Fatal Case Due to Methicillin-Resistant Staphylococcus Small Colony Variants in an AIDS Patient.

We describe the first known case of a fatal infection with small colony variants of methicillin-resistant Staphylococcus aureus in a patient with AIDS. Recovered [ILLEGIBLE TEXT] blood cultures as well as from a deep hip abscess, these variants may have [ILLEGIBLE TEXT] from long-term antimicrobial therapy with trimethoprim/sulfamethoxazole for [ILLEGIBLE TEXT] of Pneumocystis carinii pneumonia.

Staphylococcus aureus causes acute and often fatal infections. Small colony [ILLEGIBLE TEXT] which are subpopulations of S. aureus, are implicated in persistent and recurrent particular osteomyelitis, septic arthritis, respiratory tract infections in patients [ILLEGIBLE TEXT] fibrosis, and deep-seated abscesses) (1-4). These phenotypic variants produce [ILLEGIBLE TEXT] growing, nonpigmented, nonhemolytic colonies on routine culture media, [ILLEGIBLE TEXT] identification difficult for clinical laboratories. Biochemical characterization of [ILLEGIBLE TEXT] suggests that they are deficient in electron transport activity (5).

We report a fatal case of a persistent deep-seated hip abscess due to methicillin-[ILLEGIBLE TEXT] aureus SCVs that led to osteomyelitis and bloodstream infection in a patient [ILLEGIBLE TEXT]

Case Report

A 36-year-old man with AIDS came to the Cologne University Hospital, Cologne in June 1997 with fever and progressive pain (of 6 weeks duration) in his right [ILLEGIBLE TEXT] infection had been diagnosed in 1986. In 1994, his CD4 cell count was 250/[micro]L, a zidovudine therapy was started. His medical history included Pneumocystis [ILLEGIBLE TEXT] pulmonary tuberculosis, and recurrent oral thrush; his medication included [ILLEGIBLE TEXT] lamivudine, fluconazole, and trimethoprim/sulfamethoxazole. In September [ILLEGIBLE TEXT] traffic accident and had severe cerebral trauma resulting in spastic hemiparesis [ILLEGIBLE TEXT] seizures. After an intramuscular injection 2 months before admission, pus was [ILLEGIBLE TEXT] drained to treat recurrent abscesses of his right hip. Specimens for culture were [ILLEGIBLE TEXT]

Physical examination found limited mobility of his right thigh and a tender, [ILLEGIBLE TEXT] at the site of surgical drainage. Neither warmth nor swelling was observed over [ILLEGIBLE TEXT] Vital signs were temperature, 38.2 [degrees] C; respiration rate, 28; and heart rate, 108. He and alert and had spastic paresis in his right arm.

Laboratory studies performed on admission showed hemoglobin, 10.8 g/dL; [ILLEGIBLE TEXT] 3,000/[micro]L with a normal differential; CD4 cell count, 20/[micro]L; platelet count, [ILLEGIBLE TEXT] reactive protein, 184 mg/L; and alkaline phosphatase, 1490 U/L. Radiographs of a plain film of the pelvis were normal. A triple-phase bone scan showed an area accumulation in the acetabulum region of the right hip. Blood cultures were [ILLEGIBLE TEXT] antimicrobial therapy was withheld until culture results became available.

On hospital day 2, one of two blood cultures drawn on admission yielded [ILLEGIBLE TEXT] staphylococci that were clumping factornegative. The organisms were initially [ILLEGIBLE TEXT] coagulase-negative staphylococci and were considered contaminants. [ILLEGIBLE TEXT] antistaphylococcal therapy with clindamycin (600 mg q8hr) was instituted. On [ILLEGIBLE TEXT] two sets of blood cultures obtained on hospital day 2 yielded phenotypically [ILLEGIBLE TEXT] organisms, which on the basis of a positive tube coagulase test were identified as resistant S. aureus. The colony morphology was suggestive of an SCV of S. aureus patient was started on parenteral vancomycin treatment (1 g q12hr). However, [ILLEGIBLE TEXT] deteriorated rapidly, and he died of refractory septic shock 6 days after [ILLEGIBLE TEXT]

Autopsy showed a large (12 x 10 x 8 cm), deep-seated abscess of the right hip an osteomyelitis of the ischial tuberosity. Both SCVs and typical large colony forms were cultured from postmortem specimens of the abscess and the bone.

Findings

S. aureus SCVs were recovered from one of two blood culture sets obtained on a from two of four blood culture sets obtained on hospital day 2. Growth was not [ILLEGIBLE TEXT] the blood culture bottles had been incubated 24 hours. S. aureus with a normal [ILLEGIBLE TEXT] recovered from nose and throat specimens but not from blood cultures, whereas and typical S. aureus phenotypes were isolated from the deep hip abscess (Figure death, as well as from a postmortem specimen. All isolates were clumping factor showed a delayed positive reaction in the tube-coagulase test at 24 hours. The [ILLEGIBLE TEXT] 32 staph test did not unambiguously identify SCVs as S. aureus because the tests and trehalose were negative. Both the nuc gene and the coa gene were identified polymerase chain reaction (PCR) amplification. Methicillin resistance was [ILLEGIBLE TEXT] small and large colony forms by PCR amplification of the mecA gene.

[Figure 1 ILLUSTRATION OMITTED]

When cultured without supplementation, all SCVs were nonpigmented and [ILLEGIBLE TEXT] Supplementation with hemin, thymidine, or menadione identified two SCVs [ILLEGIBLE TEXT] thymidine auxotrophy and a combined thymidine and menadione auxotrophy, [ILLEGIBLE TEXT] SCVs were stable on repeated subculturing.

Epidemiologic typing by PCR analysis of inter-IS256 spacer length polymorphis and pulsed-field gel electrophoresis of genomic DNA (data not shown) showed [ILLEGIBLE TEXT] banding patterns for both SCVs and large colony forms, which indicates that the phenotypically different S. aureus isolates represented a single strain. [ILLEGIBLE TEXT] susceptibility testing was performed by microbroth dilution, according to the [ILLEGIBLE TEXT] Committee for Clinical Laboratory Standards guidelines. Susceptibility to trimethoprim/sulfamethoxazole was tested with Etest (AB Biodisk, Solna, [ILLEGIBLE TEXT] contrast to current standards, the MICs for SCVs were determined after 48 hours at 35 [degrees] C. Susceptibility testing showed that all S. aureus isolates were resistant to (MIC, [is greater than] 8 [micro]g/mL), ampicillin (MIC, [is greater than] 32 [micro]g/mL), oxacillin (MIC, [is greater than] 8 [micro]g/mL), [ILLEGIBLE TEXT] (MIC, [is greater than] 32 [micro]g/mL), clindamycin (MIC, [is greater than] 32 [micro]g/mL), ciprofloxacin (MIC, [is greater than] 8 [micro]g/mL gentamicin (MIC, [is greater than] 500 [micro]g/mL), and trimethoprim/sulfamethoxazole (MIC, [is greater than] 32 susceptible to vancomycin (MICs, 1-2 [micro]g/mL), teicoplanin (MICs, 0.5-1 [micro]g/mL) quinupristin/dalfopristin (MICs, 0.5-1 [micro]g/mL). No differences in MICs were [ILLEGIBLE TEXT] S. aureus SCVs and S. aureus isolates with normal phenotype.

To our knowledge, this case represents the first of a serious S. aureus infection in patient in which all blood cultures yielded SCVs. The SCVs' unusual morphology and slow growth delayed the correct identification of these organisms as S. aureus empiric antimicrobial regimen in our patient did not include a glycopeptide, [ILLEGIBLE TEXT] rate of methicillin resistance in community-acquired S. aureus infection in [ILLEGIBLE TEXT] Appropriate antistaphylococcal therapy was, therefore, not started until hospital antimicrobial therapy on day 4 rather than on day 2 may have contributed to the

Proctor and colleagues recently reported five cases in which SCVs of S. aureus implicated in persistent and relapsing infections. They identified only a single [ILLEGIBLE TEXT] the previous 17 years and ascribed this to insufficient ability of laboratories to [ILLEGIBLE TEXT] organisms (8). In most cases, patients had received antibiotics. Aminoglycoside [ILLEGIBLE TEXT] have selected for S. aureus SCVs (10), and in cases of osteomyelitis or deep-seat persistence of these variants in the intracellular milieu may have permitted [ILLEGIBLE TEXT] defenses and allowed for the development of resistance-to antimicrobial therapy Eiff and colleagues recently reported four cases of chronic osteomyelitis due to [ILLEGIBLE TEXT] aureus in patients who had received gentamicin beads as an adjunct to surgical [ILLEGIBLE TEXT] osteomyelitis (2). Kahl et al. described persistent infection with S. aureus SCVs [ILLEGIBLE TEXT] with cystic fibrosis (4). All these patients had received long-term trimethoprim/sulfamethoxazole prophylaxis. It may be tempting to speculate that administration of trimethoprim/sulfamethoxazole for prophylaxis against P. [ILLEGIBLE TEXT] may have selected for SCVs within the patient's large hip abscess. Further [ILLEGIBLE TEXT] are needed to assess the role of S. aureus SCVs in HIV-infected patients on long-antimicrobial therapy.

[Figure 2 ILLUSTRATION OMITTED]

References

(1.) Proctor RA, Balwit JM, Vesga O. Variant subpopulations of [ILLEGIBLE TEXT] cause of persistent and recurrent infections. Infectious Agents and Disease 12.

(2.) von Eiff C, Bettin D, Proctor RA, Rolauffs B, Lindner N, Winkelmann W, Recovery of small colony variants of Staphylococcus aureus following [ILLEGIBLE TEXT] placement for osteomyelitis. Clin Infect Dis 1997;25:1250-1.

(3.) Spearman P, Lakey D, Jotte S, Chernowitz A, Claycomb S, Stratton C. [ILLEGIBLE TEXT] joint septic arthritis with small colony variant Staphylococcus aureus. [ILLEGIBLE TEXT] Infect Dis 1996;26:13-5.

(4.) Kahl B, Herrmann M, Everding AS, Koch HG, Becker K, Harms E, et al. infection with small colony variant strains of Staphylococcus aureus in [ILLEGIBLE TEXT] cystic fibrosis. J Infect Dis 1998;177:1023-9.

(5.) von Eiff C, Heilmann C, Proctor RA, Woltz C, Peters G, Gotz F. A site-[ILLEGIBLE TEXT] Staphylococcus aureus hemB mutant is a small colony variant which [ILLEGIBLE TEXT] intracellularly. J Bacteriol 1997;179:4706-12.

(6.) Kloos WE, Bannerman TL. Staphylococcus and micrococcus. In: Murray Pfaller MA, Tenover FC, Yolken RH, editors. Manual of clinical [ILLEGIBLE TEXT] Washington: American Society for Microbiology; 1995. p. 282-98.

(7.) Balwit JM, van Langevelde P, Vann JM, Proctor RA. Gentamicin-resistant and hemin auxotrophic Staphylococcus aureus persist within cultured end Infect Dis 1994;170:1033-7.

(8.) Proctor RA, van Langevelde P, Kristjansson M, Maslow JN, Arbeit RD. P relapsing infections associated with small colony variants of [ILLEGIBLE TEXT] Clin Infect Dis 1995;20:95-102.

(9.) Deplano A, Vaneechoutte M, Verschraegen G, Struelens MJ. Typing of [ILLEGIBLE TEXT] aureus and Staphylococcus epidermidis by PCR analysis of inter-IS256 [ILLEGIBLE TEXT] polymorphisms. J Clin Microbiol 1997;35:2580-7.

(10.) Pelletier LL Jr, Richardson M, Feist M. Virulent gentamicin-induced small variants of Staphylococcus aureus. J Lab Clin Med 1979;94:324-34.

(11.) Proctor RA, Kahl B, von Eiff C, Vaudaux PE, Lew DP, Peters G. [ILLEGIBLE TEXT] colony variants have novel mechanisms for antibiotic resistance. Clin [ILLEGIBLE TEXT] Suppl 1:S68-74.

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Emerging Infectious Diseases Journal National Center for Infectious Diseases Centers for Disease Control and Prevention 

URL: http://www.cdc.gov/ncidod/eid/vol5no3/seifert.htm

Harald Seifert,(*) Christoph von Eiff,([dagger]) and Gerd Fatkenheuer([dagger])

(*) University of Cologne, Cologne, Germany; and ([dagger]) Westfalische Wilhelms-[ILLEGIBLE TEXT] Munster, Germany

Dr. Seifert is assistant professor at the Institute of Medical Microbiology and Hygiene, [ILLEGIBLE TEXT] Germany. His research interests include the molecular epidemiology of nosocomial pathogens, [ILLEGIBLE TEXT] Acinetobacter species, catheter-related infections, and antimicrobial resistance.

Address for correspondence: Harald Seifert, Institute of Medical Microbiology and Hygiene, Cologne, Goldenfelsstra[Beta]e 19-21, 50935 Cologne, Germany; fax: [phone]; e-mail: harakoeln.de.