Catheter-related bloodstream infections are a main contributor to the morbidity and mortality in patients with pulmonary hypertension (PH) receiving continuous intravenous (IV) infusion of epoprostenol (epoprostenol sodium [Flolan]; Gilead, Foster City, CA).1 The frequent occurrence of micrococcal bloodstream infections among PH patients on epoprostenol was first reported in 1998.2 These observations were later confirmed in 2 different studies in which Micrococcus species was the second most common cause of bacteremia only after Staphylococcus aureus in patients treated with epoprostenol.3,4 Micrococci are considered contaminants from the skin and mucous membranes nevertheless can cause bacteremia, pneumonia, and endocarditis in immunocompromised patients.5-9 Interestingly, the occurrence of micrococcal bloodstream infections is rarely reported in patients with long-term central venous catheters placed for medical reasons other than PH.10-12 Although micrococcal catheter-related bloodstream infection is a common occurrence among patients with PH on epoprostenol, no studies have been published about risk factors, clinical manifestations, or therapeutic options for this infection.
In March 2006, we were consulted on the case of a patient with mixed connective tissue disease and PH complaining with worsening shortness of breath and fever. She was on continuous epoprostenol treatment for 21 months through a Groshong catheter. The patient was previously admitted to the hospital because of the same symptoms 1 month prior. At that time, she had a positive urine culture for Escherichia coli and 1 of 2 blood cultures positive for Micrococcus species. The patient was treated for urinary infection, and the blood culture was regarded as a contaminant. On the second admission, 2 blood cultures were positive again for Micrococcus species. The patient was treated with IV ampicillin/sulbactam based on the antibiogram for 4 weeks, through a peripherally inserted central catheter. The Groshong catheter was left in place. After 4 weeks, her blood cultures were still positive for Micrococcus species, which became resistant to ampicillin/sulbactan based on a new antibiogram. An echocardiogram was negative for vegetations. Peripherally inserted central catheter and Groshong catheters were removed, and the tips of both catheters grew Micrococcus species. The patient was successfully treated with vancomycin.
Prompted by this case, we reviewed all the blood cultures in patients with PH on continuous epoprostenol treated at our institution. The study was approved by the institutional review board of the Ohio State University. We searched in our database for patients with PH treated with epoprostenol and with positive blood cultures from January 2001 to December 2006. Catheter-related bloodstream infection was defined as the presence of a recognized pathogen isolated from one or more blood cultures obtained from peripheral stick and from the port of the catheter and not related to infection at another site.13 The charts of patients with positive cultures for micrococcal infection were reviewed. Micrococcus species were identified by Gram stain, biochemical testing (catalase positive, oxidase positive) and yellow colony morphology. Susceptibility testing was performed with the use of MicroScan (Siemens Healthcare Diagnostics, Inc., New Castle, Del) using Gram-positive panel PC26.
From January 2001 to September 2006, we had 93 PH patients requiring continuous infusion of epoprostenol through a Groshong catheter. Thirty-one (33%) of these patients had a total of 45 episodes of bacteremia. Staphylococcus aureus and Staphylococcus epidermidis accounted for 21 episodes (46.6%) followed by 5 cases of Micrococcus species and Corynebacterium species (11.1% each one) (Table 1). A similar incidence of micrococcal infection was reported in 1998 by Ehrensing et al,2 although significantly less than the incidences of 20% to 35% recently reported.3,4,14 During the same period, at our medical center, 657 patients had a Groshong catheter inserted for different medical conditions other than PH and epoprostenol infusion; interestingly, none of these patients had a micrococcal bloodstream infection.
Four of 5 patients described fever. Three patients had an acute presentation, with generalized symptoms and localized infection on the exit site, whereas 2 had a subacute presentation (up to 2 months) without evidence of local infection at the catheter insertion site and intermittent fevers. Case 5 developed respiratory symptoms and pulmonary infiltrates that improved after treatment, a phenomenon previously reported.3 None of the patients had an elevated white blood cell count at presentation or during the course of the infection; case 1 had a low white blood cell count which was part of his underlying disease, and case 2 presented with leukopenia that improved after treatment (Table 2). None of these patients had any complications such as death, endocarditis, diskitis, osteomyelitis, or abscesses. All patients were discharged from the hospital after treatment.
All isolates were susceptible to vancomycin, cefazolin, gentamicin, and clindamycin. However, the lack of antimicrobial standard testing methods makes these data difficult to interpret. Patients 1 and 5 were discharged on proper antibiotics based on the antibiogram results, but the catheters were not removed in either of them. Both patients were readmitted because of persistent bacteremia. After catheter removal, the infection cleared in both patients. Conversely, the infection cleared effectively in the 3 patients who had the Groshong catheter removed early. This is consistent with the few case reports available in which micrococci only resolved after line removal.9 This raises the question whether the catheters should be removed in all patients with micrococcal bloodstream infections. The current guidelines recommend removal of a tunneled central venous catheter in any complicated bloodstream infection (local and distant infection) or if blood cultures show the presence of S. aureus, Gram-negative bacilli, or Candida species.13
The reason(s) why micrococcal infection is more prevalent in patients with PH requiring continuous epoprostenol infusion are unknown. The subspecies of Micrococcus involved are unknown because additional identification tests are not routinely performed in the majority of centers, including ours. It has been postulated that the process of reconstitution of epoprostenol by patients at home is a risk factor for contamination with the skin flora.4 In vitro studies recently showed that synthetic prostacyclin analogs may inhibit phagocytosis, bacterial killing, and cytokine generation potentially increasing the risk of infection on these patients.15 Interestingly, during the preparation of this article, the Center for Disease Control and Prevention issued a report about the higher incidence of bloodstream infections with Pseudomonas and Enterobacter species in patients with PH on IV treprostinil (treprostinil sodium [Remodulin]; United Therapeutics, Silver Spring, MD).14 This evidence suggests that these drugs may regulate the host immune response favoring the development of certain type of infections.
In conclusion, Micrococcus species is a common cause of bloodstream infections in patients receiving long-term IV epoprostenol, and their presence on a blood culture should not be interpreted as skin contamination. The clinical presentation can be acute or subacute; treatment should be based on the organism antibiotic susceptibilities; and removal of the line should be considered if the symptoms or the bacteremia persists. The microbiology laboratory should routinely evaluate the cultures for micrococci. The reasons why IV prostacyclins (epoprostenol, treprostinil) seem to favor the development of bacteremia due to a certain group of pathogens deserve to be further investigated.
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