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.

Carriage of penicillin-susceptible and non-susceptible pneumococci in healthy young children in Göteborg, Sweden.

OBJECTIVES: To study carriage of Streptococcus pneumoniae among healthy young children, determine the proportion of strains with decreased susceptibility to penicillin, and study possible risk factors for the carriage of penicillin-resistant strains. METHODS: Between February 1996 and February 1997, 620 healthy, 18-month-old children in Goteborg, Sweden were screened for carriage of S. pneumoniae with decreased susceptibility to penicillin. Nasopharyngeal samples were obtained from children visiting child health centres for routine health control. RESULTS: Streptococus pneumoniae was found in 322 samples and 18 strains (5.6%, CI95 3.4; 8.8) of all pneumococci showed decreased susceptibility to penicillin G with minimum inhibitory concentrations (MICs) ranging from 0.125 to 1.0 mg/l. The proportion of strains with decreased susceptibility was similar to that found in a laboratory-based material (6%), from the same geographical area and time period. A majority of the children with strains with decreased susceptibility to penicillin (n = 11) were not attending day-care centres. CONCLUSIONS: The prevalence of S. pneumoniae with reduced susceptibility to penicillin is still low in unselected healthy Swedish children.

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.

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.

Aminoglycosides do not improve the efficacy of cephalosporins for treatment of acute pyelonephritis in women.

A prospective, coordinated, randomized multicentre trial was conducted to determine whether tobramycin 160 mg intravenously (i.v.) once daily for 2 days would improve the efficacy of cefotaxime 1 g i.v. twice daily for 2 days followed by a 10-day course of oral cefadroxil 1 g twice daily, in the treatment of community-acquired acute pyelonephritis in women. Of 73 patients enrolled in the study, 51 could be evaluated according to the protocol. There were no significant differences in bacteriological cure rates between the combined treatment with tobramycin/cefotaxime and cefotaxime alone, either at short-term follow-up (63.0% vs 59.1%; 95% confidence interval (CI) for difference in proportions -23.4% to 31.2%), or up to 7 weeks after cessation of treatment (42.9% vs 52.2%; 95% CI, -18.0% to 36.6%). A modified intention-to-treat analysis showed no difference in clinical efficacy between the two regimens (68.6% vs 69.2%; 95% CI, -22.9% to 24.1%). Tobramycin seemed to enhance the resolution of inflammation by a more rapid decline in C-reactive protein levels. The high recurrence rates after treatment with beta-lactam antibiotics in this and previous studies of acute pyelonephritis may be explained by adverse ecological effects rather than failure to eradicate the infection.

The effect of inhaled and intranasal sodium cromoglycate on symptoms of upper respiratory tract infections.

BACKGROUND: A well established drug for the treatment of asthma and allergy, sodium cromoglycate, was found in open trials to be useful as a symptomatic treatment for upper respiratory tract infections. OBJECTIVE: To compare the efficacy of inhaled and intranasal sodium cromoglycate and matching placebos on the symptoms of upper respiratory tract infections. METHODS: Adult subjects with symptoms of runny nose, throat pain, or cough for less than 24 h were recruited. They were treated for 7 days using a randomized, double-blind, placebo-controlled, group comparative design. The medication given was: sodium cromoglycate dry powder 20 mg per inhalation in spincaps; sodium cromoglycate aqueous nasal spray delivering 5.2 mg per dose; or matching placebo as dry powder and nasal spray. One spincap and one spray per nostril were taken every 2 h during waking hours on days 1 and 2 and then four times daily on days 3-7. Severity of nine symptoms (general malaise, body aches and pains, chills and shivering, sneezing, nasal running, nasal blocking, sore throat, cough and voice disturbance) was recorded twice daily by subjects on diary cards, using a scale of 0 (absent) to 3 (severe). RESULTS: The study was conducted between February and April 1993. One hundred and eighteen patients aged 21-63 years (mean 41 years) were included. Symptoms resolved faster (P < 0.001) and the severity in the last three days of treatment was significantly less in patients treated with sodium cromoglycate than with placebo (P < 0.05-day 5; P < 0.01-day 6; P < 0.001-day 7). Side effects were local and mild and did not differ between the treatment groups. CONCLUSION: Sodium cromoglycate administered both by inhalation and intranasally is an effective treatment for the symptoms of upper respiratory tract infection. Its combined safety and efficacy would make it an acceptable form of treatment for these conditions.

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.

Incidence and prognosis of meningitis due to Haemophilus influenzae, Streptococcus pneumoniae and Neisseria meningitidis in Sweden.

The incidence, concomitant conditions and case fatality rate of Haemophilus influenzae (Hi) and pneumococcal meningitis and of invasive meningococcal infections were studied retrospectively in Sweden (population 8.4 million) for the years 1987-89, the period before vaccination against Hi type b started. A total of 1,019 cases with culture-verified infection were found. The incidence rates per 100,000 per year were 1.8 for Hi meningitis, 1.2 for pneumococcal meningitis and 1.0 for invasive meningococcal infections. The age-specific incidence was highest in the 3-23 months age group for the 3 bacterial species. Pneumococcal meningitis was common in individuals > or = 60 years and meningococcal infections in the age-group 10-24 years. A serious concomitant condition was known in 57% of all patients with pneumococcal meningitis while this was uncommon for the other organisms. The case fatality rate was 2% for Hi meningitis, 24% for pneumococcal meningitis and 10% for meningococcal infections. All 81 pneumococcal isolates which had been serotyped belonged to serotypes in the 23-valent pneumococcal vaccine. Of the meningococcal isolates, 65% belonged to serogroup B. In conclusion, the high incidence of Hib meningitis justifies general Hib vaccination. Development of a vaccine against N. meningitidis group B should have high priority. Furthermore, improved pneumococcal vaccines are needed for patients with predisposing conditions. The currently available pneumococcal polysaccharide vaccine seems to be underused.

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.

Incidence, serogroups and case-fatality rate of invasive meningococcal infections in a Swedish region 1975-1989.

In a retrospective study of invasive meningococcal infections in Greater Gothenburg, Sweden, 213 cases of culture-verified meningitis or septicaemia were identified during the 15-year period 1975-1989. The annual incidence was 2.0/100,000. Cases were seen in all age-groups with the highest rates in the 0-4 and 15-19 year-old groups, 9.5 and 6.2/100,000 respectively. 20% of the patients were less than 2 years. 91% of the patients had no known risk factors. In only 10 cases (5%) was contact with another case of meningococcal infection known. The main clinical manifestations were meningitis (57%), septicaemia with no sign of focal infection (25%) and septic shock (17%). The case-fatality rate for all the patients was 6.6% and did not change during the 15-year period. One-third of the patients who presented with septic shock died. The serogroup was known for strains from 192 patients. 51% of the strains belonged to serogroup B, 10% to group A and 23% to group C. In conclusion, the incidence of meningococcal infection was low but the relatively high case-fatality rate warrants a search for effective prophylaxis. About 30% of the cases were potentially preventable by the currently available tetravalent (A, C, Y and W135) polysaccharide vaccine, which is immunogenic in children greater than 2 years. Widespread use of antibiotic prophylaxis to close contacts of known cases would not lower the incidence markedly.

Neurovirulence of herpes simplex virus types 1 and 2 isolates in diseases of the central nervous system.

Herpes simplex virus (HSV) isolates derived from the central nervous system of ten patients with HSV-1-induced encephalitis, one patient with multiple sclerosis, and 14 patients with HSV-2-induced meningitis were investigated for neurovirulence by assaying the LD50 after nose and intracerebral (i.c.) inoculation of mice. HSV-1 encephalitis strains were significantly more virulent after nose inoculation (i.e. neuroinvasive) when compared with HSV-1 isolates from patients with oral lesions only, whereas HSV-2 meningitis strains were significantly more virulent after i.c. inoculation when compared with HSV-2 isolates from patients with genital lesions only. No correlation between high neurovirulence (defined as low LD50 for both routes of infection) and replication in cell cultures of neuronal and non-neuronal cell lines was found, but the weakly neurovirulent HSV-1 strain isolated from a patient with multiple sclerosis gave low replication yields. After nose inoculation, a highly neuroinvasive HSV-1 laboratory reference strain replicated to high titers in nose tissue, the trigeminal ganglia and brainstem, while a strain with low neuroinvasiveness but high i.c. virulence replicated less well in the brainstem. Neuroinvasiveness of the virus strain might be one factor of relevance in the pathogenesis of HSV-1 encephalitis in man.

Primary and recurrent herpes simplex virus type 2-induced meningitis.

In 27 patients with a first episode of herpes simplex virus type 2 (HSV-2)-induced meningitis, confirmed by virus isolation from the cerebrospinal fluid (CSF) or seroconversion to HSV-2, initial neurologic complications were found in 10 (37%) but subsided before 6 months in all patients. Long-term complications were recurrent meningitis in 5 (19%) and periodic headache related to genital HSV recrudescences in 4 (15%). Seven additional patients had possible HSV-2-induced recurrent meningitis. In contrast to the first episode of meningitis, virus isolation, HSV antigen detection, and IgG analyses in consecutive serum samples were of no diagnostic value in episodes of HSV-2-induced recurrent meningitis. Instead, immunoblotting was used to assay intrathecally produced IgG antibodies to the HSV-2 type-specific protein gG-2 in recurrent meningitis, when CSF was collected at a minimum of 3 days after onset.