Alan A. Harris

Prosthetic Valve Endocarditis Resulting from Nosocomial Bacteremia: A Prospective, Multicenter Study

More than 100 000 artificial heart valves are implanted annually in the United States, and the number is increasing [1]. Because the number of invasive therapeutic and diagnostic procedures done during hospitalization is also increasing, the risk for bacteremia is correspondingly greater. A common dilemma for the clinician is determining the optimal therapeutic approach to a patient with a prosthetic valve who develops bacteremia. There has been controversy regarding the optimal duration of antibiotic therapy for bacteremic patients with prosthetic valves. An informal survey of infectious disease and cardiology specialists revealed that the recommended duration of therapy ranged widely, from 10 days to 8 weeks. To clarify this issue, we conducted a prospective, observational, multicenter study during a 3-year period in six university teaching hospitals with high-volume cardiac surgery. Our objectives were to determine 1) the incidence of endocarditis in bacteremic patients with an implanted heart valve, 2) the risk factors for development of subsequent prosthetic valve endocarditis, and 3) the optimal duration of antibiotic therapy in this select group of patients who experience bacteremia. We also report mortality rates. Methods We did a prospective, observational study at six university teaching hospitals: The Cleveland Clinic, Cleveland, Ohio; St. Lukes Episcopal Hospital, Houston, Texas; Rush-Presbyterian-St. Lukes Medical Center, Chicago, Illinois; St. Vincent Hospital and Medical Center, Portland, Oregon; Hunter-McGuire Veterans Affairs Medical Center, Richmond, Virginia; and Presbyterian University Hospital and Veterans Affairs Medical Center, Pittsburgh, Pennsylvania. The study lasted approximately 2 years at each hospital and was conducted in the period from 1986 to 1989; start dates differed among hospitals. Bacteremic patients were identified through a daily review of blood culture results in the microbiology laboratory; these patients were then screened by the infection control practitioner for presence of a prosthetic heart valve. The study group comprised bacteremic patients with a prosthetic valve who were prospectively monitored during the hospitalization and after discharge for 1 year. All treatment decisions were made by the attending physicians without intervention by the investigators. Bacteremia was considered to be present if one or more blood cultures yielded an organism. Endocarditis was classified as definitive, presumptive, and suspicious. Definitive endocarditis was defined by 1) culture positivity or proven pathology [demonstration of vegetations or isolation of the organism from a prosthetic valve obtained at autopsy or during open heart surgery] or 2) vegetations documented on echocardiogram. Presumptive endocarditis was defined by peripheral embolic signs, including Osler nodes, Janeway lesions, Roth spot, petechiae, splenomegaly, acute cerebrovascular accident; or a new or changing murmur. The criterion for suspicious endocarditis was sustained bacteremia (defined by three positive blood cultures of three or the occurrence of at least four positive blood cultures within 72 hours) with no identified portal of entry. Thus, four positive cultures obtained within 72 hours fulfilled the criterion for suspicious endocarditis, whereas two positive of two or three positive of four blood cultures obtained within 72 hours did not. Demonstration of vegetations by transthoracic echocardiography in a bacteremic patient with a prosthetic valve was arbitrarily considered as definitive evidence for endocarditis; transesophageal echocardiography was not routinely done at the time of study. Patients were classified as having bacteremia only, as having bacteremia with endocarditis at the outset, or as having bacteremia with subsequent development of new endocarditis (Table 1). Patients who were identified as having endocarditis at the time the initial blood culture was obtained were classified as having endocarditis at the outset. Patients in whom bacteremia led to the subsequent development of prosthetic valve endocarditis were classified as having new endocarditis. Table 1. Criteria for Diagnosis of Endocarditis The portal of entry for bacteremic infection was defined by isolation of the same organism from a source other than blood or cardiac vegetation and by review of the patient record by the investigators. Subtyping of the isolates was not done. We assessed severity of illness for each patient at the time of bacteremia using an index based on mental status, vital signs, the need for respiratory support, and the occurrence of cardiac arrest; previous investigators have found this index to be highly predictive of outcome [2-4]. All bacteremic patients with prosthetic valves were prospectively studied for up to 1 year after the onset of bacteremia. Outcome and cardiac status were assessed 1, 2, 6, and 12 months after the detection of bacteremia. Discharged patients had telephone follow-up on chart review at 6 and 12 months. Clinical and laboratory data for analysis were entered into a computer database (Prophet Systems, Division of Research Resources, National Institutes of Health, Bethesda, Maryland). Categorical data were analyzed using a chi-square or Fisher exact test. Continuous variables (age, days hospitalized, and laboratory values) were compared using the t-test or Newman-Keuls test. A multiple regression model was used to examine the effects of several factors on the development of endocarditis. The regression model was also used to evaluate the risk factors for death. Factors used in the regression model were those found to be significant by univariate analysis and those hypothesized to seriously affect outcome. Results One hundred seventy-one patients with bacteremia and a prosthetic heart valve constituted the study group. The mean number of positive blood cultures per patient was 3.0 and the median number was 3.6 (range, 1 to 14 blood cultures). All patients had fever, which was usually the motivating factor for obtaining the blood culture. At 6 months, follow-up data were complete for all 171 study patients. By 12 months, 4 patients with bacteremia had been lost to follow-up, but follow-up data were obtained on all 74 patients with endocarditis. Patient age ranged from 23 to 89 years (mean age, 65 years). Bacteremic patients were significantly older (mean age, 69 years) than those with endocarditis (mean age, 60 years) (P < 0.001). Other clinical and demographic characteristics are shown in Table 2. Table 2. Demographic and Clinical Characteristics of 171 Patients with Bacteremia Who Had Prosthetic Valves Endocarditis Seventy-four of 171 patients (43%) were classified as having prosthetic valve endocarditis. Of these 74 patients, 42 (57%) were classified as having definitive endocarditis, 22 (30%) as having presumptive endocarditis, and 10 (13%) as having suspicious endocarditis. Of the 171 study patients, 56 (33%) were classified as having endocarditis at the time bacteremia occurred (endocarditis at the outset) and 18 (10%) as having endocarditis that developed after bacteremia (new endocarditis). The remaining 97 patients (57%) with bacteremia had no evidence of endocarditis (see Table 2). Twenty-three patients had vegetations detectable by transthoracic echocardiography: Seven patients were classified as having definitive prosthetic valve endocarditis based solely on echocardiographic demonstration of vegetations; another 6 patients had abnormal echocardiographic findings but also showed other objective evidence of endocarditis (including new or changing murmur and peripheral stigmata); and 10 patients with abnormal echocardiographic findings had the diagnosis confirmed at open heart surgery or at autopsy. Transesophageal echocardiography was not routinely used at the time of our study. Of the 74 patients with prosthetic valve endocarditis, 2 (3%) had peripheral embolism (cerebral emboli or cerebrovascular accident), 15 (20%) had stigmata (Osler nodes, Janeway lesions, Roth spot, petechiae), 4 (5%) had splenomegaly, and 23 (31%) had new or changing murmur. No significant difference was found regarding the presence of these signs between patients with new endocarditis and those with endocarditis at the outset (data not shown). Location and Type of Valvular Prosthesis Eighty-seven of the 171 study patients (51%) had prosthetic mitral valves, 102 (60%) had prosthetic aortic valves, and 8 (5%) had prosthetic tricuspid valves (the number of patients totals more than 171 because 25 patients [15%] had more than one prosthetic valve) (Table 3). Presence of a prosthetic mitral valve was seen significantly more often in patients with new endocarditis (P = 0.005), whereas prosthetic aortic valves were seen significantly more often in patients with endocarditis at outset (P < 0.001) (Table 3). Of the 171 study patients, 82 (48%) had mechanical valves and 87 (51%) had biological valves (including 5 patients with both mechanical and biologic valves). In seven cases (4%), the exact valve type was not known because the operation had been done elsewhere and past medical records were not available (see Table 3). No association was observed between type of valve and the occurrence of endocarditis. Table 3. Valvular Location and Type in 171 Bacteremic Patients with Prosthetic Valves Timing of Endocarditis Prosthetic valve endocarditis has been arbitrarily classified as early when it occurs within 60 days of valve insertion and late when it occurs more than 60 days after valve insertion [5]. Of the 74 patients with prosthetic valve endocarditis, 23 (31%) were classified as having early endocarditis and 51 (69%) as having late endocarditis. Twelve of the 18 patients (67%) with new endocarditis were classified as having early onset disease compared with 11 of 56 patients with endocarditis at the outset (difference, 48%; 95% CI, 19 to 75; P < 0.001). Cause of Bacteremia As shown in Table 4, 206 o

Pseudomonas maltophilia pseudosepticemia

During a 17 month period, 25 hospitalized adult patients had blood cultures reported as positive for Pseudomonas maltophila. Review of the hospital records suggested that these were contaminants and that blood for coagulation studies and for cultures that were subsequently positive had been drawn simultaneously. The source of contamination appeared to be black-top evacuated collection tubes used for coagulation studies in adults. Cultures of the liquid anticoagulant tubes yielded a pure growth of greater than 10(5) colony forming units (CFU)/cc of Ps. maltophilia on blood agar. Mock trials demonstrated that following venipuncture by syringe, inoculation of contaminated black-top tubes prior to inoculation of blood culture bottles would yield false-positive blood cultures (pseudosepticemia). One patient being treated for streptococcal prosthetic valve endocarditis and having frequent coagulation studies with blood obtained via direct venipuncture into evacuated collection tubes was found to have superinfection of his prosthetic valve with Ps. maltophilia at autopsy. Prosthetic valve infection may have occurred after reflux of contaminated anticoagulant from an evacuated collection tube directly into the vein. Contaminated evacuated collection tubes are a potential source of confusion in the diagnosis of infection as well as a potential source of true infection.

Antibodies to hepatitis B surface antigen as the sole hepatitis B marker in hospital personnel.

The epidemiologic and serologic differences between hospital employees with antibodies to hepatitis B surface antigen (anti-HBs) alone or in combination with antibodies to hepatitis B core antigen (anti-HBc) were evaluated. Of 105 employees with anti-HBs, 38 (36%) did not have anti-HBc. Sera from employees with anti-HBs alone had significantly lower mean sample ratio units of anti-HBs than sera with both antibodies (15.9 +/- 43.2 as compared to 110.3 +/- 73.9, p less than 0.0005) and more commonly had less than 10 sample ratio units of anti-HBs (32 [84%] of 38 as compared to 9 [13%] of 67, p = 0.0001). The anti-HBs in sera with anti-HBs alone was predominantly IgM as shown by inactivation with 2-mercaptoethanol and the presence of anti-HBs activity in serum IgM fractions. Failure of protection from hepatitis B virus infection in persons with anti-HBs alone and the presence of nonprotective IgM anti-HBs in chimpanzees has been reported. Our data suggest the use of anti-HBs as a single serologic screening test for hepatitis B virus immunization programs may not be reliable in identifying employees with protective antibodies.

Panniculitis associated with histoplasmosis and alpha1-antitrypsin deficiency

A patient with mediastinal histoplasmosis, alpha 1-antitrypsin deficiency, and panniculitis is presented. The patient showed dramatic response to treatment with ketoconazole. The associations of panniculitis with histoplasmosis and alpha 1-antitrypsin deficiency are discussed.

Clinical efficacy of cefotaxime in serious infections.

Thirty-five patients underwent 38 treatment courses with cefotaxime. Documented infections included 11 bacteremias, 7 cases of nosocomial pneumonia, 6 surgical wound infections, 3 bone infections, 1 biliary infection, and 1 urinary tract infection. Granulocytopenic patients with fever received 15 courses of empiric cefotaxime therapy alone; in 8 courses, no definite site of infection or pathogen was isolated. Broad-spectrum antibiotics had been administered to 23 patients before cefotaxime. Thirty-seven bacterial pathogens were isolated from 25 patients. Three such pathogens were resistant to cefotaxime and required alternative therapies. Pathogenic isolates included 13 Serratia marcescens, 12 Pseudomonas aeruginosa, 4 Escherichia coli, 2 Klebsiella pneumoniae, 2 Providencia stuartii, 1 Enterobacter cloacae, 1 Haemophilus influenzae, 1 Enterococcus, and 1 Staphylococcus aureus. Of the treatment courses, 25 of 38 resulted in a favorable response to cefotaxime, including 9 of 15 in granulocytopenic patients. Superinfection was seen in one patient. The emergence of resistance was documented in another patient. Of 15 patients with multiply resistant pathogens, 12 improved with cefotaxime. Of 12 patients with Pseudomonas aeruginosa, 6 favorably responded. Possible complications of cefotaxime were observed in 14 of 42 treatment courses. Cefotaxime is most useful in treatment of infections due to multiply resistant, gram-negative pathogens other than Pseudomonas aeruginosa.

Effect of zidovudine postexposure prophylaxis on the development of HIV-specific cytotoxic T-lymphocyte responses in HIV-exposed healthcare workers.

We evaluated the effects of zidovudine postexposure prophylaxis (PEP) on the development of human immunodeficiency virus (HIV) envelope-specific cytotoxic T-lymphocyte responses in 20 healthcare workers with occupational exposures to HIV. Seven healthcare workers were treated with zidovudine PEP. Only 1 of 7 treated, versus 6 of 13 not treated, developed an HIV envelope-specific cytotoxic T-lymphocyte response. These data suggest that zidovudine abrogated HIV-specific cytotoxic T-lymphocyte responses. HIV-specific cytotoxic T-lymphocyte responses may be useful as a surrogate marker of HIV replication in the evaluation of new regimens for PEP of occupational HIV exposures.

In vitro activity of tosufloxacin (A-61827; T-3262) against selected genital pathogens.

The in vitro activity of tosufloxacin (A-61827; T-3262) against 15 clinical isolates of Chlamydia trachomatis and 31 recent clinical isolates of Neisseria gonorrhoeae, including 15 spectinomycin-resistant N. gonorrhoeae and 16 penicillinase-producing N. gonorrhoeae, was determined. Tosufloxacin was compared with doxycycline, ciprofloxacin, and temafloxacin against C. trachomatis. Susceptibility testing was performed by using McCoy cell monolayers. The in vitro activity of tosufloxacin against N. gonorrhoeae was compared with that of ciprofloxacin, temafloxacin, doxycycline, ceftriaxone, and spectinomycin by using an agar dilution method. Tosufloxacin was as active as temafloxacin against C. trachomatis (MIC for 90% of strains tested [MIC90], 0.25 microgram/ml; MBC for 90% of strains tested [MBC90], 0.25 microgram/ml) and was almost as active as doxycycline (MIC90, 0.06 microgram/ml; MBC90, 0.125 microgram/ml). Ciprofloxacin, temafloxacin, and tosufloxacin were extremely active against N. gonorrhoeae, including spectinomycin-resistant N. gonorrhoeae and penicillinase-producing N. gonorrhoeae, with MIC90s of 0.004, 0.015, and 0.008 microgram/ml, respectively. Ceftriaxone was slightly less active (MIC90, 0.03 microgram/ml), and doxycycline was the least active drug tested (MIC90, 4.0 micrograms/ml). Tosufloxacin and temafloxacin had excellent activity against the C. trachomatis and N. gonorrhoeae strains tested.

Haemophilus influenzae Meningitis in the Presence of a Cerebrospinal Fluid Shunt

Haemophilus influenzae meningitis in the presence of a cerebrospinal fluid shunt has been reported uncommonly. Staphylococcus aureus and Staphylococcus epidermidis, the most common etiological agents, are usually acquired by contiguous spread from an intraoperative or perioperative source. These infections usually occur within 2 months of shunt insertion and are rarely associated with bacteremia. Review of the literature shows that infection with H. influenzae typically occurs later than with the more common pathogens, is commonly associated with bacteremia, and frequently can be treated with antibiotics alone.

Frequency of Salmonella typhimurium the year after a massive outbreak

In 1985, Illinois experienced a large milkborne outbreak of Salmonella typhimurium with over 16,000 cases. During this year, 49.4% of United States and 86.4% of Illinois salmonellae were S. typhimurium. In 1986, 1133 microbiologically confirmed and serotyped cases of salmonellosis were reported in the City of Chicago, comprising 37% of the 3034 cases reported for the State of Illinois. The most frequent serotypes were S. typhimurium (21.3%), Salmonella heidelberg (18.2%), Salmonella enteritidis (10.7%), and Salmonella braenderup (7.7%), similar to the state as a whole. Nationally, excluding Illinois, the most frequent serotypes in 1986 were S. typhimurium (26.1%), S. enteritidis (14.7%), and S. heidelberg (13.0%). S. braenderup comprised 0.9% of the non-Illinois total. Regional variations in the epidemiology of salmonellae are probable and may reflect detected or undetected outbreaks. Within a year of the nations largest Salmonella outbreak, there was no trace of any effect on the frequency of isolation of Salmonella spp.

Selected Aspects of Nosocomial Infections in the 1980s

Unusual or rare pathogens and syndromes may become significant problems in nosocomial infection. Pathogens that usually produce community-onset disease, particularly respiratory viruses, Legionella, and atypical mycobacteria, also cause nosocomial infection. Conversely, nosocomial pathogens may also produce disease in the community, as has been seen with Clostridium difficile. Contamination of parenteral and antiseptic solutions continues to be a problem in hospitals. Hospital-acquired viral infections are receiving increasing recognition. Nosocomial gastrointestinal infections, although of low frequency, are of major import because of their epidemic potential. Airborne transmission of pathogens is becoming more apparent at the same time that recognition of the importance of hand transmission creates hope for infection control. Antibiotics influence the type of microorganisms that colonize patients, but the host determines superinfection.