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Dispatch
Small Colony Variants of Staphylococcus
aureus and Pacemaker-related Infection
Harald Seifert,* Hilmar Wisplinghoff,* Petra Schnabel,* and Christof
von Eiff†
*University of Köln, Germany; and †University of Münster Hospital
and Clinics, Münster, Germany
Suggested citation
for this article:
Seifert H, Wisplinghoff H, Schnabel P, von Eiff C. Small colony variants
of Staphylococcus aureus and pacemaker-related infection. Emerg Infect
Dis [serial online] 2003 Oct [date cited]. Available from: URL:
http://www.cdc.gov/ncidod/EID/vol9no10/03-0200.htm
We describe the
first known case of a device-related bloodstream infection caused by
Staphylococcus aureus small colony variants. Recurrent pacemaker-related
bloodstream infection within a 7-month period illustrates the poor clinical
and microbiologic response to prolonged antimicrobial therapy in a patient
infected with this S. aureus subpopulation.
Infections caused by Staphylococcus aureus range from mild skin
infections to acute life-threatening diseases such as pneumonia, osteomyelitis,
and endocarditis. However, S. aureus may also cause a chronic disease
with persistent and recurrent infections. Skin and soft tissue infections,
chronic osteomyelitis, and persistent infections in patients with cystic
fibrosis have been associated with small colony variants, a naturally
occurring subpopulation of the species S. aureus (1–6).
S. aureus small colony variants are characterized as electron transport
deficient bacteria because of their auxotrophism to hemin or menadione
or are recognized as thymidine-dependent. These variants produce very
small, mostly nonpigmented and nonhemolytic colonies. In addition, they
also demonstrate various other features that are atypical for S. aureus,
including reduced coagulase production, failure to use mannitol, and increased
resistance to aminoglycosides and cell-wall active antibiotics (3–10).
Furthermore, the ability of these variants to persist intracellularly
within nonprofessional phagocytes has been described (3,5,11).
Because of their fastidious growth characteristics and unusual morphologic
appearance, small colony variants present a challenge both to the microbiologist
and the clinician, often resulting in misidentification and misinterpretation
(1,2,7,8). Prerequisite for recovering and identifying
these variants is the application of extended conventional culture and
identification techniques (3,5,8). We report the first
case of a pacemaker-related bloodstream infection caused by S. aureus
small colony variants. This case illustrates the poor clinical and microbiologic
response to prolonged antimicrobial therapy in patients infected with
these variants.
Case Report
A 63-year-old man was transferred to our facility with the presumptive
diagnosis of endocarditis related to a pacemaker-lead infection. Past
medical history included hypertension, coronary artery disease, and noninsulin-dependent
diabetes mellitus. A VVI (ventricular ventricular inhibited) pacemaker
had been implanted for treatment of sick sinus syndrome 9 years earlier.
Six weeks before admission, this device had been removed because of a
pocket infection after blunt trauma with dislocation of the device and
perforation of the skin. Specimens for microbiologic culture were not
obtained at this time. The pacemaker leads were left in place, a gentamicin-containing
sponge was applied to the infection site, and a new pacemaker was implanted
on the other side of the chest. Four weeks later, the patient sought treatment
at the local hospital for a high fever (39.7°C) and chills and a subcutaneous
abscess with oxacillin-susceptible S. aureus at the primary insertion
site. After surgical drainage, antimicrobial therapy was initiated with
intravenous cefuroxime. The remaining pacemaker leads were partially cut
but not completely removed. Ten days later, spiking fever and chills unresponsive
to the administration of meropenem and vancomycin developed, and the patient
was transferred to our medical center for pacemaker ablation. The physical
examination did not indicate auscultation abnormalities or stigmata of
endocarditis. Laboratory studies were unremarkable except a C-reactive
protein (CRP) level of 170 mg/L (normal value <8 mg/L) and a
blood sedimentation rate of 79 mm/h. Multiple blood cultures taken on
admission remained negative. Transesophageal echocardiography did not
show vegetations or other evidence of endocarditis. On hospital day 6,
the new pacemaker was completely removed by percutaneous ablation as were
the remaining leads of the old device. Only the tip of the pacemaker lead
remained fixed in the myocardium, and surgical removal involving extracorporal
circulation was not attempted. The patient’s condition improved rapidly,
CRP level returned to normal, and on hospital day 32, the patient was
transferred to the local hospital to complete a 6-week course of intravenous
vancomycin and rifampin as empirical antistaphylococcal therapy. Before
transfer, the daily vancomycin dose had been reduced to 250 mg twice a
day after an elevated vancomycin serum level. Eight days later, the patient
was readmitted with recurrent high fever. Blood cultures taken on readmission
were again negative. After the vancomycin dose was increased to 500 mg
every 12 hours, the patient promptly became afebrile. Antimicrobial therapy
was discontinued after the patient had completed a 10-week course of vancomycin
and rifampin. Three days later, the patient again had spiking fever. After
6 to 48 hours of incubation, four sets of blood cultures obtained on four
consecutive days yielded nonpigmented and nonhemolytic staphylococci,
initially identified on the basis of a negative tube coagulation test
and the API ID 32 Staph system (bioMérieux, Marcy-L’Etoile, France) as
coagulase-negative staphylococci, susceptible to oxacillin (MIC 0.5 mg/mL)
and vancomycin (MIC 1.0 mg/mL) but resistant to rifampin (MIC >32 mg/mL).
However, the colony morphologic findings were suggestive of small colony
variants of S. aureus, confirmed by polymerase chain reaction amplification
of the nuc and coa genes as well as by determination of
the strain’s auxotrophy for hemin. The patient responded promptly to flucloxacillin,
4 g intravenously three times a day. After another 6-week course of parenteral
therapy, antimicrobial therapy was discontinued, and the patient was discharged
(CRP 7 mg/L, ESR 35 mm/h); he was readmitted after 6 days with chills
and high fever. Antimicrobial therapy with intravenous flucloxacillin
was resumed and followed by immediate defervescence. Three blood cultures
taken on readmission were again positive with S. aureus small colony
variants. Clonal identity of all isolates was demonstrated by pulsed-field
gel electrophoresis of bacterial DNA (data not shown). A transesophageal
echocardiogram showed the residual tip of the pacemaker lead fixed in
the myocardial septum without vegetations. The remaining device was finally
removed by open-heart surgery with use of cardiopulmonary bypass. Microbiologic
culture of the pacemaker electrode performed at a different institution
yielded abundant growth of staphylococci that were misidentified as S.
warneri, showing the same biochemical profile as the previously isolated
bacteria as determined by the ID 32 Staph system. The patient recovered
completely and was discharged on the 10th postoperative day after a total
hospital course of 7 months.
Conclusions
S. aureus small colony variants have been implicated in persistent
and recurrent infections that give a poor clinical and bacteriologic response
to standard antimicrobial therapy in patients with abscess, chronic osteomyelitis,
and bronchopulmonary infections, particularly after prolonged exposure
to antibiotics (1–6). Bloodstream infection related to
an implantable intravascular device with this S. aureus variant
has not been reported before. These phenotypic variants are characterized
by their fastidious growth and atypical colony morphologic findings on
routine media, making recovery as well as correct identification difficult
for microbiologic laboratories (3,5,8). The ability to
interrupt electron transport and to form a variant subpopulation affords
S. aureus a number of survival advantages, including the ability
of this subpopulation to persist intracellularly within nonprofessional
phagocytes (11,12). The intracellular position may shield
small colony variants from host defenses and decrease exposure to antibiotics
(3,5,11). S. aureus small colony
variants can be selected by gentamicin in vitro and in vivo as shown in
patients with osteomyelitis after gentamicin bead placement (4,12).
Chuard et al. demonstrated that, in contrast to their normal phenotype
parental strain, S. aureus small colony variants that were attached
to fibronectin-coated coverslips were highly resistant to cell-wall–active
antimicrobial agents such as oxacillin and vancomycin (13).
In our case, findings suggest that S. aureus small colony variants
might have been selected from the parent strain population with a normal
phenotype after exposure to the locally applied aminoglycoside or to the
prolonged administration of vancomycin. Continually positive blood cultures
with the same strain as demonstrated by molecular typing and the presumable
persistence of these organisms on the pacemaker lead tip may partly be
explained by the poor effectiveness of vancomycin and flucloxacillin against
these slow-growing organisms that were adhering to the remaining foreign
body and the ability of these variants to persist intracellularly (7,8,13).
This case adds to the spectrum of persistent and relapsing infections
attributed to S. aureus small colony variants and emphasizes that
these variants may also play a role in intravascular device–related infections.
It also illustrates that complete removal of any foreign body material
is essential for the complete cure of prosthetic intravascular device–related
S. aureus infection. Laboratories should be particularly alert
for S. aureus small colony variants when samples are submitted
from patients who have received long-term antimicrobial therapy, especially
if the infection is unusually persistent or recurrent.
Dr. Seifert is professor
of clinical microbiology at the Institute for Medical Microbiology,
Immunology and Hygiene at the University of Cologne, Köln, Germany.
His research interests include the molecular epidemiology of nosocomial
pathogens, in particular Acinetobacter species and methicillin-resistant
Staphylococcus aureus, catheter-related infections, and antimicrobial
resistance and its mechanisms.
References
- Proctor RA, Bates DM, McNamara PJ. Electron transport
deficient Staphylococcus aureus small-colony variants as emerging
pathogens. In: Scheld WM, Craig WA, Hughes JM, editors. Emerging infections
5. Washington: ASM Press; 2001.
- Proctor RA, van Langevelde P, Kristjansson M, Maslow JN, Arbeit RD.
Persistent
and relapsing infections associated with small-colony variants of Staphylococcus
aureus. Clin Infect Dis 1995;20:95–102.
- von Eiff C, Becker K, Metze D, Lubritz G, Hockmann J, Schwarz T, et
al. Intracellular
persistence of Staphylococcus aureus small-colony variants within
keratinocytes: a cause for antibiotic treatment failure in a patient
with Darier’s disease. Clin Infect Dis 2001;32:1643–7.
- von Eiff C, Bettin D, Proctor RA, Rolauffs B, Lindner N, Winkelmann
W, et al. Recovery
of small colony variants of Staphylococcus aureus following gentamicin
bead placement for osteomyelitis. Clin Infect Dis 1997;25:1250–1.
- Kahl B, Herrmann M, Schulze-Everding A, Koch HG, Becker K, Harms E,
et al. Persistent
infection with small colony variant strains of Staphylococcus aureus
in patients with cystic fibrosis. J Infect Dis 1998;177:1023–9.
- Seifert H, von Eiff C, Fätkenheuer G. Fatal
case due to methicillin-resistant Staphylococcus aureus small
colony variants in an AIDS patient. Emerg Infect Dis 1999:5:450–3.
- Proctor RA, Kahl B, von Eiff C, Vaudaux PE, Lew DP, Peters G. Staphylococcal
small colony variants have novel mechanisms for antibiotic resistance.
Clin Infect Dis 1997;27(Suppl 1):S68–S74.
- Proctor RA, Peters G. Small
colony variants in staphylococcal infections: diagnostic and therapeutic
implications. Clin Infect Dis 1998;27:419–23.
- Kahl BC, Belling G, Reichelt R, Herrmann M, Proctor RA, Peters G.
Thymidine-dependent
small-colony variants of Staphylococcus aureus exhibit gross
morphological and ultrastructural changes consistent with impaired cell
separation. J Clin Microbiol 2003:41:410–3.
- Baumert N, von Eiff C, Schaaff F, Peters G, Proctor RA, Sahl HG. Physiology
and antibiotic susceptibility of Staphylococcus aureus small
colony variants. Microb Drug Resist 2002;8:253–60.
- Vaudaux P, Francois P, Bisognano C, Kelley WL, Lew
DP, Schrenzel J, et al. Increased
expression of clumping factor and fibronectin-binding proteins by hemB
mutants of Staphylococcus aureus expressing small colony variant
phenotypes. Infect Immun 2002;70:5428–37.
- Balwit JM, van Langevelde P, Vann JM, Proctor RA. Gentamicin-resistant
menadione and hemin auxotrophic Staphylococcus aureus persist
within cultured endothelial cells. J Infect Dis 1994;170:1033–7.
- Chuard C, Vaudaux PE, Proctor RA, Lew DP. Decreased
susceptibility to antibiotic killing of a stable small colony variant
of Staphylococcus aureus in fluid phase and on fibronectin-coated
surfaces. J Antimicrob Chemother 1997;39:603–8.
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