Antimicrobial resistance in clinical isolates of Staphylococcus aureus from hospital and community sources in southern Jamaica

International Journal of Infectious Diseases (2007) 11, 220—225

http://intl.elsevierhealth.com/journals/ijid

Antimicrobial resistance in clinical isolates of Staphylococcus aureus from hospital and community sources in southern Jamaica Paul D. Brown a,*, Charles Ngeno b a b

Department of Basic Medical Sciences (Biochemistry Section), University of the West Indies, Mona, Jamaica Department of Microbiology, Royal Sussex County Hospital, Eastern Road, Brighton, BN2 5BE, UK

Received 18 August 2005; received in revised form 24 March 2006; accepted 9 April 2006 Corresponding Editor: J. Peter Donnelly, Nijmegen, The Netherlands

KEYWORDS Staphylococcus aureus; Antimicrobial; Methicillin resistance; MRSA; MSSA

Summary Objectives: In this study, we assessed the antimicrobial susceptibility patterns and prevalence of methicillin resistance among Staphylococcus aureus isolates from hospital and community sources in southern Jamaica. Methods: Eighty isolates of S. aureus obtained from hospital and community-based patients with staphylococcal infections were collected, and antimicrobial susceptibilities were determined by disk diffusion. Results: While all specimens yielded isolates, multidrug-resistant isolates were obtained only from urine, high vaginal swab, abscess aspirate, and catheter tip samples. The overall prevalence of methicillin-resistant S. aureus (MRSA) was 23%. The proportions of MRSA isolated from hospital sources (18/39) and community sources were 46% and 0%, respectively ( p < 0.05). The pattern of antibiotic susceptibility of S. aureus differed significantly between MRSA and methicillin-susceptible (MSSA) isolates. For MRSA isolates, multiple-drug resistance was common and only few antibiotics were active against these isolates. However, no MRSA was resistant to vancomycin. Except for penicillin and to some extent co-trimoxazole (trimethoprim—sulfamethoxazole), most MSSA isolates were susceptible to nearly all antimicrobial agents used in this study. Conclusions: This is the first report of MRSA from this region of Jamaica. Because methicillin resistance is associated with multiple-drug resistance in S. aureus, it is imperative that surveillance initiatives be focused on both the hospital and community in order to monitor and limit the spread of this organism. # 2006 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Introduction * Corresponding author. Tel.: +1 876 927 2290; fax: +1 876 977 7852. E-mail address: [email protected] (P.D. Brown).

Staphylococcus aureus is among the most important nosocomial pathogens because of both the diversity and the severity

1201-9712/$32.00 # 2006 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2006.04.005

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Antimicrobial resistance of Staphylococcus aureus from hospital and community sources in southern Jamaica of the infections it causes, including superficial, deep skin, and soft-tissue infections, endocarditis, and bacteremia, as well as a variety of toxin-mediated diseases such as gastroenteritis, staphylococcal scalded-skin syndrome, and toxic shock syndrome.1,2 Methicillin (oxacillin)-resistant S. aureus (MRSA) was first described in 1961,3 and since then has become a significant pathogen in nosocomial infections.4 Community-acquired MRSA is now increasingly recognized5 with many of these infections occurring in patients with no prior hospital exposure. These community-based infections have been reported in patients from both rural and urban settings.6—8 For clinicians, the spread of these methicillin-resistant strains has been critical as the therapeutic outcome of infections that result from MRSA is worse that those from methicillin-sensitive strains (MSSA).9 Consequently, knowledge of community and nosocomial antimicrobial susceptibility profiles of S. aureus would prevent abuse of glycopeptides. In Jamaica, health services are delivered through four semi-autonomous regional health authorities that have direct management responsibility within a geographically defined region.10 Antibiotic treatment recommended locally for urinary tract infections include the penicillins (penicillin, ampicillin, amoxicillin, and oxacillin) and trimethoprim— sulfamethoxazole (co-trimoxazole) as primary therapy, followed by the first and second generation cephalosporins, and the quinolones. In other infections, tetracycline, cefaclor, clindamycin, and trimethoprim—sulfamethoxazole are the first drugs of choice, followed by erythromycin, gentamicin, and ciprofloxacin. S. aureus shows acquired resistance to many structurally unrelated antibiotics and as rapidly as new antibiotics are introduced, S. aureus have developed resistance mechanisms.11,12 Because of these facts, it is important to isolate and identify the offending strain in order for appropriate antibiotic therapy to be initiated. The aim of this study was to assess the antimicrobial susceptibility patterns and prevalence of methicillin resistance among Staphylococcus aureus isolates from hospital and community sources in southern Jamaica.

Mueller—Hinton broth or agar (BD Biosciences, Cockeysville, MD, USA). Isolates were identified as Staphylococcus aureus based on conventional bacteriological tests, which included Gram staining, catalase test, tube coagulase test using rabbit plasma (Difco Laboratories, USA), and the Pastorex Staphplus latex agglutination test (Bio-Rad, CA, USA), including appropriate controls according to the manufacturer’s instructions.

Antibiotic susceptibility testing Susceptibility to clindamycin, gentamicin, penicillin, oxacillin, erythromycin, ciprofloxacin, trimethoprim—sulfamethoxazole, tetracycline, vancomycin, chloramphenicol, and nitrofurantoin was determined by the standard disc diffusion technique in accordance with the guidelines of the National Committee for Clinical Laboratory Standards.14 Cartridges of antimicrobial-containing discs were obtained from Oxoid, Mast Diagnostics (Merseyside, UK), BD Biosciences, or Janssen—Cilag (Puebla, Mexico), stored between 4 and 20 8C, and allowed to come to room temperature prior to use. Mueller—Hinton plates were incubated at 35 8C for 16—18 h after inoculation with organisms and placement of discs, and zones of inhibition were measured. Plates with oxacillin and vancomycin were incubated for 24 h. S. aureus ATCC 25923 and 29213 were used as reference strains.

Statistical analysis Statistical analysis was performed using the x2 test. Differences were considered significant at p  0.05.

Table 1 Distribution of positive specimens among hospital and community sources Specimen

Hospital samples n

Materials and methods Clinical specimens and isolations Non-duplicate hospital and community specimens of high vaginal swabs, blood, urine, aspirates, sputum, wound and abscess swabs, cerebrospinal fluid, and semen submitted by patients being investigated for staphylococcal infections between May and August 2002 were analyzed in this study. The clinical specimens were brought without delay to the laboratory and were processed according to standard techniques.13 Hospital specimens were from in-patients at the Mandeville Regional Hospital, Manchester, which serves the parishes of Manchester, Clarendon, and St. Elizabeth. Community specimens were from persons seen at private primary care centers in Manchester and specimens referred to the laboratory. During history-taking at these primary care centers, patients were assessed as to whether they had previously been hospitalized for a medical condition. Unless otherwise noted, bacteria were grown at 37 8C in Luria—Bertani medium (Oxoid, Hampshire, UK) or in

Urine High vaginal swabs Urethral swabs Eye swabs Wound swabs Vaginal swabs Skin swabs Peritoneal aspirates Knee aspirates Semen Wound abscess Abdominal abscess Cervical abscess Blood CSF Catheter tip Catheter urine Sputum Total CSF, cerebrospinal fluid.

9 4 2 0 1 0 1 1 1 0 3 3 1 4 1 3 2 3 39

Community samples %

n

%

23.1 10.3 5.1 0 2.6 0 2.6 2.6 2.6 0 7.7 7.7 2.6 10.3 2.6 7.7 5.1 7.7

14 8 3 1 6 2 0 0 0 3 3 0 0 1 0 0 0 0

34.1 19.5 7.3 2.4 14.6 4.9 0 0 0 7.3 7.3 0 0 2.4 0 0 0 0

41

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P.D. Brown, C. Ngeno

Table 2

Number and percentages of Staphylococcus aureus isolates resistant to antimicrobial agents by NCCLS diffusion method

Antibiotic

All isolates (n = 80)

Isolates from hospital sources (n = 39)

Isolates from community sources (n = 41)

Aminoglycosides Clindamycin Gentamicin

6 (7.5%) 11 (13.8%)

4 (10.3%) 4 (10.3%)

2 (4.9%) a 7 (17.1%) a

Antifolates Trimethoprim—sulfamethoxazole

18 (22.5%)

10 (25.6%)

8 (19.5%)

b-lactams Oxacillin Penicillin G

18 (22.5%) 48 (60%)

18 (46.2%) 32 (82.1%)

7 (8.8%)

7 (17.9%)

0a

Glycopeptides Vancomycin

0

0

0

Quinolones Ciprofloxacin

9 (11.3%)

5 (12.8%)

4 (9.8%)

Tetracyclines Tetracycline

11 (13.8%)

8 (20.5%)

3 (7.3%) a

8 (10%) 3 (3.8%)

5 (12.8%) 3 (7.7%)

3 (7.3%) a 0a

Erythromycin

Other antibiotics Chloramphenicol Nitrofurantoin a

0a 16 (39%) a

p < 0.05 compared to isolates from hospital sources.

isolates were resistant to at least one antibiotic, and eight isolates (10%) were resistant to four or more antibiotics. Forty-eight (60%) isolates were resistant to penicillin G, 18 (22.5%) each to trimethoprim—sulfamethoxazole and oxacillin, and 11 (13.8%) to tetracycline (Table 2). More isolates from hospital sources were resistant to the antimicrobials tested (with the exception of gentamicin). In the majority of cases, these differences were significant ( p < 0.05). Of interest was that 82% of hospital isolates were resistant to penicillin, compared to 39% of community isolates. Further, all isolates resistant to oxacillin and nitrofurantoin were from hospital sources. While it was possible for the patients seen

Results Eighty isolates of Staphylococcus aureus were recovered from the specimens, most of which were from urine (n = 23), high vaginal swabs (n = 12) and abscesses (n = 10). Forty-one isolates (51%) were from community samples (Table 1). All positive isolates gave positive reactions in mannitol salt fermentation, in catalase and tube coagulase and latex agglutination tests. Sixteen isolates demonstrated beta hemolysis on horse blood agar while four were variable. All isolates were susceptible to vancomycin and only three were resistant to nitrofurantoin. Overall, 62 (77.5%) of the Table 3

Antibiotic resistance profiles for multi-resistant S. aureus isolates

Antibiotic

Clindamycin Gentamicin Trimethoprim— sulfamethoxazole Oxacillin Penicillin Erythromycin Vancomycin Ciprofloxacin Tetracycline Chloramphenicol Nitrofurantoin

Isolate (source) #9 (Urine)

#12 (Urine)

#14 (Urine)

#24 (HVS)

#44 (Wound swab)

#57 (Wound abscess)

#64 (Abdominal aspirate)

#73 (Catheter tip)

S R S

R R R

R R S

S R S

R S R

S R S

S R R

R R R

R R S S R R R R

R R R S R R R R

S R R S S R R S

R R R S R R R S

R R S S R R R S

R R R S R R S S

R R S S R S R S

R R R S R R R R

HVS, high vaginal swab; R, resistant; S, susceptible.

Antimicrobial resistance of Staphylococcus aureus from hospital and community sources in southern Jamaica

223

Table 4 Comparison of frequency and percentage rates of resistance to non-b-lactam antibiotics between methicillin-resistant (MRSA) and methicillin-sensitive S. aureus (MSSA) isolates Non-b-lactam antibiotics

All isolates (n = 80)

MRSA (n = 18)

MSSA (n = 62)

Clindamycin Gentamicin Trimethoprim—sulfamethoxazole Erythromycin Vancomycin Ciprofloxacin Tetracycline Chloramphenicol Nitrofurantoin

6 11 18 7 0 9 11 8 3

4 6 6 4 0 3 6 5 3

2 (3.2%) a 5 (8.1%) a 12 (19.4%) a 3 (4.8%) a 0 6 (9.7%) 5 (8.1%) a 3 (4.8%) a 0a

a

(7.5%) (13.8%) (22.5%) (8.8%) (11.3%) (13.8%) (10%) (3.8%)

(22.2%) (33.3%) (33.3%) (22.2%) (16.7%) (33.3%) (27.8%) (16.7%)

p < 0.05 compared to MRSA isolates.

at private primary care centers to have had some contact with a hospital, there was no indication of previous hospitalization. The eight multi-resistant isolates were recovered from urine, high vaginal swab, wound swab, wound abscess, abdominal abscess, and catheter tip (Table 3). All of these isolates were resistant to penicillin, and most (87.5%) were resistant to gentamicin, oxacillin, ciprofloxacin, tetracycline, and chloramphenicol. However, all multiple-resistant isolates that were susceptible to oxacillin were also susceptible to trimethoprim—sulfamethoxazole, ciprofloxacin, nitrofurantoin, and vancomycin. Table 4 shows a comparison of the susceptibilities of MRSA and MSSA to the non-b-lactam antimicrobial agents used in this study. We found that a significantly greater proportion of the MRSA isolates (compared to the MSSA isolates) were resistant to these antimicrobials. In particular, those isolates resistant to nitrofurantoin were MRSA. Of note was that twice as many MSSA isolates were resistant to trimethoprim—sulfamethoxazole and ciprofloxacin, and almost equal numbers of MSSA and MRSA isolates were resistant to gentamicin, erythromycin and tetracycline. All MRSA isolates were susceptible to vancomycin. Among antimicrobials used in this study, penicillin showed the least anti-staphylococcal activity and almost half of the MSSA isolates were resistant to penicillin.

Discussion Because of the widespread use of antibiotics, especially in developing countries, the resistance profile of microorganisms is changing, evidenced by increasing occurrences of antibiotic resistance among bacterial populations.15—17 Additionally, resistance rates are typically higher in developing countries (with rates up to 99%)18—20 as compared to developed countries (where rates are less than 20%).21,22 Consequently, it is imperative that local surveillance of common pathogenic organisms and their antibiograms be implemented to advise the current use of antibiotics. This is essential to the formulation of prescribing policies based on local statistics. This study provides important data on current antimicrobial resistance, including methicillin resistance, for a collection of recent clinical isolates of S. aureus from hospital and community sources in southern Jamaica. We found a 23% prevalence rate of methicillin (oxacillin) resistance. This compares with prevalence rates of 43% observed in a study

from the USA,23 30% in European countries,24 and up to 54% in Japan.25 Further, we noted that 82% of the isolates from hospital sources were resistant to penicillin. This is almost identical to a previous study26 at the University Hospital of the West Indies (UHWI), a 500-bed multi-disciplinary teaching hospital, which serves the metropolitan area of Kingston and St. Andrew. This facility is situated about 124 km from Mandeville, where our study was conducted. By contrast with that study, which recorded a similar level of penicillin resistance in isolates from outpatients, we found a 39% prevalence in our isolates from community sources. This difference could be due in part to the increased antimicrobial resistance associated with teaching hospitals, possibly due to increased selective pressure arising from widespread antimicrobial use, as well as high density patient population in contact with healthcare staff and the attendant risk of cross infection.27,28 To further elaborate the distinction between the isolates, the majority (72%) of resistant isolates in our study were from hospital patients, suggesting a pattern of antibiotic exposure among patients in hospitals. A significant number of S. aureus isolates were recovered from high vaginal swabs and urine in this study. High vaginal swab isolates are usually associated with puerperal sepsis or neglected foreign bodies, and less frequently with bacterial vaginosis, and significant numbers of MRSA organisms have been found among these isolates.29—32 While it is likely that many S. aureus organisms might be passive colonizers or due to contamination from the skin, some are associated with complications of pregnancy.31 Although S. aureus is a rare cause of urinary tract infections, accounting for only 0.5% to 6% of all positive urine cultures,33,34 their finding is increasingly being recognized as significant, especially in patients with urinary tract catheterization, as under-treatment or delayed treatment could lead to development of staphylococcal bacteremia.33,35,36 The pattern of antibiotic susceptibility of S. aureus differed significantly between MSSA and MRSA isolates. Except for penicillin and to some extent co-trimoxazole, most MSSA isolates were susceptible to nearly all antimicrobial agents used in this study. In contrast, in the case of MRSA, multipledrug resistance was common and only few antibiotics were active against these isolates. Chloramphenicol did not show good activity against MRSA isolates, which is in concert with the disappointing results of clinical trials that used chloramphenicol for treatment of MRSA infections.37 Clindamycin

224 was active against most MSSA and MRSA isolates (97% and 78%, respectively). There is debate on the efficacy of clindamycin as an alternative agent for treatment of infections caused by S. aureus, due to problems with toxicity and reports of emergence of resistance during therapy.38 There are few clinical reports on the use of ciprofloxacin for treatment of infections caused by MRSA.39 In this study, we found 17% and 10% of the MRSA and MSSA isolates, respectively, were resistant to ciprofloxacin. This is of concern because this broad-spectrum antibiotic has only recently entered clinical use. Co-trimoxazole, like ciprofloxacin, was not as active as expected against MSSA isolates. The rate of resistance among MRSA isolates to co-trimoxazole was high (33%) compared to 20% for MSSA isolates. However, it is one of the few antibiotics with clinically documented efficacy for treatment of infections caused by susceptible MRSA isolates.40 This is the first report of MRSA in this region in Jamaica. Because methicillin resistance is associated with multi-drug resistance in S. aureus, it is likely that consistent use of oxacillin as the first-line drug could be the reason for the high prevalence of MRSA isolates among hospital patients in southern Jamaica. Against this background, methicillin resistance might be useful as an index for the selection of appropriate antimicrobial agents for the treatment of infections caused by S. aureus due to the difference in drug resistance patterns of hospital vs. community MRSA organisms. While no MRSA isolate was obtained from community sources in this study, it is imperative that surveillance initiatives be focused on both the hospital and community in order to monitor and limit the spread of this organism. Conflict of interest: No conflict of interest to declare.

References 1. Lowy FD. Staphylococcus aureus infections. N Engl J Med 1998;339:520—32. 2. Waldvogel FA. Staphylococcus aureus (including toxic shock syndrome). In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases. 4th ed. New York: Churchill Livingstone; 1995. p. 754—77. 3. Jevons MP. ‘Celbenin’-resistant staphylococci. Br Med J 1961;1:124—5. 4. Hartman BJ, Tomasz A. Expression of methicillin resistance in heterogeneous strains of Staphylococcus aureus. Antimicrob Agents Chemother 1986;29:85—92. 5. Chambers HF. The changing epidemiology of Staphylococcus aureus? Emerg Infect Dis 2001;7:178—82. 6. Groom AV, Wolsey DH, Naimi TS, Smith K, Johnson S, Boxrud D, et al. Community-acquired methicillin-resistant Staphylococcus aureus in a rural American Indian community. JAMA 2001; 286:1201—5. 7. Herold BC, Immergluck LC, Maranan MC, Lauderdale DS, Gaskin RE, Boyle-Vavra S, et al. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA 1998;279:593—8. 8. Moreno F, Crisp C, Jorgensen JH, Patterson JE. Methicillin-resistant Staphylococcus aureus as a community organism. Clin Infect Dis 1995;21:1308—12. 9. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003;36:53—9.

P.D. Brown, C. Ngeno 10. Brown PD, Izundu A. Antibiotic resistance in clinical isolates of Pseudomonas aeruginosa in Jamaica. Rev Panam Salud Publica 2004;16:125—30. 11. Lowy FD. Antimicrobial resistance: the example of Staphylococcus aureus. J Clin Invest 2003;111:1265—73. 12. Lyon BR, Skurray R. Antimicrobial resistance of Staphylococcus aureus: genetic basis. Microbiol Rev 1987;51:88—134. 13. Cheesbrough M. Medical laboratory manual for tropical coun.tries, Volume II. Doddington, UK: Tropical Health Technology; 1984 14. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disc susceptibility testing. Document M100-S9. National Committee for Clinical Laboratory Standards, Wayne, PA, USA; 2002. 15. Ako-Nai AK, Lamikanra AB, Onipede AO. Incidence of pathogenic microorganisms in clinical specimens from hospitals in southwestern Nigeria. East Afr Med J 1995;72:436—41. 16. Farrar WE. Antibiotic resistance in developing countries. J Infect Dis 1994;152:1103—6. 17. O’Brien TF. Resistance to antibiotics at medical centers in different parts of the world. J Antimicrob Chemother 1986; 18(Suppl C):919—26. 18. Lamikanra A, Ndap RB. Trimethoprim resistance in urinary tract pathogens in two Nigerian hospitals. J Antimicrob Chemother 1989;3:151—4. 19. Orrett FA, Shurland SM. Production of b-lactamase in Trinidad: an association with multiple resistance to b-lactam antibiotics. Med Sci Res 1996;24:519—22. 20. Young HK, Jesudason MV, Koshi G, Anges SGB. Trimethoprim resistance amongst urinary pathogens in South India. J Antimicrob Chemother 1986;17:615—21. 21. Lacey RW. Multi-resistant Staphylococcus aureus: a suitable cause for inactivity. J Hosp Infect 1987;9:103—5. 22. Thompson KS, Sanders WE, Sanders CL. USA resistance patterns among UTI pathogens. J Antimicrob Chemother 1994;33:9—15. 23. Kuehnert MJ, Hill HA, Kupronis BA, Tokars JI, Solomon SL, Jernigan DB. Methicillin-resistant-Staphylococcus aureus hospitalizations, United States. Emerg Infect Dis 2005;11:868—72. 24. Voss A, Doebbeling BN. The worldwide prevalence of methicillinresistant Staphylococcus aureus. Int J Antimicrob Agents 1995;5:101—6. 25. Lotsu DK, Imamura T, Takamine F. Current status of antimicrobial susceptibility in MRSA isolates typed by coagulase and phage typing in Okinawa. Acta Med Okayama 1995;49:81—9. 26. Bodonaik NC, King SD, Narla VR. Antimicrobial resistance in clinical isolates of Staphylococcus aureus at the University Hospital of the West Indies. West Indian Med J 1984;33:8—13. 27. Gold HS, Moellering Jr RC. Antimicrobial-drug resistance. N Engl J Med 1996;335:1445—53. 28. Mulligan ME, Murray-Leisure KA, Ribner BS, Standiford HC, John JF, Korvick JA, et al. Methicillin-resistant Staphylococcus aureus: a consensus review of the microbiology, pathogenesis, and epidemiology with implications for prevention and management. Am J Med 1993;94:313—28. 29. Anupurba S, Sen MR, Nath G, Sharma BM, Gulati AK, Mohapatra TM. Prevalence of methicillin resistant Staphylococcus aureus in a tertiary referral hospital in eastern Uttar Pradesh. Indian J Med Microbiol 2003;21:49—51. 30. Balaka B, Agbere AD, Baeta S, Kessie K, Assimadi K. Bacterial flora in the genital tract the last trimester of pregnancy. J Gynecol Obstet Biol Reprod (Paris) 2003;32:555—61. 31. Balaka B, Agbere A, Dagnra A, Baeta S, Kessie K, Assimadi K. Genital bacterial carriage during the last trimester of pregnancy and early-onset neonatal sepsis. Arch Pediatr 2005;12:514—9. 32. Dykhuizen RS, Harvey G, Gould IM. The high vaginal swab in general practice: clinical correlates of possible pathogens. Fam Pract 1995;12:155—8. 33. Muder RR, Brennen C, Rihs JD, Wagener MM, Obman A, Stout JE, Yu VL. Isolation of Staphylococcus aureus from the urinary tract:

Antimicrobial resistance of Staphylococcus aureus from hospital and community sources in southern Jamaica association of isolation with symptomatic urinary tract infection and subsequent staphylococcal bacteremia. Clin Infect Dis 2006;42:46—50. 34. Sheth S, DiNubile MJ. Clinical significance of Staphylococcus aureus bacteriuria without concurrent bacteremia. Clin Infect Dis 1997;24:1268—9. 35. Jensen AG, Wachmann CH, Espersen F, Scheibel J, Skinhoj P, Frimodt-Moller N. Treatment and outcome of Staphylococcus aureus bacteremia: a prospective study of 278 cases. Arch Intern Med 2002;162:25—32. 36. Weems Jr JJ. The many faces of Staphylococcus aureus infection. Recognizing and managing its life-threatening manifestations. Postgrad Med 2001;110:24—36.

225

37. Brumfitt W, Miller H. Methicillin-resistant: Staphylococcus aureus. N Engl J Med 1989;320:1188—96. 38. Massanari RM, Pfaller MA, Wakefield DS. Implication of acquired oxacillin resistance in the management and control of Staphylococcus aureus infections. J Infect Dis 1988; 158:702—9. 39. Maple PAC, Hamilton GMT, Brumfitt W. World-wide antibiotic resistance in methicillin-resistant, Staphylococcus aureus. Lancet 1989;1:537—40. 40. Markowitz N, Quinn EL, Saravolatz LD. Trimethoprim—sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection. Ann Intern Med 1992;117: 390—8.