Staphylococcus aureus develops increased resistance to antibiotics by forming dynamic small colony variants during chronic osteomyelitis.

OBJECTIVES: Staphylococcus aureus osteomyelitis often develops to chronicity despite antimicrobial treatments that have been found to be susceptible in in vitro tests. The complex infection strategies of S. aureus, including host cell invasion and intracellular persistence via the formation of dynamic small colony variant (SCV) phenotypes, could be responsible for therapy-refractory infection courses. METHODS: To analyse the efficacy of antibiotics in the acute and chronic stage of bone infections, we established long-term in vitro and in vivo osteomyelitis models. Antibiotics that were tested include ß-lactams, fluoroquinolones, vancomycin, linezolid, daptomycin, fosfomycin, gentamicin, rifampicin and clindamycin. RESULTS: Cell culture infection experiments revealed that all tested antibiotics reduced bacterial numbers within infected osteoblasts when treatment was started immediately, whereas some antibiotics lost their activity against intracellular persisting bacteria. Only rifampicin almost cleared infected osteoblasts in the acute and chronic stages. Furthermore, we detected that low concentrations of gentamicin, moxifloxacin and clindamycin enhanced the formation of SCVs, and these could promote chronic infections. Next, we treated a murine osteomyelitis model in the acute and chronic stages. Only rifampicin significantly reduced the bacterial load of bones in the acute phase, whereas cefuroxime and gentamicin were less effective and gentamicin strongly induced SCV formation. During chronicity none of the antimicrobial compounds tested showed a beneficial effect on bone deformation or reduced the numbers of persisting bacteria. CONCLUSIONS: In all infection models rifampicin was most effective at reducing bacterial loads. In the chronic stage, particularly in the in vivo model, many tested compounds lost activity against persisting bacteria and some antibiotics even induced SCV formation.

Mass mortality of harbor seals: pneumonia associated with influenza A virus.

More than 400 harbor seals, most of them immature, died along the New England coast between December 1979 and October 1980 of acute pneumonia associated with influenza virus, A/Seal/Mass/1/180 (H7N7). The virus has avian characteristics, replicates principally in mammals, and causes mild respiratory disease in experimentally infected seals. Concurrent infection with a previously undescribed mycoplasma or adverse environmental conditions may have triggered the epizootic. The similarities between this epizootic and other seal mortalities in the past suggest that these events may be linked by common biological and environmental factors.

Virulence patterns of Staphylococcus aureus strains from nasopharyngeal colonization.

BACKGROUND: The prevalence of nasopharyngeal colonization with Staphylococcus aureus can reach 20-30% among the population, which can lead to invasive infection. AIM: To investigate the prevalence of colonization among different age groups, and analyse S. aureus strain-specific virulence patterns. METHOD: For analysis of the prevalence of colonization, groups consisting of newborns, healthy volunteers aged 5-60 years, and nursing home residents aged >80 years were examined with nasopharyngeal swabs. After S. aureus was cultured, genetic analysis and phenotypic virulence testing were performed by cell-based assays. FINDINGS: Among 924 volunteers, the overall colonization rate was approximately 30%, with a peak in subjects aged 5-10 years (49%). Neonates and subjects aged >80 years showed different distributions of clonal clusters. Overall, the strains of all age groups exhibited virulence characteristics that can contribute to the development of infection. In particular, the neonatal strains exhibited a high incidence of toxin genes that resulted in increased cytotoxic effects compared with the other strains tested. CONCLUSIONS: Colonizing strains showed a virulence profile in all age groups, which may lead to the establishment of invasive infection. Consequently, decolonization measures could be considered for selected patients depending on the risk of infection.

Acute myocardial infarction: clinical characteristics, management and outcome in a metropolitan Veterans Affairs Medical Center teaching hospital.

OBJECTIVES: The influence of race and age on thrombolytic therapy, invasive cardiac procedures and outcomes was assessed in a Veterans Affairs teaching hospital. The influence of Q wave evolution on the use of invasive cardiac procedures and outcome was also assessed. BACKGROUND: It is not well known how early revascularization procedures for acute myocardial infarction are delivered or influence survival in a Veterans Affairs patient population. METHODS: From October 1993 to October 1995, all patients with myocardial infarction were identified by elevated creatine kinase, MB fraction (CK-MB) and one of the following: chest pain or shortness of breath during the preceding 24 h or electrocardiographic (ECG) abnormalities. RESULTS: Racial groups were similar in terms of age, time to ECG, peak CK and length of hospital stay. Mortality increased with age (odds ratio [OR] 1.93, 95% confidence interval [CI] 1.33 to 2.81). A trend toward increased mortality occurred for race other than Caucasian. Patients meeting ECG criteria were given thrombolytic agents in 49% of cases, but age, comorbidity count and Hispanic race decreased the probability of thrombolytic use. Cardiac catheterization was performed more often after thrombolytic agents (OR 1.85, 95% CI 0.97 to 3.54), but less often in African-Americans (OR 0.59, 95% CI 0.35 to 1.02), older patients (OR 0.39, 95% CI 0.24 to 0.64) or patients with heart failure (OR 0.30, 95% CI 0.17 to 0.52). Patients evolving non-Q wave infarctions were older and had increased comorbidity counts and trends toward increased mortality. Angioplasty was chosen less for patients > or = 65 years old (p = 0.02); angioplasty and coronary artery bypass graft surgery were performed less in patients > or = 70 years old (p = 0.02). Patients treated invasively had lower mortality rates than those treated medically (p < 0.02). CONCLUSIONS: The use of thrombolytic agents and invasive treatment plans declined with age, and mortality increased with age. Trends toward increased mortality occurred with non-Q wave infarctions and race other than Caucasian.

Infective endocarditis--a 25 year overview of diagnosis and therapy.

Diagnosis and management of infective endocarditis have significantly changed in the past 25 years. Improved bacteriologic techniques have allowed detection of cases of infective endocarditis caused by unusual organisms. Bactericidal therapy has become available for patients with gram-negative endocarditis and antimicrobial therapy has improved. Echocardiography has become an important diagnostic and management aid, and cardiac valve replacement has dramatically improved the outlook for many patients.

Group B streptococcal infective endocarditis.

From 1970 to 1983, five patients with group B streptococcal endocarditis were treated at the Mayo Clinic, Rochester, Minn. The minimal inhibitory concentration and the minimal bactericidal concentration of penicillin were 0.09 microgram/mL or less and 1.56 micrograms/mL or less, respectively. The in vitro activity of cefazolin against group B streptococci was similar to that of penicillin. In three of the five cases, penicillin and streptomycin acted synergistically in vitro against group B streptococci. Four of the five patients were cured, three by use of an aminoglycoside combined with penicillin, ampicillin, or vancomycin. Three of the five patients had multiple large systemic emboli, and one of the three died of brain-stem infarct. Penicillin alone or in combination with an aminoglycoside is effective therapy for group B streptococcal endocarditis. Patients unable to tolerate penicillin may be treated with cefazolin or vancomycin. Clindamycin therapy should be avoided in patients with endocarditis caused by strains that are tolerant in vitro to clindamycin.

Epidermal growth in the bottlenose dolphin, Tursiops truncatus.

Epidermal growth in two mature female bottlenose dolphins, Tursiops truncatus, was investigated by following the movement of a cohort of tritiated thymidine-labeled epidermal cells for 59 days. The majority of the cells migrated in a cluster which was estimated to reach the skin surface in 73 days. We calculate that the outermost cell layer is sloughed 12 times per day. Turnover time and sloughing rate are estimated to be 1.7 times longer and 8.5 times faster than the respective values for epidermal cell kinetics in humans. This apparent inconsistency of slow transit time and rapid sloughing rate is reconciled by the convoluted structure of the stratum germinativum in the dolphin which results in a ratio of germinatival to superficial cells of 876:1. The stratum germinativum of dolphin epidermis appears to lack morphologically distinct, spatially segregated subpopulations of anchoring and stem cells. Dolphin epidermis has a large capacity for cell population, relatively long turnover time, and rapid sloughing rate. The adaptive advantages of these characteristics are discussed.

Treatment of streptococcal infective endocarditis.

Patients with infective endocarditis caused by penicillin-sensitive streptococci (minimal inhibitory concentration for penicillin of 0.1 microgram/ml or less) may be treated successfully with one of the following regimens: aqueous penicillin G administered intravenously for four weeks, intravenous aqueous penicillin G for four weeks combined with streptomycin for the first two weeks of therapy, or parenterally administered penicillin plus streptomycin for two weeks. A cure rate of at least 98 percent may be anticipated with each of these regimens. During a 12-year period among 142 patients treated for two weeks with penicillin and streptomycin, one (0.7 percent) had relapse and four (3 percent) had vestibular toxicity. The major advantage of the two-week regimen is that it is more cost-effective than the four-week regimens. The major disadvantage of the use of streptomycin is the relatively low risk of vestibular toxicity. Patients with enterococcal endocarditis were treated initially for four weeks with aqueous penicillin G together with either streptomycin (streptomycin-susceptible enterococci, 36 patients) or gentamicin (streptomycin-resistant enterococci, 20 patients). Compared with patients who had symptoms for less than three months, patients with symptoms for longer than three months had a higher relapse rate (0 percent versus 44 percent; p less than 0.001) and mortality (2.5 percent versus 25 percent; p less than 0.001). Patients with mitral valve endocarditis had a significantly higher relapse rate (25 percent) than patients with aortic valve infection (0 percent; p less than 0.01]. Gentamicin-associated nephrotoxicity was more frequent (p less than 0.001) among patients treated with more than 3 mg/kg per day of gentamicin than among those treated with 3 mg/kg per day or less (100 percent versus 20 percent). Relapse and mortality rates did not differ significantly between patients treated with low-dose or high-dose gentamicin regimens. Patients who have had symptoms of enterococcal endocarditis for longer than three months or perhaps patients with mitral valve infection should receive at least six weeks of penicillin therapy together with an aminoglycoside; patients without either high-risk factor may be treated successfully for four weeks.

Radiation, methotrexate, and white matter necrosis: laboratory evidence for neural radioprotection with preirradiation methotrexate.

To investigate the interactions between methotrexate (MTX) and irradiation of the central nervous system, adult rats were infused with MTX via the lateral cerebral ventricle either before, during, or following single fraction irradiation to the cervical spine. Single doses ranging from 1600 cGy to 3200 cGy were administered and the dose-response curve for forelimb paralysis was compared with that seen in irradiated animals which did not receive MTX. There was no effect on the dose-response curve when MTX was administered simultaneously with or following irradiation compared to radiation alone. When MTX was given prior to irradiation, however, the entire dose-response curve shifted in the direction of radioprotection by approximately 225 cGy. Histopathologic examinations were consistent with this observation, with animals pretreated with methotrexate demonstrating significantly less white matter necrosis than observed in untreated controls. Protection of normal CNS tissue from radionecrosis, and from the associated paralysis, may be achieved with preradiation methotrexate.

Vancomycin.

Vancomycin, a useful bactericidal antibiotic for selective clinical infections, is the therapy of choice for serious staphylococcal infections when the penicillins and cephalosporins cannot be used. The antibacterial spectrum of vancomycin also covers other gram-positive cocci and bacteria and gram-negative cocci. Vancomycin is given intravenously in most cases, usually in a dose of 1 g every 12 hours in patients who have normal renal function. The indications for vancomycin therapy are as follows. 1. Serious staphylococcal infections in patients who are intolerant to the penicillins and cephalosporins or when the organism is resistant to the commonly used bactericidal agents. 2. Streptococcal endocarditis in patients intolerant to penicillin G; in enterococcal infections, it is used with an associated aminoglycoside. Vancomycin is not used alone in enterococcal endocarditis. In nonenterococcal (Streptococcus bovis) and viridans streptococcal endocarditis, vancomycin may be used alone if the minimum bactericidal concentration is less than or equal to 10 microgram/ml; otherwise, it is combined with an aminoglycoside. 3. Other serious infections caused by organisms resistant to the commonly used agents such as corynebacterial endocarditis. 4. Acute staphylococcal ileocolitis, for which vancomycin is given orally or orally and intravenously if indicated. Vancomycin is relatively nontoxic; the predominant toxic response is neurotoxicity, but this is rarely seen if the serum levels are 30 microgram/ml or less.

Symposium on infective endocarditis. III. Endocarditis due to gram-negative bacteria. Report of 56 cases.

At the Mayo Clinic, 56 patients with infective endocarditis caused by gram-negative bacteria were seen from 1958 through 1979, 35 of whom were seen from 1970 through 1979. The patients were categorized into two divisions: those with medical, naturally acquired valve infections (40 [71%]) and those with infective endocarditis after cardiac operation (16 [29%]). The overall cure rate was 82% (46 of 56 patients); 35 of 40 patients (88%) were cured in the medical group, and 11 of 16 patients (69%) were cured in the surgical group. The patients were further classified on the basis of organism: group 1 (33 patients)--infections caused by Haemophilus (18), Actinobacillus actinomycetemcomitans (4), Cardiobacterium hominis (6), Eikenella corrodens (2), Kingella kingii (2), and Bordetella bronchiseptica (1); 32 of these 33 patients (97%) were cured, and 6 of these infections were on prosthetic valves; group 2 (21 patients)--infections caused by enteric aerobic bacilli; 13 of the 21 patients (62%) were cured; group 3 (1 patient)--infection caused by anaerobes (Bacteroides fragilis); this patient died; and group 4 (1 patient)--infection caused by Neisseria gonorrhoeae; this patient was cured. The gram-negative bacteria in the survivors and nonsurvivors and the curative antibiotic regimens were tabulated. Among the 35 survivors in the medical group, a combined antibiotic regimen cured 21 patients (60%) and a single antibiotic agent cured 14 (40%). Among the 11 survivors in the surgical group, combined therapy was given to 8 (73%), a single drug was used once, and operation alone achieved a cure in 2 patients. Compared with past data, the current study indicates an increasing incidence of gram-negative bacterial endocarditis (approximately 10%) and an improving cure rate 82%).

Vancomycin.

Vancomycin is a narrow-spectrum bactericidal antistaphylococcal antibiotic that was introduced in 1956 because of its efficacy against resistant penicillinase-producing staphylococci. It was effective for serious staphylococcal infections for which no satisfactory alternative to penicillin G was available at the time. When methicillin and the other semisynthetic penicillins and the cephalosporins were introduced, the role of vancomycin was relegated to the alternative therapy of choice when the penicillins and the cephalosporins could not be used. In the future, vancomycin may be used more frequently in (1) methicillin-resistant Staphylococcus aureus infections, (2) streptococcal endocarditis in conjunction with an aminoglycoside in patients intolerant to penicillin or ampicillin, (3) infections associated with prosthetic devices caused by organisms with multiple antibiotic resistance, and (4) antibiotic-induced enterocolitis associated with Clostridium difficile.

Infective endocarditis caused by Actinobacillus actinomycetemcomitans: report of four cases.

Four patients with infective endocarditis caused by Actinobacillus actinomycetemcomitans are reported. The clinical course was characterized by chronicity. Three of the four patients were treated with combined penicillin and aminoglycoside therapy on an empiric basis; the fourth patient was given ampicillin alone for 3 weeks. Cure was achieved in all four cases, with antibiotic therapy alone in the first three and ampicillin alone plus valve replacement surgery in the fourth patient. Further in vitro bactericidal data are needed, and actual therapy with ampicillin alone is desirable to see whether these patients with endocarditis of natural valves cannot be treated with ampicillin alone for a 3-week period.

Visceral leishmaniasis (kala-azar) as a cause of fever of unknown origin.

A patient with a rare cause of fever of unknown origin, visceral leishmaniasis (kala-azar), is reported. The diagnosis was made by exploratory laparotomy and splenectomy after diagnostic studies had failed to reveal the cause of the fever. The patient was cured with a 6-day course of therapy with Pentostam (sodium antimony gluconate). Visceral leishmaniasis should be considered in the differential diagnosis of patients with obscure fever who have traveled in endemic areas.

Treatment of penicillin-sensitive streptococcal infective endocarditis.

Patients with infective endocarditis caused by penicillin-sensitive streptococci (minimal inhibitory concentration less than or equal to 0.1 microgram/ml of penicillin) may be treated successfully with one of the following three regimens: (1) aqueous penicillin G administered intravenously for 4 weeks, (2) aqueous penicillin G administered intravenously for 4 weeks in combination with streptomycin for the first 2 weeks of therapy, or (3) parenterally administered penicillin plus streptomycin for 2 weeks. No substantial difference in the relapse rate exists among the three regimens, and a cure rate of at least 98% may be anticipated with each of the three forms of therapy. The major advantage of the 2-week regimen is that it is more cost-effective than 4 weeks of hospitalization and therapy. The major disadvantage of the 2-week regimen and the 4-week regimen that uses streptomycin is the relatively low risk of streptomycin-associated vestibular toxicity. Patients unable to tolerate penicillin may be treated with vancomycin or a cephalosporin administered parenterally for 4 weeks.

Cardiobacterium hominis endocarditis. Four cases with clinical and laboratory observations.

The clinical and microbiologic features of Cardiobacterium hominis endocarditis in four patients seen at the Mayo Clinic from 1971 through 1976 are described. All four were men ranging in age from 39 to 60 years. The precipitating factor in three was a dental procedure, and the illness was a prolonged, chronic one, with symptoms having been present 10 to 18 months before diagnosis. The other patient had a late prosthetic valve endocarditis and had had symptoms for only 3 months. Three patients were cured; the fourth died after 32 days of adequate therapy and what was considered a bacteriologic cure. Because of the pronounced fastidiousness of these bacteria, in vitro susceptibility tests could be done in only two of the four; the minimum inhibitory concentration for penicillin G was 0.07 microgram/ml in both. The therapeutic regimens were penicillin G plus streptomycin in the first case, predominantly penicillin G alone in the second, penicillin G for 2 weeks in the third, and ampicillin for 4 weeks in the fourth (prosthetic valve case) in addition to valve replacement. Clinical and laboratory experiences in the total reported cases lead us to believe that 3 weeks of therapy with penicillin G or ampicillin alone is adequate therapy for C. hominis endocarditis of natural valves.

Haemophilus endocarditis. Report of 14 patients.

From 1963 through December 1976, 14 patients with Haemophilus endocarditis were seen, 10 since January 1972. Four different species representing 15 isolates were cultured from the 14 patients: H. influenzae (1), H. aphrophilus (5), H. PARAPHROPHILUS (5), and H. parainfluenzae (4). One patient had infection with both H. aphrophilus and H. paraphrophilus. Minimal inhibitory concentrations of 12 of the tested 14 strains with ampicillin were 1.25 mug/ml or less. Tube dilution tests were not possible for minimal bactericidal concentrations (7 times) or serum bactericidal titers (5 times) of the 12 tested strains. The clinical picture varied from an insidious onset and mild uncomplicated disease to abrupt onset with severe multisystem disease. Twelve patients had murmurs on admission; congestive heart failure was absent in all 14 but embolization occurred in 6. Treatment periods of 3 to 7 weeks consisted of penicillin G or ampicillin plus aminoglycoside in nine patients and ampicillin alone in five. All 14 patients were cured; no relapses occurred. Value surgery was not needed for bacteriologic cure but was necessary 15 days after therapy in one patient and in four others from 12 to 22 months after therapy. We believe that ampicillin, 12 g/day alone for 3 weeks, is adequate treatment for Haemophilus endocarditis.

Coryneform bacterial endocarditis: difficulties in diagnosis and treatment, presentation of three cases, and review of literature.

Three patients who had coryneform bacterial endocarditis affecting a prosthetic valve are presented and 64 case reports are reviewed. Diagnostic difficulties occur because coryneform bacteria often are fastidiuos, with long incubation periods, and often contaminate blood cultures. Although some coryneform bacteria are killed by penicillin G, many are resistant to most of the commonly used antibiotics. Vancomycin is bactericidal in resistant strains studied. Treatment with vancomycin is indicated until in vitro bactericidal data are available. Coryneform endocarditis often occurs on prosthetic valves, thus making therapy and its evaluation even more difficult.

Prosthetic valve endocarditis.

Prosthetic valve endocarditis is an infrequent but serious complication of cardiac valve replacement. The overall frequency of prosthetic valve endocarditis is approximately 2%. The frequency of early-onset and late-onset infections is 0.78% and 1.1%, respectively. Staphylococci are the most common isolate from patients with early-onset infection, accounting for 47.5% of the total number of isolates. Staphylococcus epidermidis causes 27% of these staphylococcal infections. Among patients with late-onset infection, streptococci are the predominant microorganism, constituting 42% of the total number of isolates from patients in this group. The overall mortality among patients with prosthetic valve endocarditis is high--59%; the mortality among patients with early- or late-onset infections is 77% and 46%, respectively. Most patients with staphylococcal prosthetic valve endocarditis should undergo cardiac valve replacement in addition to antimicrobial therapy. Closely monitored anticoagulant therapy should be cautiously continued in patients with prosthetic valve endocarditis.

Management of complications of infective endocarditis.

Complications of infective endocarditis may be considered as those that involve the heart and adjacent structures or those that are extracardiac. Congestive heart failure is the most common serious complication of infective endocarditis and is the leading cause of death among patients with this infection. In patients with severe heart failure unresponsive to medical therapy after 24 to 48 hours, prompt cardiac valve replacement should be considered, irrespective of the duration of preoperative antimicrobial therapy. We believe that all patients with bacterial infective endocarditis who are stable hemodynamically and who have not had multiple large emboli should receive at least one course of antimicrobial therapy in an attempt to sterilize the infected valve before cardiac valve replacement is considered. Most patients with multiple major embolic events should undergo cardiac valve replacement or debridement of the infected valve. The technical limitations and the experience with two-dimensional echocardiography in patients with infective endocarditis who have valve vegetations demonstrated by echocardiography are not yet sufficient to justify cardiac valve replacement solely on the basis of echocardiographic findings. The highest frequency of major embolic events occurs in association with infections that produce large mobile valve vegetations, such as those caused by Haemophilus parainfluenzae and other slow-growing fastidious gram-negative bacilli, fungi (especially Aspergillus), and nutritionally variant viridans streptococci.