Community case of methicillin-resistant Staphylococcus aureus infection.

To the Editor: Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) is an emerging infectious disease worldwide and is increasingly reported in Asia (1). We describe a community case of invasive MRSA infection, which appeared as bacteremia and pneumonia; CA-MRSA was initially suspected, and eventually the patient was treated successfully with ampicillin/sulbactam.

A 52-year-old man with chronic eczema was admitted to the Prince of Wales Hospital, Hong Kong, with fever and chills. Before admission, he had been treated for infected eczematous lesions for several weeks with oral ampicillin, cloxacillin, and cefazolin. He had no history of hospitalization in the past 10 years, and none of his family members were healthcare workers. Examination showed an oral temperature of 40[degrees]C, blood pressure 95/55 mm Hg, and no audible murmur. Cellulitis in the left leg complicated his eczematous skin lesions. Chest radiograph showed right-middle-zone pneumonia. Neutrophilia (leukocytes 15.5 x [10.sup.9]/L, neutrophils 86%), thrombocytopenia (platelets 55 x [10.sup.9]/L), prolonged activated partial thromboplastin time (43.6 s), and elevated bilirubin level (31 [micro]mol/L) were observed. Two initial blood cultures grew gram-positive cocci in clusters, identified as S. aureus by positive results for catalase and slide/tube coagulase and a negative result for ornithine decarboxylase. Intravenous cloxacillin (2 g every 6 h) was given on days 2-5. Antimicrobial drug susceptibility testing was performed by the disk-diffusion method (1 [micro]g oxacillin/disk, Mueller-Hinton agar, 2% NaCl), followed by MIC determination with the agar dilution method in accordance with NCCLS (former National Committee for Clinical Laboratory Standards, now Clinical and Laboratory Standards Institute) recommendations (2). One blood isolate was identified as methicillin-resistant S. aureus (MRSA), with an oxacillin MIC 4 [micro]g/mL. The other isolate was identified as methicillin-sensitive S. aureus (MSSA), with an oxacillin MIC of 0.5 [micro]g/mL. In view of a possible CA-MRSA infection (which could have been [beta]-lactam--resistant), cloxacillin was substituted with intravenous vancomycin plus rifampin on day 5.

However, the patient's condition progressively deteriorated from day 2 to day 10 with persistent fever, chills, hypotension, and hemoptysis. A repeated chest radiograph showed small lung cavities with fluid, and a thoracic computed tomographic scan confirmed multiple lung abscesses. Results of an initial transthoracic echocardiograph were normal, but a subsequent transesophageal echocardiograph demonstrated tricuspid valve vegetation.

The MRSA isolate was susceptible to gentamicin, cotrimoxazole, erythromycin, ciprofloxacin, clindamycin, fusidic acid, tetracycline, chloramphenicol, vancomycin, and rifampin; a different pattern of multidrug-resistant MRSA isolates from that usually found in our facility (2,3). The isolate was also susceptible to ampicillin/sulbactam, with an equivalent breakpoint MIC <8/4 [micro]g/mL by disk testing (2). Latex detection for PBP2a (Slidex MRSA-Detection, bioMerieux, Marcy l'Etoile, France) and polymerase chain reaction (PCR) detection for mecA were both negative, predicting nonresistance to oxacillin (2-5). A nitrocefin-disk test was positive for [beta]-lactamases, and a 4-fold reduction in MIC was demonstrated in the presence of sulbactam (6). Panton-Valentine leukocidin (PVL) gene locus was not detected (1). Community-acquired BORSA (borderline oxacillin-resistant S. aureus), infective endocarditis, and lung abscesses were diagnosed. Intravenous ampicillin/sulbactam (3 g every 6 h) was given on day 10 with rifampin; vancomycin treatment was stopped. Defervescence occurred 3 days later, subsequent blood cultures became sterile, and radiographic changes gradually resolved. Ampicillin/sulbactam was given for 6 weeks without complication.

As this case suggests, BORSA can sometimes be confused with CAMRSA because of similar clinical signs and symptoms and overlapping oxacillin MICs (2 8 [micro]g/mL and 4-64 [micro]g/mL, respectively) (1,4,6). Both pathogens can appear as community-acquired infections and may be related to previous antimicrobial drug usage (6, 7). Although CA-MRSA has been associated with soft tissue infections and necrotizing pneumonia (7,8), MSSA or BORSA strains can also cause these diseases. Thus, in view of potentially different treatment options, when MRSA isolates (e.g., oxacillin MICs [greater than or equal to] 4-8 [micro]g/mL) are associated with community-acquired, serious infections (e.g., blood isolates) and are not multidrug resistant, one can consider mecA (or PBP2a) testing to delineate the resistance mechanism (Table). If mecA is present, further testing for PVL gene locus with or without staphylococcal chromosomal cassette mec (SCCmec) type IV can be performed to diagnose CA-MRSA; if mecA is not detected, further testing for BORSA may be indicated, and [beta]-lactam therapy should be evaluated individually. If these pathogens are not differentiated and all are treated as CA-MRSA, a non-[beta]-lactam antimicrobial drug, such as vancomycin, will be used (1,4,7,8). However, for serious and deep-seated S. aureus infections (e.g., bacteremia, endocarditis), vancomycin is inferior to [beta]-lactam antimicrobial drugs, even when in vitro testing indicates susceptibility. Treatment failures have been encountered (4). Linezolid is a good alternative but limited by availability and cost, and clindamycin therapy can be associated with inducible resistance. For BORSA-associated infections, [beta]-lactam antimicrobial drugs, including high-dose penicillinase-resistant penicillins (PRPs) (e.g., cloxacillin) or [beta]-lactam/[beta]-lactamase--inhibitor combinations (e.g., ampicillin/sulbactam) are regarded as treatments of choice (4,6,9).

BORSA initially described non-heteroresistant strains of S. aureus with oxacillin MIC [less than or equal to] 2 mg/L, which produce ample [beta]-lactamases and are rendered fully susceptible to PRP by [beta]-lactamase-inhibitors (4,6). Subsequent BORSA strains described have had higher oxacillin MICs (4-8 mg/L) (4). The proportion of BORSA among clinical isolates of S. aureus varies (1.4%-12.5%) but is usually ?5% (4,10). A BORSA infection outbreak among dermatology patients with severe skin diseases has also been reported (10). Postulated resistance mechanisms include overproduction of conventional penicillinases, production of an inducible, plasmid-mediated, membrane-bound methicillinase, and in some cases, point mutations of penicillin-binding-proteins (4). The clinical importance of BORSA is unknown since early clinical/animal data suggest treatment efficacy of PRP (against strains with MIC [less than or equal to] 2 mg/L) (4,6,9). Whether BORSA with higher oxacillin MICs (4-8 mg/L) will respond equally well to PRP is less clear. Further studies into the treatment of BORSA, including pharmacokinetic considerations, are needed (4). However, high-dose [beta]-lactam/[beta]-lactamase inhibitor combinations (e.g., ampicillin/sulbactam), as shown in animal models, are at least as effective as PRP (9). In conclusion, our report suggests that mecA (or PBP2a) detection may help manage serious, community-acquired, non-multidrug-resistant MRSA infections because of the potential contusion between BORSA and CAMRSA.

Lee Nelson, * Clive S. Cockram, * Grace Lui, * Rebecca Lam, * Edman Lam, * Raymond Lai, * and Margaret Ip*

* Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong SAR, People's Republic of China

References

(1.) Vandenesch F, Naimi T, Enright MC, Lina G, Nimmo GR, Heffernan H, et al. Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence. Emerg Infect Dis. 2003;9:978-84.

(2.) National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing. Fifteenth informational supplement. NCCLS document M100-S15. Wayne (PA): The Committee; 2005.

(3.) Ip M, Lyon DJ, Chio F, Enright MC, Cheng AF. Characterization of isolates of methicillin-resistant Stapylococcus aureus from Hong Kong by phage typing, pulsed-field gel electrophoresis, and fluorescent amplified-fragment length polymorphism analysis. J Clin Microbiol. 2003;41:4980-5.

(4.) Chambers HF. Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications. Clin Microbiol Rev. 1997;10:781-91.

(5.) Brown DF. Detection of methicillin/ oxacillin resistance in staphylococci. J Antimicrob Chemother. 2001;48(Suppl 1):65-70.

(6.) Varaldo PE. The "borderline methicillin-susceptible" Staphylococcus aureus. J Antimicrob Chemother. 1993;31:1-4.

(7.) Naimi TS, LeDell KH, Como-Sabetti K, Borchardt SM, Boxrud DJ, Etienne J, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA. 2003:290:2976-84.

(8.) Francis JS, Doherty MC, Lopatin U, Johnson CP, Sinha G, Ross T, et al. Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin gene. Clin Infect Dis. 2005;40:100-7.

(9.) Hirano L, Bayer AS. Beta-lactam--beta-lactamase-inhibitor combinations are active in experimental endocarditis caused by beta-lactamase--producing oxacillin-resistant staphylococci. Antimicrob Agents Chemother. 1991;35:685-90.

(10.) Balslev U, Bremmelgaard A, Svejgaard E, Havstreym J, Westh H. An outbreak of borderline oxacillin-resistant Staphylo-coccus aureus (BORSA) in a dermatological unit. Microb Drug Resist. 2005;11:78-81.

Address for correspondence: Margaret Ip, Department of Microbiology, Prince of Wales Hospital, Chinese University of Hong Kong, Ngan Shing St, Hong Kong SAR, People's Republic of China; fax: [phone]; email: [e-mail]

Table. Comparison between methicillin-sensitive and
methicillin-resistant strains of Staphylococcus aureus

                               Strain and major resistance mechanism *

                                                        BORSA/novel
                                                       methicillinase
                                                         [+ or -]
                               MSSA/penicillinase      penicillinase
                                   production         hyperproduction

PBP2a detection (e.g.,                 -                     -
latex-agglutination
method)
mecA gene detection                    -                     -
(e.g., PCR method)
PVL gene detection              Infrequent (<5%)        Data limited
(PCR method)
Coresistance to non-                [+ or -]              [+ or -]
[beta]-lactam antimicrobial
drugs
Usual antimicrobial               PRP (e.g.,            PRP (e.g.,
drugs to which MSSA is           cloxacillin),         cloxacillin),
susceptible                      [beta]-lactam/        [beta]-lactam/
                               [beta]-lactamase-     [beta]-lactamase-
                                   inhibitor             inhibitor
                                  combinations         combinations
                               (e.g., ampicillin/    (e.g., ampicillin/
                                  sulbactam);        sulbactam), other
                                   linezolid,         drugs to which
                                  vancomycin,             MSSA is
                                 erythromycin,          potentially
                                 clindamycin,           susceptible
                                trimethoprim-
                               sulfamethoxazole,
                               fluoroquinolones,
                                   rifampin,
                                  gentamicin,
                                 fusidic acid,
                                 tetracyclines

                               Strain and major resistance mechanism *

                                  CA-MRSA/PBP           HA-MRSA/PBP
                                   alteration            alteration

PBP2a detection (e.g.,                 +                     +
latex-agglutination
method)
mecA gene detection              + (SCCmec IVa)              +
(e.g., PCR method)
PVL gene detection                  Frequent          Infrequent (<5%)
(PCR method)                      (>66%-100%)
Coresistance to non-                   +                    +++
[beta]-lactam antimicrobial
drugs
Usual antimicrobial               Vancomycin,           Vancomycin,
drugs to which MSSA is             linezolid,           linezolid;
susceptible                        rifampin,             [+ or -]
                                  gentamicin,          fusidic acid,
                                 trimethoprim-           rifampin,
                               sulfamethoxazole,        gentamicin,
                                 fusidic acid,         trimethoprim-
                                 tetracyclines,      sulfamethoxazole,
                                fluoroquinolone,     fluoroquinolones
                                  clindamycin        ([double dagger])
                                   ([dagger])

* MSSA, methicillin-susceptible Staphylococcus aureus; BORSA,
borderline oxacillin-resistant S. aureus; MRSA, methicillin-resistant
S. aureus; CA-MRSA, community-associated MRSA; HA-MRSA,
hospital-associated MRSA; PBP, penicillin-binding protein; PCR,
polymerase chain reaction; PVL, Panton-Valentine leukocidin; PRP,
penicillinase-resistant penicillins; +, positive; -, negative.
[+ or -], occasionally present; +++, usually present.

([dagger]) Concern over inducible clindamycin resistance; also,
macrolide resistance is common.

([double dagger]) Fluoroquinolone resistance increasing.