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A report from the microbiology laboratory that a blood culture is positive for gram-positive cocci in grapelike clusters suggests that the organism most likely is Staphylococcus aureus or Staphylococcus epidermidis. Rarely, the organism will be identified as a Micrococcus or a Peptococcus (an anaerobic gram-positive coccus) species. Staphylococci are catalase-positive organisms that belong to the family Micrococcaceae. The staphylococci that produce coagulase are S. aureus, and those that are coagulase-negative are designated as coagulase-negative staphylococci or Staphylococcus not aureus. There are multiple species of coagulase-negative staphylococci, but S. epidermidis is the most common. Another pathogenic coagulase-negative staphylococcal organism is S. saprophyticus, a well-recognized cause of urinary tract infections, especially in women. Resistance to novobiocin is the characteristic used most often to distinguish S. saprophyticus from other species of coagulase-negative staphylococci. All the factors that determine the virulence of S. epidermidis are unknown. The organism can adhere to and proliferate on prosthetic devices. Coagulase-negative staphylococci produce a slime-like substance that covers the organism but is not a true capsule. This substance interferes with phagocytosis.
Most (85%) coagulase-negative staphylococci isolated from a blood culture are contaminants, as the organisms colonize human skin and mucosal surfaces. In the other 15% of cases, the organisms are considered pathogens, especially in patients with indwelling medical devices such as prosthetic valves, central venous catheters, central nervous system shunts, vascular grafts, and pacemakers. S. epidermidis can also cause bacteremia in neutropenic patients with malignancy, neonatal bacteremia in low-birth-weight infants, and native valve endocarditis. To be able to interpret the meaning of a positive blood culture for a gram-positive coccus in clusters, the clinician must ask the following questions:

How many blood cultures are positive? A single positive culture suggests contamination unless the patient has an indwelling prosthetic device; if that is the case, repeated blood cultures are indicated, depending on the clinical situation. Obtaining a single set of blood cultures in an adult with a prosthetic device poses a dilemma for the clinician if the culture becomes positive. To avoid this problem, three sets of blood cultures should be obtained in the setting of suspected infection in a patient with an indwelling medical device.

What if there are multiple positive blood cultures? The finding of multiple positive blood cultures for coagulase-negative staphylococci suggests true invasive disease. The clinician should compare the antibiograms of the staphylococci isolated from the different blood culture bottles to determine if they are the same or different strains. The advantage of using the antimicrobial susceptibility test results to compare the strains is that the antibiograms are readily available. However, the technique is limited by the resistance of most nosocomial staphylococci to multiple antimicrobials, and the resistance may be unstable. Other methods of epidemiologic analysis are phage typing, biotyping, plasmid profile analysis, and restriction endonuclease analysis. The various techniques used to determine strain uniqueness are costly and may not be readily available, so that it is imperative to obtain blood cultures with the utmost care to avoid contamination.

Does the patient have a persistent bacteremia? Persistent recovery of a unique organism from the blood is powerful evidence that the coagulase-negative staphylococcal organism is a real pathogen and not a contaminant.

Were the positive blood cultures obtained in a patient with intravascular lines? Intravascular lines are often the source of S. epidermidis and should be inspected, removed, and cultured. If there is no obvious primary focus such as an IV line and the patient has persistent bacteremia, infective endocarditis must be suspected.

Does the patient have cardiac valve involvement? Two-dimensional or transesophageal echocardiography may be of value in documenting a vegetation on a cardiac valve, which supports the diagnosis of infective endocarditis.
If the interpretation of the blood culture reports supports the diagnosis of a real bacteremia rather than contamination, therapy should be selected based on the results of antimicrobial susceptibility testing. Several caveats must be considered when therapy is selected for a coagulase-negative staphylococcal infection.

If the organism is b-lactamase-negative, penicillin can be used. However, this rarely occurs.

If the organism is b-lactamase-positive and susceptible to methicillin, nafcillin can be selected. However, these organisms can be heteroresistant—that is, a culture can comprise two populations, one susceptible to methicillin and the other resistant. This resistance can be overlooked unless testing is performed with a large inoculum on salt-containing media and the culture is incubated at 30°C to 35°C. Unfortunately, methicillin resistance can be seen in as many as 40% to 80% of strains, depending on the hospital.

If an organism is resistant to methicillin, it must be assumed that it is resistant to all the cephalosporins, even if it is found to be susceptible by testing.

Vancomycin susceptibility testing is reliable.

Prospective studies to determine the optimal therapy of S. epidermidis native valve infection are lacking. Retrospective studies favor the use of a b-lactam antimicrobial (e.g., nafcillin or oxacillin), or vancomycin plus gentamicin. The dosage of gentamicin is that used for synergy (1 mg/kg every 8 hours) in a patient with normal renal function. The duration of gentamicin administration varied between 3 and 42 days in different studies. Rifampin can be substituted for gentamicin and given with nafcillin or vancomycin for the duration of therapy (4 weeks). I favor using gentamicin only for the initial 5 days, unless the patient is doing poorly, and then using a single drug for the remainder of the therapy.

If the patient has a prosthetic device and an infection caused by a methicillinsusceptible S. epidermidis, then nafcillin or oxacillin plus rifampin should be selected for a 6-week course. Antimicrobial susceptibility testing of the S. epidermidis must be appropriate to detect the presence of heteroresistance. If the organism is susceptible to gentamicin, administer gentamicin in doses to achieve a peak serum concentration of 3 g/mL. Gentamicin should be given only for the initial 2 weeks of therapy. In patients with infection caused by a methicillin-resistant S. epidermidis, use vancomycin plus rifampin along with gentamicin for the first 2 weeks, then continue vancomycin plus rifampin for the remaining 4 weeks of therapy. The role of teicoplanin, a glycopeptide antimicrobial, and quinupristin-dalfopristin in patients unable to tolerate vancomycin remains to be determined.

The mortality rate for native valve S. epidermidis endocarditis ranges from 13% to 36%.

The mortality rate for S. epidermidis prosthetic valve endocarditis is about 20%. However, a cure rate of 80% usually requires a combination of surgery plus 6 weeks of antimicrobial therapy. (N.M.G.)
Arber N, et al. Native valve Staphylococcus epidermidis endocarditis: report of seven cases and review of the literature. Am J Med 1991;90:758.
In this small series, the authors describe a disease with an indolent course and few complications.
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The hands of a cardiac surgeon were identified as the source of infection. The authors used plasmid profiles and restriction endonuclease digest analysis to determine that the strains were identical.
Calderwood SB, et al. Risk factors for the development of prosthetic valve endocarditis. Circulation 1985;72:31.
The risk for prosthetic valve endocarditis was 3.1% at 12 months and 5.7% at 60 months.
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Although the presentation is usually subacute, complications such as arterial emboli, conduction system abnormalities, congestive heart failure, myocardial abscesses, and valve leaflet disruption occur frequently.
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Quinupristin-dalfopristin is an alternative drug to vancomycin for catheter-related staphylococcal infections.
Hedin G. A comparison of methods to determine whether clinical isolates of Staphylococus epidermidis from the same patient are related. J Hosp Infect 1996;34:31–42.
Biotyping and antibiotic resistance testing were helpful in determining whether the strains isolated were causing infection or were contaminants.
Herwaldt LA, et al. The positive predictive value of isolating coagulase-negative staphylococci from blood cultures. Clin Infect Dis 1996;22:14–20.
Twenty-six percent of coagulase-negative staphylococci isolated represented infections. Clues to infection-associated isolates included identification of the species as S. epidermidis, in one of five biotypes, and demonstration of resistance to at least five antibiotics.
Karchmer AW. Staphylococcal endocarditis: laboratory and clinical basis for antibiotic therapy. Am J Med 1985;78(Suppl 6B):116.
Outline of guidelines for therapy.
Karchmer AW, Archer GL, Dismukes WE. Staphylococcus epidermidis causing prosthetic valve endocarditis: microbiologic and clinical observations as guides to therapy. Ann Intern Med 1983;98:447.
Surgery is indicated for patients on appropriate therapy who have persistent fever for more than 9 days or evidence of prosthetic valve dysfunction.
Kloos WE, Bannerman TL. Update on clinical significance of coagulase-negative staphylococci. Clin Microbiol Rev 1994;7:117.
Lowy FD, Hammer SM. Staphylococcus epidermidis infections. Ann Intern Med 1983;99:834.
S. epidermidis is an important cause of infection in patients with a prosthetic valve, prosthetic hip, central nervous system shunt, vascular graft, or peritoneal dialysis catheter.
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The leading cause of nosocomial bacteremia, associated with an 8.5-day increase in length of stay.
Patrick CC. Coagulase-negative staphylococci: pathogens with increasing clinical significance. J Pediatr 1990;116:497.
Rupp ME. Coagulase-negative staphylococcal infections: an update regarding recognition and management. In: Remington JS, Swartz MN, eds. Current Clinical Topics in Infectious Diseases. Clin Boston: Blackwell Science, 1997;17:51–87.
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Review. Most infections are nosocomial and involve indwelling foreign devices.
Tenover FC, Arbeit RD, Goering RV. How to select and interpret molecular strain typing methods for epidemiological studies of bacterial infections: a review for health care epidemiologists. Infect Control Hosp Epidemiol 1997;18:426–439.
A review of strain typing methods. For coagulase-negative staphylococci, pulse-field gel electrophoresis is preferred.
Whitener C, et al. Endocarditis due to coagulase-negative staphylococci. Infect Dis Clin North Am 1993;7:81.
Review. Cure of prosthetic valve endocarditis usually requires a combination of antimicrobials plus surgery.
Winston DJ, et al. Coagulase-negative staphylococcal bacteremia in patients receiving immunosuppressive therapy. Arch Intern Med 1983;143:32.
An important pathogen in the patient with granulocytopenia and an IV catheter.


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