Comparison of broad-range bacterial PCR and culture of cerebrospinal fluid for diagnosis of community-acquired bacterial meningitis.

Appropriate, rapid and reliable laboratory tests are essential for the diagnosis and optimal antibiotic therapy of acute bacterial meningitis. Broad-range bacterial PCR, combined with DNA sequencing, was compared with culture-based methods for examining cerebrospinal fluid (CSF) samples from patients with suspected meningitis. In total, 345 CSF specimens from 345 patients were analysed, with acute community-acquired bacterial meningitis being diagnosed in 74 patients. The CSF of 25 patients was positive by both PCR and culture; 26 patients had CSF specimens positive by PCR only, and 14 patients had specimens positive by culture only. The sensitivity of PCR and culture for clinically relevant meningitis was 59% (44/74) and 43% (32/74), respectively, while the specificity was 97% (264/271) and 97% (264/271), respectively. The commonest bacterial rRNA gene sequences detected by PCR only were those of Streptococcus pneumoniae and Neisseria meningitidis (n = 12). PCR failed to detect the bacterial rRNA gene in seven specimens from patients with symptoms compatible with acute bacterial meningitis. Overall, the results demonstrated that PCR in conjunction with sequencing may be a useful tool in the diagnosis of bacterial meningitis. PCR is particularly useful for analysing CSF from patients who have been treated with antibiotics before lumbar puncture.

Infective endocarditis: a diagnostic and therapeutic challenge for the new millennium.

This review on infective endocarditis (IE) is based on clinical studies carried out in Göteborg since 1984, data obtained from a Swedish national registry of IE since 1995 and existing literature. IE is still a great challenge in medicine, although improved bacteriological and echocardiographical techniques have facilitated diagnosis. In Sweden the incidence of IE is about 6 per 100,000 inhabitants a year. During recent decades IE has changed character. Patients are older, fever is often the only major symptom and a new murmur is less frequent. Streptococci, including viridans species and staphylococci, are still the most common bacteria found. Antibiotic treatment for 4-6 weeks may reduce mortality of IE to 30-50%. For further reduction, heart surgery is necessary in 20-25% of patients in order to remove infected tissues and restore valve function. Rapid diagnosis, careful antibiotic treatment and optimal surgery may reduce mortality associated with treatment to 10%. Antibiotic treatment is still mainly empiric. Penicillin and aminoglycoside for 2 weeks only seem to be effective in uncomplicated IE caused by alpha-streptococci. Otherwise, 4 weeks of treatment is needed, but aminoglycoside treatment may be reduced to 1 week in general and 2 weeks for enterococcal infections.

Incidence of beta-lactam-induced delayed hypersensitivity and neutropenia during treatment of infective endocarditis.

BACKGROUND: Long-term parenteral beta-lactam treatment is often complicated by adverse reactions that necessitate drug withdrawal. OBJECTIVE: To evaluate the incidence and mechanism of beta-lactam adverse reactions during an 8-year period in all episodes of suspected infective endocarditis in patients treated at a university-affiliated institution. METHODS: Patients with 215 consecutive episodes of beta-lactam treatment for 10 days or more were prospectively enrolled during 2 periods, January 1984 through December 1988 and January 1993 through December 1995, and compared with 51 episodes of vancomycin hydrochloride treatment for 10 days or more. Incidents of adverse reactions, such as fever, rash, or neutropenia, were registered. Neutrophil counts, eosinophil counts, and penicillin antibodies were studied. Patients with delayed adverse reactions to penicillin G sodium were rechallenged with penicillin v potassium. RESULTS: Incidence of delayed adverse reactions during treatment was 33% with beta-lactams compared with 4% with vancomycin. Rates of adverse event for beta-lactams increased continuously from treatment day 15 to day 30. A 6-fold difference in capacity to induce adverse events was found with different beta-lactams. Penicillin G induced neutropenia in 14% and any adverse event in 51% of treated episodes. Mean daily doses significantly influenced the frequency of adverse events. Occurrence of hemagglutinating penicillin antibodies was significantly related to patients whose penicillin-treated episodes were complicated with adverse events. Patients with delayed adverse reactions to penicillin G were safely rechallenged with penicillin. CONCLUSIONS: Incidence of delayed adverse reactions to beta-lactams increases sharply when parenteral treatment is extended beyond 2 weeks. Penicillin G is the most frequent inducer of adverse reactions among beta-lactams studied. An immunological reaction mediated by antibodies to the penicilloyl determinant may be involved in the pathogenesis, possibly enhanced by a dose-related toxic trigger mechanism. Beta-Lactam-induced neutropenia followed a uniform pattern, occurring after, on average, 21 days of treatment, and might be due to both immunologic and toxic effects of treatment. Patients with a late adverse reaction to penicillin can safely be re-treated with penicillin, although they should remain under close surveillance if treatment extends beyond 2 weeks.

Virulence factors of Staphylococcus aureus strains causing infective endocarditis--a comparison with strains from skin infections.

The objective was to study potential bacterial virulence factors in S. aureus endocarditis. S. aureus strains isolated from patients with well-classified episodes of infective endocarditis (IE) (n=26) were compared with control S. aureus strains from consecutive patients with skin infections (n=30). The potential virulence factors studied were Staphylococcal enterotoxin A-D (SEA, SEB, SEC, SED) and toxic shock syndrome toxin-1 (TSST-1) production and binding capacity to the extracellular matrix proteins: fibronectin, collagen type I, collagen type II and bone sialoprotein (BSP). None of the potential virulence factors studied was more prevalent among the IE strains. BSP binding was more often found in the control group with skin infections. Endocarditis patients with previous damage of the heart valves were more often infected by strains not producing any enterotoxin. No correlation was found between the potential bacterial virulence factors studied and IE. Concerning the toxins known to act as superantigens (SEA-E and TSST-1), the tendencies in this and other studies indicate that a larger study group might identify them as pathogenic factors in a subgroup of staphylococcal endocarditis.

Fever, C-reactive protein, and other acute-phase reactants during treatment of infective endocarditis.

BACKGROUND: Fever and sustained elevations of levels of C-reactive protein, erythrocyte sedimentation rate, and other inflammatory markers are common problems during treatment of infective endocarditis. We studied the value of these measurements during an 8-year period in all episodes of infective endocarditis treated in 1 university-affiliated institution. METHODS: A total of 193 consecutive episodes that fulfilled the criteria for infective endocarditis were prospectively enrolled during 2 periods, 1984 through 1988 and 1993 through 1995. Fever and results of serial measurements of C-reactive protein, erythrocyte sedimentation rate, white blood cell counts, and platelet counts were related to the clinical course of infective endocarditis. RESULTS: Fever persisted or recurred in 108 episodes (57%) despite appropriate antibiotic treatment. The causes of persistent fever and recurrent fever were different. Persistent fever that lasted 7 days or longer was caused by a complicating cardiac infection in 56% of these episodes. Recurrent fever, noted in 31% of all episodes and the major cause of fever during the third and fourth treatment weeks, was caused most often by hypersensitivity reactions to beta-lactams. Elevations in C-reactive protein levels were significantly prolonged in the episodes with complicated courses compared with the episodes with uncomplicated courses, while mean erythrocyte sedimentation rate remained unchanged during treatment, not differentiating between complicated and uncomplicated episodes. CONCLUSIONS: Fever during treatment must be analyzed in terms of persistence and recurrence to provide a basis for clinical decisions. Serial measurements of C-reactive protein are useful to monitor the response to antimicrobial therapy and to detect complications, while serial determinations of erythrocyte sedimentation rate are of no value.

C-reactive protein is more sensitive than erythrocyte sedimentation rate for diagnosis of infective endocarditis.

The objective of this study was to evaluate the sensitivity of C-reactive protein (CRP) elevation compared to erythrocyte sedimentation rate (ESR), leucocyte count and thrombocyte count in the diagnosis of infective endocarditis (IE). It was designed as a prospective study of suspected episodes of IE in adults in tertiary care at a university-affiliated department of infectious diseases. In 89 episodes of IE, CRP was available from the start of treatment. Median age was 66 years, 45 were men and 44 women. Median CRP concentration was found to be 90 (range 0-357) mg/l with only 4% normal values. Episodes involving native valves had higher CRP than episodes occurring with prosthetic valves. Staphylococcal origin, short duration of symptoms, short duration of fever and highest recorded temperature all correlated to higher CRP levels. The CRP response was also prominent among patients > 70 years old. Among non-responders, a few cases with simultaneous cirrhosis were noted. ESR was less sensitive than CRP, with a normal level in 28% of the episodes. It was concluded that CRP determination is superior to erythrocyte sedimentation rate, leucocyte count and thrombocyte count in the diagnosis of infective endocarditis.

Early surgery in infective endocarditis.

Optimal timing of surgical intervention in infective endocarditis is important in reducing mortality. We prospectively studied 126 consecutive episodes of infective endocarditis treated in one institution over 5 years, with special emphasis on long-term results and on the effects on outcome of surgical interventions. Twenty-six patients (21%) underwent acute surgery on median treatment day 14. Mortality during treatment was 8% for patients undergoing acute surgery vs. 11% for those not undergoing surgery, and the adjusted 5-year survival rate of acute surgically treated patients was 91%, compared with 69% for the medically treated patients. Using univariate analysis, excess mortality during 5 years follow-up was associated with new cardiac decompensation at entry (p < 0.01), age (p < 0.01), no acute surgery (p < 0.05) and mitral valve involvement (p < 0.05). Multivariate analysis showed new cardiac decompensation at entry to be an independent predictor of cardiac death at 5 years follow-up (relative risk 2.39; CI 1.05-5.45), while no surgery during active disease implied a relative risk of 3.45, though not statistically significant. Patients undergoing surgery very early (< or = 10 days of treatment) did not have a poorer outcome. Acute valve replacement, as compared with medical therapy only, might be important to increase both short-term and long-term survival in infective endocarditis.

Comparison of the von Reyn and Duke criteria for the diagnosis of infective endocarditis: a critical analysis of 161 episodes.

The newly proposed diagnostic criteria for infective endocarditis (Duke criteria) were evaluated in 161 consecutive episodes treated for suspected infective endocarditis (IE) at one institution over a 5-year period. A significantly higher proportion of episodes were diagnosed as definite endocarditis by the new Duke criteria compared with a diagnosis as definite or probable endocarditis by the older von Reyn criteria (68% vs 56%; p < 0.05). If all 161 episodes were to be reclassified, excluding pathological data, which are seldom available at the start of treatment, the Duke criteria classified significantly more episodes as 'definite' compared with the analogous category 'probable' endocarditis by the von Reyn criteria (60% vs 44%; p < 0.01). Forty-four pathologically proven episodes were reclassified in the same way, and 73% of these episodes were classified as 'definite' IE by the Duke criteria compared to 55% classified as 'probable' IE using the von Reyn criteria In 33 (20%) episodes no heart murmur could be detected on admission and the Duke criteria provided an initial diagnosis of 'definite' IE in 58% of these episodes compared with only 6% classified as 'definite' or 'probable' IE by the von Reyn criteria (p < 0.0001). The newly proposed Duke criteria are an improvement on the older von Reyn criteria in the clinical diagnosis of IE, especially in initial phase of treatment. However, the sensitivity when establishing a correct clinical diagnosis of 'definite' IE for the pathologically proven cases was only 73%. The category of 'possible' IE by the Duke criteria is confusing, since it does not say anything of the likelihood on an actual IE; the only objective fact is that no alternative diagnosis has been proven.

Fungal endocarditis--a report on seven cases and a brief review.

Candida endocarditis is an unusual but severe complication of systemic infection caused by Candida albicans and occasionally by other fungal species. We describe seven cases that occurred during a period of 20 years in western Sweden. In four cases infections were located on prosthetic valves and in three cases native valves were involved. Three patients died of the disease in the acute phase. A definite diagnosis was established in one of four survivors. This patient had an aortic valve endocarditis and a saddle embolisation and was treated with immediate surgery, followed by intensive treatment with liposomal amphotericin B+ flucytosine. Fungal endocarditis is still a serious disease with a high mortality and whenever the diagnosis is suspected, antifungal therapy must be started and transesophageal sonography should be performed to visualize vegetations. Immediate surgery should be considered.

Epidemiologic aspects of infective endocarditis in an urban population. A 5-year prospective study.

A prospective study of the epidemiology of infective endocarditis (IE) in a well-defined urban population of 428,000 inhabitants during a 5-year period was carried out. All patients were treated in the same institution, and history, diagnostic procedures, and treatment were standardized. Of 233 consecutive suspected episodes of IE, 127 fulfilled the modified von Reyn criteria. After patients not living in the defined area were excluded, 99 episodes in 90 patients were analyzed in the epidemiologic part of the study. Of these, 33 episodes were definite endocarditis, verified by surgery or autopsy; 35 probable; and 31 possible endocarditis episodes. Another 34 episodes were found retrospectively and are included in the incidence calculation. The crude incidence was calculated to be 6.2/100,000 inhabitants per year, which is high compared to earlier studies. Adjusted to the population of Sweden, the incidence was 5.9/100,000 inhabitants per year. The annual incidence was higher for women, 6.6/100,000, than for men, 5.8/100,000. In the oldest age-group (80-89 years) the annual incidence was 22/100,000 in the prospective study and 30/100,000 if retrospective cases were included. Contrary to almost all other studies, we did not find a male predominance among our cases. Only 7% of patients were intravenous drug abusers, and 15% had a prosthetic valve. The most common bacteria were methicillin-susceptible Staphylococcus aureus (31%) and alpha-streptococci (28%); 12% of episodes were culture negative. The mortality from IE in the population was 1.4/100,000 inhabitants per year. A higher-than-expected incidence of IE was found, especially among older patients and women.

Empiric treatment of acute diarrheal disease with norfloxacin. A randomized, placebo-controlled study. Swedish Study Group.

OBJECTIVE: To evaluate the clinical and microbiologic efficacy and safety of norfloxacin for acute diarrhea. DESIGN: Double-blind, placebo-controlled, randomized clinical multicenter trial. SETTING: Six departments of infectious disease. PARTICIPANTS: Patients 12 years of age or older with a history of acute diarrhea lasting 5 or fewer days. Eighty-five percent of patients (511/598) were evaluable for efficacy. Of these evaluable patients, 70% had traveled abroad within the previous 6 weeks. INTERVENTIONS: Patients received either norfloxacin, 400 mg, or placebo twice daily for 5 days. MEASUREMENTS: Enteric pathogens were isolated in 51% of the evaluable patients: Campylobacter species in 29%, Salmonella species in 16%, Shigella species in 3.5%, and other pathogens in 2.6%. RESULTS: Norfloxacin had a favorable overall effect compared with placebo (cure rate, 63% compared with 51%; P = 0.003). There were statistically favorable effects in culture-positive patients, patients with salmonellosis, and severely ill patients but not in culture-negative patients or patients with campylobacteriosis or shigellosis. A significant difference was noted between norfloxacin and placebo in median time to cure among all evaluable patients (3 compared with 4 days, P = 0.02) and in patients with campylobacteriosis (3 compared with 5 days, P = 0.05) but not in patients. Culture-positive, but not culture-negative patients, in the norfloxacin group had significantly fewer loose stools per day compared with patients in the placebo group from day 2 onward (P less than or equal to 0.01). Norfloxacin was significantly less effective than placebo in eliminating Salmonella species on days 12 to 17 (18% compared with 49%, P = 0.006), whereas the opposite was true for Campylobacter species (70% compared with 50%, P = 0.03). In six of nine patients tested, norfloxacin-resistant Campylobacter species (MIC, greater than or equal to 32 micrograms/mL) appeared after norfloxacin treatment. CONCLUSION: Empiric treatment reduced the intensity and, to some extent, the duration of symptoms of acute diarrhea. The effect was restricted to patients who had bacterial enteropathogens or who were severely ill. The clinical usefulness of this treatment is limited by the fact that norfloxacin seems to delay the elimination of salmonella and to induce resistance in campylobacter.