Uncomplicated Bacteremia Research Articles

Role of Echocardiography in Evaluation of Patients With Staphylococcus aureusBacteremia: Experience in 103 Patients

Objectives. The purpose of this prospective study was to examine the role of echocardiography in patients with Staphylococcus aureusbacteremia (SAB).Background. The reported incidence of infective endocarditis (IE) among patients with SAB varies widely. Distinguishing patients with uncomplicated bacteremia from those with IE is therapeutically and prognostically important, but often difficult.Methods. One hundred-three consecutive patients undergoing both transthoracic (TTE) echocardiography and transesophageal (TEE) echocardiography were prospectively evaluated. All patients presented with fever and ≥1 positive blood culture and were followed up for 12 weeks.Results. Although predisposing heart disease was present in 42 patients (41%), clinical evidence of infective endocarditis (IE) was rare (7%). TTE revealed anatomic abnormalities in 33 patients, but vegetations in only 7 (7%), and was considered indeterminate in 19 (18%). TEE identified vegetations in 22 patients (aortic valve in 5, mitral valve in 9, tricuspid valve in 4, catheter in 2 and pacemaker in 2, abscesses in 2, valve perforation in 1 and new severe regurgitation in 1; 26 total [25%]). Using Duke criteria for the diagnosis of IE, definite IE was present in 26 patients (25%). Clinical findings and predisposing heart disease did not distinguish between patients with and without IE. The sensitivity of TTE for detecting IE was 32%, and the specificity was 100%. The addition of TEE increased the sensitivity to 100%, but resulted in one false positive result (specificity 99%). TEE detected evidence of IE in 19% of patients with a negative TTE and 21% of patients with an indeterminate TTE. At follow-up, cure of staphylococcal infection occurred in a similar percentage of patients with and without IE (77% and 75%, respectively). However, death due to sepsis was significantly more likely among patients with IE (4 of 26 [15%]) than among those without IE (2 of 77 [3%]) (p = 0.03).Conclusions. Our results suggest that IE is common among patients admitted to the hospital with SAB and is associated with an increased risk of death due to sepsis. TEE is essential to establish the diagnosis and to detect associated complications. Therefore, the test should be considered part of the early evaluation of patients with SAB.

Clinical courses of seven survivors of Clostridium septicum infection and their immunologic responses to alpha toxin.

Clostridium septicum bacteremia typically portends a fulminant disease associated with high mortality. We describe the clinical courses of seven survivors of C. septicum infection and their antibody responses to the alpha toxin produced by C. septicum. Three patients had clinical syndromes ranging from uncomplicated bacteremia to early typhlitis, and three patients had syndromes ranging from abscess to myonecrosis and septic shock. In addition, an AIDS patient who developed septic shock and who had extensive gas in the retroperitoneal musculature did not undergo surgery but survived after receiving antimicrobial therapy and intensive supportive care. Both immunocompetent patients with myonecrosis had detectable IgG to alpha toxin by immunoblot analysis. IgG to alpha toxin was not detected in the four immunocompetent patients who had C. septicum bacteremia but who did not have myonecrosis or in the AIDS patient with myonecrosis. Therefore, humoral responses to alpha toxin during C. septicum infection may be related to the host's clinical syndrome and immune status.

Optimum treatment of staphylococcal infections.

Serious staphylococcal infections remain a significant clinical problem despite advances in antibacterial therapy. Resistance to penicillin is common and methicillin-resistant staphylococci have become troublesome nosocomial pathogens in many institutions. Penicillinase-resistant penicillins (e.g. flucloxacillin, cloxacillin and oxacillin) are the preferred drugs for all methicillin-susceptible staphylococcal infections, although first generation cephalosporins, beta-lactam/beta-lactamase inhibitor combinations, clindamycin, and occasionally erythromycin and cotrimoxazole (trimethoprim/sulfamethoxazole) are alternatives. Serious infections due to methicillin-resistant staphylococci should be treated with parenteral vancomycin. Teicoplanin, where available, is a suitable alternative. Rifampicin, fusidic acid and some fluoroquinolones may be useful oral alternatives, although resistance develops rapidly if they are used as single agents. Cotrimoxazole and minocycline have also proven useful when strains are susceptible. Staphylococcal toxic shock syndrome often requires aggressive resuscitation and anti-staphylococcal therapy for generally 10 to 14 days. Staphylococcus aureus bacteraemia remains a life-threatening condition which, in all but one-third of cases, is associated with an underlying septic focus such as endocarditis, osteomyelitis or occult abscess. Differentiating between complicated and uncomplicated bacteraemia is critical to define the appropriate treatment regimen. Serious staphylococcal sepsis such as endocarditis and acute osteomyelitis generally requires prolonged (4 to 6 weeks) antibiotic treatment. Coagulase-negative staphylococci are the commonest cause of prosthetic device infection, and generally require prolonged therapy with an agent to which they have proven to be sensitive, e.g. a penicillinase-resistant penicillin or vancomycin. Removal of infected foreign or prosthetic material, and drainage of deep collections remain a critical aspect of all therapy.

Course and outcome of bacteremia due to Staphylococcus aureus: evaluation of different clinical case definitions.

In a retrospective survey of patients hospitalized in the University Hospital of Basel, Switzerland, the course and outcome of 281 cases of true bacteremia due to Staphylococcus aureus over a 7-year period were analyzed. The main purpose was to evaluate different case definitions. In 78% of cases the source of bacteremia was obvious; vascular access sites (27%) and wounds (10%) were the most common sources. Metastasizing foci were more common in cases of primary vs. secondary bacteremia (P < .001). The incidence of endocarditis was higher in cases in which no portal of entry was defined (P < .03). The overall mortality rate was high at 34% partly because of inappropriate initial antibiotic therapy. With the introduction of an infectious disease service at the hospital, the fraction of misjudged results of blood culture diminished 2.5-fold. Among the differently defined cases, the mortality rate was significantly higher for cases of complicated vs. uncomplicated bacteremia (P < .01), for cases of primary vs. secondary bacteremia (P = .05), and for patients with endocarditis or other secondary foci (P < .001). Since only one methicillin-resistant strain was isolated, multiresistant staphylococci were not a problem in the hospital. Different case definitions allowed the detection of patients at increased risk for complications and death. In the treatment of sepsis with no evident focus, initial antimicrobial therapy should include the use of agents with antistaphylococcal activity.

Detection of teichoic acid antibodies in Staphylococcus aureus infections

A commercially available agar gel diffusion (AGD) assay was used to investigate the teichoic acid antibody (TAA) response in 183 patients with proven Staphylococcus aureus (SA) infections. Two control groups were also investigated. One consisted of 100 hospitalized patients with a variety of medical and surgical conditions other than SA infection and the other consisted of 116 healthy hospital staff members. The sensitivity of the AGD assay varied markedly depending on the site of infection in the patients with proven SA infections. All patients with SA endocarditis developed positive TAA titres (greater than or equal to 1:4), although more than one third of these were initially negative. In patients with chronic osteomyelitis or septic arthritis, 41% had positive TAA titres, whereas no positive titres were detected in patients with acute osteomyelitis or septic arthritis. Lower rates of positive TAA titres were found in patients with deep abscesses (27%), pneumonia (14%) and post-operative infections (9%), but no positive titres occurred in patients with acute uncomplicated bacteremia, cellulitis or meningitis. In 100 hospitalized control patients, no positive titres were detected, and only 1 of 116 (0.9%) healthy hospital staff controls was positive. Suggested guidelines for the use of the AGD assay are discussed.

Detection of staphylococcal antigen in urine from patients with severe Staphylococcus aureus infections

A method for rapid diagnosis of Staphylococcus aureus bacteremia by antigen detection would be useful. Detection of staphylococcal antigenemia has been hampered by formation of immune complexes with pre-formed antibodies. Subsequently, urine from patients with S. aureus bacteremia and controls have been tested by radioimmunoassay for antigen. Antigen was present in the urine of five of six patients with endocarditis, two of six with complicated bacteremia but none of eight with uncomplicated bacteremia caused by S. aureus. Antigen was also found in urine from 18 of 30 patients with staphylococcal urinary tract infections, in one of 48 with urinary tract infections caused by other bacteria (a patient infected with Escherichiae coli), but not in 71 uninfected control urines. Detection of antigenuria offers a rapid new method for diagnosing S. aureus endocarditis or complicated bacteremia in the absence of staphylococcal bacteriuria (5 × 10 4 cfu ml −1).

Collagen binding in clinical isolates of Staphylococcus aureus.

Collagen binding was examined in 90 strains of Staphylococcus aureus derived from patient samples. Slightly under one-half (39 of 90) of the S. aureus strains bound collagen. Collagen binding in S. aureus did not correlate with either immunoglobulin G or fibronectin binding by these organisms. Chi-square analysis of isolates obtained from patients with complicated bacteremia (bacteremia associated with deep tissue infection) compared with isolates from patients with uncomplicated bacteremia (bacteremia without other infection) showed that the former strains were significantly more likely to have collagen-binding ability. Subcloning of primary isolates from patients with bacteremia showed that all clones from individual patients were either all positive for collagen binding or all negative, suggesting a common clonal origin for this characteristic. The ability to bind collagen could not be induced in strains lacking collagen affinity by repeated subculture in media supplemented with collagen.

Solid-Phase Radioimmunoassay for IgG Antibodies to Staphylococcus epidermidis

A radioimmunoassay (RIA) for human IgG antibodies to Staphylococcus epidermidis was compared with an agar-gel-diffusion assay in patients with a variety of infections. The RIA was sensitive and reproducible and discriminated between endocarditis and uncomplicated bacteremias due to coagulase-negative staphylococci. Anti-S epidermidis antibodies by RIA were elevated in 16 (89%) of 18 patients with coagulase-negative staphylococcal endocarditis but in none of 28 patients with uncomplicated bacteremia (n = 18) or with blood culture contaminated with these organisms (n = 10). Cross-reacting IgG antibodies to S epidermidis antigens were also detected by RIA in 13 (76%) of 17 patients with Staphylococcus aureus endocarditis but in none of 17 patients with nonvalvular S aureus bacteremias and in none of 25 patients with endocarditis or bacteremia caused by other pathogens. Agar-gel-diffusion assay was less sensitive than RIA for detecting coagulase-negative staphylococcal endocarditis, being positive in nine (50%) of 18 such patients. This RIA may be useful in distinguishing patients with endocarditis from those with nonvalvular staphylococcemias or blood culture contamination.

Enzyme-linked immunosorbent assay for detection of Staphylococcus epidermidis antibody in experimental S. epidermidis endocarditis.

The immune response against Staphylococcus epidermidis, as determined by an enzyme-linked immunosorbent assay, was evaluated in experimental S. epidermidis infections in rabbits. Antigens from 8 of 10 clinical S. epidermidis strains detected significant antibody production in five rabbits immunized with different strains of S. epidermidis and in five of six rabbits with experimental endocarditis caused by four different strains. The antigens from two strains detected antibody production in all rabbits, and strain ATCC 14990 discriminated best between positive and negative samples. Consecutive blood samples from rabbits with endocarditis and control rabbits with bacteremia, which were successfully prevented from developing endocarditis by using prophylactic antibiotics, were examined by using an enzyme-linked immunosorbent assay and an ultrasonic extract of strain ATCC 14990 as the antigen. This assay discriminated between rabbits with endocarditis and rabbits with uncomplicated bacteremia. Antibody production was detected as early as 3 days after the onset of infection in rabbits with endocarditis.

Distinguishing complicated from uncomplicated bacteremia caused by Staphylococcus aureus: the value of "new" and "old" serological tests.

Antibody responses to staphylococcal alpha-toxin, cell wall teichoic acid, and cell wall peptidoglycan were measured in 259 serum samples from 74 consecutive patients with Staphylococcus aureus bacteremia. All patients with complicated bacteremia were seropositive in at least one of three tests, and 18 (72%) of 25 were positive in two or three assays; six (75%) of eight patients with endocarditis were positive for all three tests. In contrast, 15 (75%) of 20 patients with uncomplicated bacteremia were positive in only one or none of the tests. These differences in antibody response patterns were statistically significant (chi 2 = 18.33, P less than .001). Patients with complicated bacteremia had peak antibody titers that were significantly higher than those of patients with uncomplicated bacteremia. The assay for antibody to alpha-toxin was as sensitive as the assays for antibody to cell wall antigens but had less specificity for complicated bacteremia. The clinical severity of the bacteremia did not correlate with a complicated vs. uncomplicated nature of the infection but was predictive of early death due to staphylococcemia. The calculated predictive values suggest that the serology of S. aureus bacteremia may be clinically valuable when multiple tests are performed in paired serum samples.

Activation and inhibition of Hageman factor-dependent pathways and the complement system in uncomplicated bacteremia or bacterial shock.

Levels of components of the contact activation, coagulation, and complement systems and their main inhibitors were measured in 45 critically ill patients during 61 episodes of uncomplicated bacteremia or bacterial shock. Levels of Hageman factor (factor XII), prekallikrein, high-molecular-weight kininogen, factor XI, factor VII, total hemolytic complement, alternative pathway activity, and C3 were within the normal range during uncomplicated bacteremia (n = 29), but during fatal bacterial shock (n = 13) a significant decrease by 40%-50% was observed in all measurements. During nonfatal bacterial shock (n = 19) a moderate decrease was observed in most of these measurements. The capacity of plasma to inactivate kallikrein was significantly higher during bacteremia than during bacterial shock because of a significant increase in the level of C1 esterase inhibitor. Levels of antithrombin III and alpha 2-macroglobulin were below normal in all groups. Thus increased inhibition of the contact activation and complement systems is beneficial during bacteremia.

Thrombocytopenia of sepsis. The role of circulating IgG-containing immune complexes.

Platelet-associated IgG (PAIgG), circulating IgG-containing immune complexes (ICs), plasma beta-thromboglobulin (beta-TG), and platelet factor 4 (PF-4) levels were assayed in 33 consecutive patients with culture-proved bacteremia. Thrombocytopenia occurred in 18%, and no correlation was seen between platelet count and PAIgG, beta-TG, or PF-4. In contrast, when patients were assigned to groups on the basis of rising or stable counts vs falling counts, a significant increase in the frequency of elevated PAIgG was seen in those with falling platelet counts. Elevated ICs did not correlate with PAIgG, platelet count, beta-TG, or PF-4. The results of this study of patients with uncomplicated bacteremia, although clearly demonstrating intravascular platelet activation and suggesting a pathologic role for elevated PAIgG, do not support the hypothesis that platelet-bound serum ICs are responsible for either phenomenon.

Thrombocytopenia of Sepsis

Platelet-associated IgG (PAIgG), circulating IgG-containing immune complexes (ICs), plasma beta-thromboglobulin (beta-TG), and platelet factor 4 (PF-4) levels were assayed in 33 consecutive patients with culture-proved bacteremia. Thrombocytopenia occurred in 18%, and no correlation was seen between platelet count and PAIgG, beta-TG, or PF-4. In contrast, when patients were assigned to groups on the basis of rising or stable counts vs falling counts, a significant increase in the frequency of elevated PAIgG was seen in those with falling platelet counts. Elevated ICs did not correlate with PAIgG, platelet count, beta-TG, or PF-4. The results of this study of patients with uncomplicated bacteremia, although clearly demonstrating intravascular platelet activation and suggesting a pathologic role for elevated PAIgG, do not support the hypothesis that platelet-bound serum ICs are responsible for either phenomenon.

Comparison of anti-alpha-haemolysin and teichoic acid antibody tests in patients with Staphylococcus aureus endocarditis or bacteraemia

To assess the value of serological tests in differentiating endocarditis and complicated bacteraemia due to Staphylococcus aureus from uncomplicated S. aureus bacteraemia and from nonstaphylococcal endocarditis we measured teichoic acid antibodies (TAA) (by means of a gel diffusion method) and antibodies to alpha-haemolysin (ASta) in the serum of 22 patients with S. aureus endocarditis, 42 patients with complicated S. aureus bacteraemia, 21 patients with uncomplicated S. aureus bacteraemia, 27 patients with other than S. aureus endocarditis, 17 patients with culture-negative endocarditis and 337 non-infected control patients. TAA and ASta titres were found significantly more often in staphylococcal endocarditis than in non-staphylococcal endocarditis, 59 per cent versus 4 per cent for the TAA test and 32 per cent versus 0 per cent for the ASta assay. The combined use of the two tests proved best for differentiating the two groups of endocarditis from each other, 72 per cent versus 4 per cent respectively. In the culture-negative endocarditis group there were two serologically positive patients whose anti-staphylococcal antibiotic therapy based on the serological findings was successful, supporting the clinical usefulness of staphylococcal serological tests in endocarditis of unknown bacterial aetiology. The serological tests were not useful, however, in differentiating S. aureus endocarditis from complicated or uncomplicated bacteraemia due to S. aureus without endocarditis.

Commercially Available (ENDO-STAPH) Assay for Teichoic Acid Antibodies

We have evaluated the clinical usefulness of a commercially available teichoic acid antibody assay (ENDO-STAPH). Teichoic acid antibody titers up to a 1:2 serum dilution were observed in 20% of normal subjects, thus, titers of 1:4 or more were considered positive. Of patients with Staphylococcus aureus infections, 16 of 23 with endocarditis, 12 of 20 with complicated bacteremia, three of 17 with uncomplicated bacteremia, and ten of 20 with nonbacteremic infections had positive titers. Only four of 70 controls had positive titers. Results agreed with those using our standard assay in 130 of 151 specimens. Results were reproducibly positive or negative in 17 of 18 specimens that were retested. Results were also reproducible in ten specimens retested using a different lot of standardized antigen. The ENDO-STAPH assay should broaden the clinical applications of assays for TAA.

IgM antibody response to staphylococcal infection.

Of patients with staphylococcal infections, high levels of IgM antibodies of staphylococci measured by radioimmunoassay were present in 13 of 17 patients with endocarditis, nine of 23 with complicated bacteremia, one of 20 with uncomplicated bacteremia, and two of 21 with nonbacteremic infections. Of control subjects, high levels of IgM antibodies were present in seven of 26 individuals with gram-positive infections, two of 16 with gram-negative infections, two of 20 with rheumatoid arthritis, and two of 50 uninfected persons. Concomitant elevation of IgG and IgM antibody levels occurred in 20 of 40 patients with endocarditis or complicated bacteremia compared with two of 41 patients with other types of staphylococcal infections and three of 112 control subjects. IgM antibodies only were present early in the infection in six of 13 patients with staphylococcal endocarditis or complicated bacteremia. IgG or IgM antibody levels remained elevated at least four weeks after initiation of treatment.

Serologic diagnosis of access device-related staphylococcal bacteremia

Staphylococcal bacteremia occurs frequently in patients undergoing long-term hemodialysis (dialysis patients). Although such bacteremia is frequently uncomplicated, it may be associated with endocarditis, metastatic infection or suppuration at the access site requiring excision of the access device for control of the infection (complicated bacteremia). To distinguish patients with uncomplicated bacteremia from those with complications, we measured Staphylococcal teichoic acid antibodies by agar-gel diffusion and immunoglobulin G (IgG) antibodies by radioimmunoassay in 18 patients with Staphylococcal bacteremia undergoing long-term hemodialysis. Although teichoic acid antibodies were not detected in five patients with uncomplicated bacteremia, they were observed in only three of 13 patients with complicated bacteremia. IgG Staphylococcal antibodies were present in 10 of 13 patients with complicated bacteremia compared to none of five patients with uncomplicated bacteremia (p <0.05). Thus, radioimmunoassay was superior to agar-gel diffusion in identifying dialysis patients with complicated bacteremia. In patients with increased concentrations of IgG Staphylococcal antibodies by radioimmunoassay, the diagnosis of endocarditis, metastatic infection and suppuration at the access site should be considered. Prolonged antibiotic therapy and/or operative removal of the access device may be necessary.

Solid-phase radioimmunoassay for immunoglobulin G Staphylococcus aureus antibody in serious staphylococcal infection.

Clinical features of 99 patients with staphylococcal infection were reviewed, and sera were tested by solid-phase radioimmunoassay and gel diffusion for staphylococcal antibodies to ascertain whether these variables predict the extent of infection and the need for prolonged therapy. Clinical features, including the presence of a primary site of infection or a continuous pattern of bacteremia, were not sufficient for differentiating endocarditis or complicated bacteremia from uncomplicated bacteremia. Patients with uncomplicated bacteremia were cured by 3 weeks of antibiotic therapy. Positive serologic tests for staphylococcal antibody helped distinguish patients with endocarditis or complicated bacteremia from patients with uncomplicated bacteremia. Radioimmunoassay was more sensitive than gel diffusion for identifying patients with complicated bacteremia. Our results indicate that patients with a positive antibody result 14 days after the onset of infection should be considered to have endocarditis or complicated bacteremia, but a negative antibody result would support short-term antibiotic therapy.

Activation of the properdin pathway of complement in patients with gram-negative bacteremia.

To determine the pathway used for activation of complement component C3, serum levels of components C1, C4, C2, C3, C5, C6, and C9 and two properdin factors, properdin and factor B, were measured in 42 patients with gram-negative bacteremia, in 19 of whom shock subsequently developed. Mean levels of the classical components C1, C4, and C2 in bacteremic patients in whom shock subsequently developed did not differ significantly (p greater than 0.05) from those of patients with uncomplicated bacteremia. Levels of properdin, factor B and C3, C5, C6, and C9 were significantly (p less than 0.05) decreased in patients with shock in comparison with those with uncomplicated bacteremia. Taken together, these findings are consistent with activation of C3 and the terminal complement sequence, C5-C9, occurring primarily by the properdin pathway, in patients with gram-negative bacteremia eventuating in shock. Biologically active products released during activation of C3-C9 may contribute to the development of shock.

Serum complement levels in bacteremia due to gram-negative organisms.

Mean (± S.D.) levels of C3 did not differ significantly between 75 control patients (141.4 ± 22 mg per 100 ml) and 68 patients with bacteremia due to gram-negative organisms(132 ± 50 mg per 100 ml). In the 41 patients with uncomplicated bacteremia the mean C3 levels (151 ± 51 mg per 100 ml) did not differ from values in controls; however, a significant reduction in C3 levels was observed in 26 patients with shock (105 ± 31 mg per 100 ml) and the 19 patients who died (98 ± 38 mg per 100 ml) of bacteremia (p less than 0.001). The frequency of occurrence of shock or fatal outcome tended to parallel the degree of lowering of C3 levels in serum specimens obtained shortly after the onset of bacteremia.