). P aeruginosa grew in 17% of isolates (13/76) and was resistant to quinolones in 18%. We found a marked increase in antibiotic resistance for both leg ulcers and superficial wounds. Over time, MRSA increased in leg ulcers from 26% in 1992 to 75% in 2001. For superficial wounds, MRSA increased from 7% in 1992 to 44% in 2001. P aeruginosa resistance to quinolones in leg ulcers increased from 19% in 1992 to 56% in 2001, whereas for superficial wounds there was no resistance in 1992 and 18% resistance in 2001. Conclusion: Rapid emergence of antibiotic-resistant bacteria continues and is a problem of increasing significance in dermatology. Common pathogenic bacteria, S aureus and P aeruginosa, showed increased resistance to commonly used antibiotics. Selection of antibiotics should be on the basis of local surveillance programs. (J Am Acad Dermatol 2004;50:845-9.)

T

he skin is populated by numerous low virulent micro-organisms, most of which do not, under normal conditions, cause infections.1 Staphylococcus aureus, a skin commensal organism at any one time in approximately 30% of the population, may be causal of infection. Penicillinase sta-

From the Department of Dermatology and Cutaneous Surgery, University of Miami, School of Medicinea; and Department of Epidemiology and Public Health and the Veterans Administration Medical Center, Miami.b Funding sources: None. Conflicts of interest: None identified. Accepted for publication November 12, 2003. Reprint requests: Francisco A. Kerdel, MD, 1400 NW 12th Ave, 6th S Derm, Miami, FL 33136. E-mail: [email protected]. doi:10.1016/j.jaad.2003.11.064

ble ␤-lactams, such as methicillin, cloxacillin, and flucloxacillin, have been the mainstay of treatment of S aureus infections for more than 35 years. Strains resistant to these drugs, referred to as methicillinresistant S aureus (MRSA), were first described in the United Kingdom in 1961.2 Emergence of MRSA organisms began in the 1980s when increased prevalence of MRSA was noted worldwide.3 Lowest rates of MRSA are observed in countries with strict infection control policies such as Scandinavia and the Netherlands, whereas highest rates are observed in Japan and Korea, where MRSA accounts for 70% of S aureus isolates.4 In the United States, increasing MRSA rates have been reported with a prevalence of 2.4% in 1975 to 29% in 1991. Interestingly, MRSA increased with hospital size, with higher rates in 845

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Table I. Origin of leg ulcers and superficial wounds, and number of patients with positive cultures Ulcer origin

Venous Diabetic Pyoderma gangrenosum Collagen vascular diseases Lymphedema Traumatic Arterial Vasculitis Not specified Total

Patients with (ⴙ) cultures

Superficial wounds

Patients with (ⴙ) cultures

29 11 8 5 4 4 1 1 9 72

Bullous diseases Dermatitis Psoriasis Drug reactions Cutaneous T-cell lymphoma Collagen vascular diseases Hidradenitis suppurativa Prurigo nodularis Other dermatoses Total

12 12 11 11 6 4 4 3 13 76

larger hospitals (14.9% if ⬍200 beds vs 38.3% if ⬎500 beds in 1991).5 In addition, resistance to vancomycin, the mainstay of MRSA treatment, has been recently reported.6 Similarly, resistance to another common pathogen, Pseudomonas aeruginosa, has emerged. Fluoroquinolones, for example ciprofloxacin, is frequently used in the community for the treatment of infected leg ulcers and other cutaneous infections.7 Quinolones are the only oral agents available to treat P aeruginosa. Our purpose was to evaluate the microbiologic profile of common bacteria in superficial wounds and leg ulcers treated at our inpatient dermatology unit. Evaluating trends from the same patient population over time, we were able to assess the extent of antibiotic resistance encountered in P aeruginosa and S aureus.

PATIENTS AND METHODS After institutional review board approval, a retrospective analysis of hospital charts was performed for patients who had undergone aerobic bacterial culture from superficial wounds and leg ulcers, admitted to the inpatient dermatology unit of University of Miami, Cedars Medical Center, Miami, Fla, from January 1 through December 31, 2001. Patients with leg ulcers were admitted for treatment of infection whereas patients with superficial wounds were admitted because of the extent of their primary disease (eg, widespread bullae in immunobullous disorders, Stevens-Johnson syndrome–like drug reactions, erythrodermic psoriasis) and were cultured when a superimposed infection was suggested. Positive aerobic bacterial isolates collected at the time of hospital admission were identified. Swab cultures were processed on blood MacConkey phenylethyl alcohol thyoglicolate agar. Standard antibiotic susceptibility testing was performed using an automated laboratory assay. Net susceptibility and resis-

tance profiles for commonly used antibiotics were logged for the 2 most common bacterial isolates: S aureus and P aeruginosa. Trends in antibiotic susceptibilities for these organisms were identified and compared with values obtained in 2 previous surveillance studies of the same patient base in 1992 and in 1995 to 1996.8,9 Although the severity of patient conditions may not be consistent over time, the criteria for admission has not changed over the years in our institution. Statistical analysis was performed using oneway analysis of variance and comparing the pairs with the Dunn method.

RESULTS During a 12-month period, 288 patients who were hospitalized had bacterial wound cultures performed and 144 grew at least one bacterial isolate. Of the 86 patients admitted for leg ulcers, 72 (84%) grew at least one bacterial isolate, whereas for superficial wounds, 76 of 202 patients (38%) had a positive culture. A total of 5 patients in the leg ulcer group and 3 patients in the superficial wounds group required more than one hospital admission during the study period for treatment of recurrent MRSA infection; however, only one culture from the first admission was included in the analysis. The origin of leg ulcers and superficial wounds, and the number of patients with positive cultures can be seen in Table I. For leg ulcers, venous ulcers accounted for the majority (40%), whereas the cause in the group of superficial wounds was more evenly distributed. More than one micro-organism was isolated in 57% (41/72) of cultures from leg ulcers and 41% (31/76) of positive cultures from superficial wounds. Both S aureus and P aeruginosa were isolated in 21% (15/72) of positive cultures from leg ulcers and 9% (7/76) of cultures from superficial wounds, and

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Table II. Bacterial isolates in leg ulcers and superficial wounds Bacterial isolate

Staphylococcus aureus Pseudomonas aeruginosa Corynebacterium species Proteus mirabilis Mixed gram-positive flora Coagulase-negative Staphylococcus Others

No. in leg ulcers

No. in superficial wounds

57 26 16 9 7 7 36

67 13 12 8 12 8 16

Enteric gram-negative bacteria such as Escherichia coli, Serratia marcescens, Stenotrophomonas maltophilia, Acinetobacter baumannii, and Enterobacter cloacae were more commonly isolated from leg ulcer wounds.

Fig 1. Antibiotic resistance for Staphylococcus aureus cultured from leg ulcers (light bar) and superficial wounds (solid bar). TMP⫹SMZ, Trimethoprim-sulfamethoxazole.

were the most common bacterial isolates for both. Culture composition is shown in Table II. MRSA in leg ulcers and superficial wounds S aureus was isolated in 48 of 72 cultures from leg ulcers and was MRSA in 36 (75%). Multidrug resistance was found for frequently prescribed agents (eg, cefazolin, ampicillin/sulbactam, clindamycin). For superficial wounds, S aureus grew in 57 of 76 cultures (75%). MRSA was detected in 25 (44%). All isolates were sensitive to vancomycin. Fig 1 depicts the antibiotic profiles for both groups. P aeruginosa resistant to quinolones in leg ulcers and superficial wounds P aeruginosa was isolated in 25 cultures from leg ulcers. Resistance to quinolones was detected in 14 isolates (56%). P aeruginosa was isolated in 13 cultures from superficial wounds, and quinolones resistance was detected in 2 of 11 tested (18%). Two isolates were not tested for quinolones. P aeruginosa was susceptible to most other antibiotics. Fig 2 depicts the antibiotic profiles. Comparison with previous analyses We compared our results to antibiotic resistance profiles using data collected in 2 previous time pe-

Fig 2. Antibiotic resistance for Pseudomonas aeruginosa cultured from leg ulcers (light bar) and superficial wounds (solid bar).

riods (1992 and May 1995-May 1996) for patients admitted to the same inpatient service. Data are depicted in Table III. MRSA was found in 26% and 50% of leg ulcers and in 7% and 24% of superficial wounds for 1992 and 1995 to 1996, respectively (P ⬍ .05 for change 1992-2001). Currently, MRSA increased to 75% in leg ulcers and 44% of superficial wounds. Similarly, in leg ulcers, P aeruginosa resistance to ciprofloxacin increased from 19% and 36% in the 2 previous studies to 56% from the current data (P ⬍ .05 for change 1992-2001), whereas for superficial wounds, ciprofloxacin resistance is at similar levels from 1995 to 1996.

DISCUSSION We found increasing antibiotic resistance for patients hospitalized for dermatologic conditions during a 10-year period. Specifically, we found marked increase in MRSA and quinolone-resistant P aeruginosa among infected leg ulcers. Resistance to methicillin has tripled in the last decade. Currently, 75% of isolates from leg ulcers are resistant to methicillin, compared with 50% and 26% found in 1995 to 19968 and 1992,9 respectively. Similarly, more than half (56%) of the P aeruginosa isolates from leg ulcers are resistant to quinolones, as compared with 19% in 1992 and 36% in 1995 to 1996.

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Table III. Comparison of current antibiotic resistance with those measured in 1992 and 1996 Leg ulcers Superficial wounds

MRSA Pseudominas aeruginosa resistant to quinolones MRSA P aeruginosa resistant to quinolones

1992

1996

2001

26%* 10%* 19%* 0%

50% 24% 36% 19%

75%* 44%* 56%* 18%

MRSA, Methicillin-resistant Staphylococcus aureus. *P ⬍ .05 for change 1992–1996 for MRSA from leg ulcers and superficial wounds and for P aeruginosa resistant to quinolones in leg ulcers.

We suspect at least some (if not all) of the antibiotic resistance in this patient population is nosocomial, rather than community-acquired secondary to evolving flora. Many patients admitted with infected leg ulcers are seen regularly in various local wound centers and a high prevalence of resistant strains has been reported in chronic wounds.10 High prevalence of antibiotic resistance in leg ulcers may also be a result of the chronicity of the wounds, the frequent antibiotic exposure, and the antibiotic prescribing habits of the community physicians referring patients to our tertiary center. Studying pathogenic organisms in diabetic foot ulcers, Dang et al11 reported the proportion of patients with MRSA (30.2%) doubled despite a concerted effort to change practices from prescribing blind broad-spectrum antibiotics. In addition, we found an increase in MRSA in superficial wounds (44% of all S aureus isolates) in patients not treated at wound centers, compared with 24% and 7% in previous years (1995 to 1996 and 1992, respectively).8,9 Quinolone resistance is also a concern and may have arisen from unwise prescribing practices. For example, ciprofloxacin and levofloxacin are broadspectrum fluoroquinolones frequently used as initial therapy for infected leg ulcers and other common skin bacterial infections. Once resistance occurs, treatment of P aeruginosa will require intravenous antibiotics as quinolones are currently the only oral agents presently available to treat pseudomonal infection. In 1984, virtually all P aeruginosa in the United States, Europe, and Japan was sensitive to even minimal doses (inhibited by ⬍1 ␮g/mL of ciprofloxacin) whereas today, in some institutions, 25% or more P aeruginosa infections are resistant to fluoroquinolones.12 The prevalence of MRSA infection suggests that empiric therapy with vancomycin may be reasonable for patients admitted with infected leg ulcers awaiting isolate sensitivities. Vancomycin, a glycopeptide antibiotic, continues to be the drug of choice for treating most MRSA infections caused by multidrug-resistant strains. Clindamycin, cotrimoxazole, fluoroquinolones, or minocycline may be

considered in some cases of nonlife-threatening infections; however, inefficacy and resistance to these compounds has frequently been reported. For example, fluoroquinolone-resistant MRSA is greater than 80% in some centers.12 For serious infections caused by strains susceptible to rifampin, adding this agent to vancomycin may improve outcomes. However, rifampin should not be the sole agent to treat MRSA infection, as S aureus strains easily develop resistance to this agent.13 The steady continual worldwide increase in the prevalence of multidrug-resistant pathogens highlights the need for new therapeutic options. Development of vaccines with various staphylococcal antigens and that of novel antimicrobial compounds is encouraging. Linezolid, an oxazolidinone derivative available in both intravenous and oral formulations,14 and Quinupristin/dalfopristin, the first injectable streptogramin antibiotic,15 are innovative treatments for multidrug-resistant gram-positive enterococci infections. However, despite the advantage of an oral delivery route, Linezolid use should be restricted, as resistance to this agent has already been reported twice; in a patient with dialysis-related peritonitis and in a patient with empyema. In the latter case, Linezolid resistance developed from a susceptible isolate during treatment.16 Other agents used in other countries to treat MRSA infections include daptomycin, a lipopeptide antibiotic,17 and teicoplanin,18 an antibiotic from the vancomycin family for which several clinical failures as a result of resistant mutants have been reported. Although agreement as to how to best control MRSA is not established, measures applicable to most care facilities can control the nosocomial transmission of MRSA. These include prospective laboratory-based surveillance programs, isolating patients with MRSA infection, use of barrier precautions such as gloves and gowns, handwashing and antisepsis, careful environmental cleaning in patient rooms, and reducing inappropriate use of broad-spectrum antibiotics. In addition, screening (culturing) patients for MRSA and then eradicating MRSA colonization in both asymptomatic health care workers

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and affected patients has also been shown to be useful in certain settings.19 Community-acquired MRSA strains differ from hospital-acquired strains in that they are more often generally susceptible to other antibiotics, share the presence of staphylococcal cassette chromosome mec type IV in their genomes, and frequently are virulent while predominantly causing skin and softtissue infections.20 However, interpretation of community-acquired trends is problematic as it is difficult to determine whether increasing MRSA in the community is occurring de novo or secondary to nosocomial spread (eg, increasing pool of patients or health care workers with MRSA moving from hospital, nursing home, or residence to the community).21 In summary, mechanisms to overcome bacterial resistance should range from instituting more effective infection control practices, decreasing nasal colonization, development of vaccines, and development of new or improved antimicrobial agents. Antibiotic control programs, which encourage appropriate use of antibiotics, can delay and, in many cases, prevent the emergence of resistance. REFERENCES 1. Espersen F. Resistance to antibiotics used in dermatological practice. Br J Dermatol 1998;139:4-8. 2. Jevons PM. ‘Celbenin’-resistant staphylococci. Br Med J 1961; 124-5. 3. Townsend DE, Ashdown N, Bolton N, Duckworth G, Moorhous EC, Grubb WB. The international spread of methicillin-resistant Staphylococus aureus. J Hosp Infect 1987;9:60-71. 4. Standing Medical Advisory Committee (Department of Health). The path of least resistance: main report. London: Department of Health, 1998. 5. Panlilio AL, Culver DH, Gaynes RP, Banerjee S, Henderson TS, Tolson JS, et al. Methicillin-resistant Staphylococcus aureus in US hospitals, 1975-1991. Infect Control Hosp Epidemiol 1992;13: 582-6.

6. Moellering RG Jr. The enterococci: a classic example of the impact of antimicrobial resistance on therapeutic options. J Antimicrob Chemother 1991;28:1-12. 7. Frieden TR, Mangi RJ. Inappropriate use of oral ciprofloxacin. JAMA 1990;264:1438-40. 8. Colsky AS, Kirsner RS, Kerdel FA. Analysis of antibiotic susceptibilities of skin wound flora in hospitalized dermatology patients. Arch Dermatol 1998;134:1006-9. 9. Teng P, Falanga V, Kerdel FA. The microbiological evaluation of leg ulcers/superficial wounds in patients requiring hospitalization. Wounds 1993;5:133-6. 10. Roghmann MC, Siddiqui A, Plaisance K, Standiford H. MRSA colonization and the risk of MRSA bacteraemia in hospitalized patients with chronic ulcers. J Hosp Infect 2001;47:98-103. 11. Dang CN, Prasad YDM, Boulton AJM, Jude EB. Methicillin-resistant Staphylococcus aureus in the diabetic foot clinic: a worsening problem. Diabet Med 2003;20:159-61. 12. Neu HC. The crisis in antibiotic resistance. Science 1992;257:1064-73. 13. Gang RK, Sanyal SC. Rifampin as an adjunct to vancomycin therapy in MRSA. Burns 1999;25:640-4. 14. Stevens DL, Herr D, Lampiris H, Hunt JL, Batts DH, Hafkin B, and the Linezolid MRSA study group. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis 2002;34:1481-90. 15. Pechere JC. Current and future management of infections due to methicillin-resistant staphylococci infections: the role of quinupristin/dalfopristin. J Antimicrob Chemother 1999;44: 11-8. 16. Wilson P, Andrews JA, Charlesworth R, Walesby R, Singer M, Farrell DJ, et al. Linezolid resistance in clinical isolates of Staphylococcus aureus. J Antimicrob Chemother 2003;51:186-8. 17. Snydman DR, Jacobus NV, McDermott LA, Lonks JR, Voyce JM. Comparative in vitro activities of daptomycin and vancomycin against resistant gram-positive pathogens. Antimicrob Agents Chemother 2000;44:3447-550. 18. Mainardi JL, Shlaes DM, Goering RV, Shlaes JH, Acar JF, Goldstein FW. Decreased teicoplanin susceptibility of methicillin-resistant strains of Staphylococcus aureus. J Infect Dis 1995;171:1646-50. 19. Boyce JM. MRSA patients: proven methods to treat colonization and infection. J Hosp Infect 2001;48:S9-14. 20. Said-Salim B, Mathema B, Kreiswirth BN. Community-acquired methicillin-resistant Staphylococcus aureus: an emerging pathogen. Infect Control Hosp Epidemiol 2003;24:451-5. 21. Cookson BD. Methicillin-resistant Staphylococcus aureus in the community: new battlefronts, or are the battles lost? Infect Control Hosp Epidemiol 2000;21:398-403.

CORRECTION Coors EA, von den Driesch P. Topical photodynamic therapy for patients with therapy-resistant lesions of cutaneous T-cell lymphoma. J Am Acad Dermatol 2004;50:363-7 (March). The legend for Fig 3 was published incorrectly. It should read: Fig 3. New lesion of a CD8⫹ T-cell lymphoma consisting of tiny red papules (a).