Peter C. Fuchs

In vitro activities of 12 orally administered antimicrobial agents against four species of bacterial respiratory pathogens from U.S. Medical Centers in 1992 and 1993.

Clinical isolates of Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, and Moraxella catarrhalis were gathered from 19 different clinical laboratories throughout the continental United States. The in vitro activities of 12 orally administered antimicrobial agents were compared by broth microdilution tests with 3,151 bacterial isolates. Among 890 H. influenzae isolates, 30% were capable of producing beta-lactamase enzymes (12 to 41% in different medical centers). Most of the 619 beta-lactamase-negative H. influenzae strains were susceptible to ampicillicin (MIC, < or = 1.0 micrograms/ml): 5 strains were intermediate in susceptibility (MIC, 2.0 micrograms/ml) and 1 strain was ampilicillin resistant (MIC, 4.0 micrograms/ml). Ninety-two percent of 698 M. catarrhalis strains were beta-lactamase positive. Of 799 S. pneumoniae isolates, 15% were intermediate in susceptibility to penicillin and 7% were resistant to penicillin. The prevalence of penicillin-susceptible pneumococci in different institutions ranged from 63 to 95%. Only 1% of 764 S. pyogenes isolates were resistant to the macrolides, but 5% of S. pneumoniae isolates were macrolide resistant. Only 71% of 58 penicillin-resistant S. pneumoniae isolates were erythromycin susceptible, whereas 97% of the 622 penicillin-susceptible strains were erythromycin susceptible. Penicillin-resistant pneumococci were also relatively resistant to the cephalosporins and amoxicillin. Penicillin-susceptible pneumococci were susceptible to amoxicillin-clavulanic acid (MIC for 90% of isolates tested [MIC90], < or = 0.12/0.06 microgram/ml), cefixime (MIC90, 0.25 microgram/ml), cefuroxime axetil (MIC90, < or = 0.5 microgram/ml), cefprozil (MIC90, < or = 0.5 micrograms/ml), cefaclor (MIC90, 0.5 microgram/ml), and loracarbef (MIC90, 1.0 microgram/ml). Most strains of the other species remained susceptible to the study drugs other than amoxicillin.

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

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

In Vitro Activities of Daptomycin against 2,789 Clinical Isolates from 11 North American Medical Centers

ABSTRACT The in vitro activity of daptomycin is affected by the concentration of calcium cations in the test medium. Mueller-Hinton broth is currently adjusted to contain 10 to 12.5 mg of magnesium per liter and 20 to 25 mg of calcium per liter, but for testing of daptomycin, greater concentrations of calcium (50 mg/liter) are recommended to better resemble the normal concentration of ionized calcium in human serum. Two levels of calcium were used for broth microdilution tests of 2,789 recent clinical isolates of gram-positive bacterial pathogens. MICs of daptomycin were two- to fourfold lower when the broth contained additional calcium. For most species, however, the percentages of strains that were inhibited by 2.0 μg of daptomycin per ml were essentially identical with the two broth media. Enterococci were the important exception; i.e., 92% were inhibited when tested in calcium-supplemented broth but only 35% were inhibited by 2.0 μg/ml without the additional calcium. This type of information should be considered when selecting criteria for defining in vitro susceptibility to daptomycin.

Daptomycin susceptibility tests: interpretive criteria, quality control, and effect of calcium on in vitro tests

Daptomycin MICs were determined for 844 Gram-positive bacteria in three concentrations of Ca(++) and compared with the MICs of vancomycin and teicoplanin. Daptomycin was twofold to fourfold more active against most species when tested in 50 microg/ml of Ca(++) than in 25 microg/ml. In 50 microg/ml of Ca(++) daptomycin was more active against methicillin-resistant staphylococci and vancomycin-resistant enterococci than teicoplanin or vancomycin; 100% of these isolates were susceptible to < or =2.0 microg/ml of daptomycin. Different lots of Mueller-Hinton agar were variable in Ca(++) content, and daptomycin disk diffusion zone diameters were affected, i.e., zones were 1 to 15 mm smaller on one lot of agar with only 6 microg/ml of Ca(++) compared to another lot with 28 microg/ml. The previously proposed daptomycin interpretive breakpoints performed satisfactorily when MICs were determined in Mueller-Hinton broth with 50 microg/ml of Ca(++) and when the agar gave appropriate zones with quality control strains. To define those control limits, replicate tests with four quality control strains were performed in ten laboratories using broth microdilution tests (with Ca(++) supplemented broth) and disk diffusion tests on Mueller-Hinton agar without cation adjustments.

Precision and Accuracy of Fluconazole Susceptibility Testing by Broth Microdilution, Etest, and Disk Diffusion Methods

ABSTRACT Interpretive agreements among the results of fluconazole broth microdilution tests, Etests, and disk diffusion tests were documented by evaluating 495 Candida spp. Microdilution reference test results were in agreement with 96% of the Etest results; most discrepancies were minor differences. Fluconazole resistance of Candida krusei strains often required a full 48 h of incubation in order to be observed by the standard method. For the disk diffusion tests that were performed on Mueller-Hinton agar with glucose and methylene blue, 97% of results were in agreement with those of the reference test, especially when zones of inhibition were measured after the first 24 h of incubation. Some Candida glabrata isolates failed to grow satisfactorily until a full 48 h of incubation was completed. Precision was determined by testing 50 selected isolates in triplicate in each of three laboratories. The reproducibility of results of disk diffusion tests was comparable to that of the reference method. With all procedures, determination of test results was particularly challenging with some strains, and new methods are needed in order to improve endpoint definition.

In Vitro Activities of Ertapenem (MK-0826) against Clinical Bacterial Isolates from 11 North American Medical Centers

ABSTRACT This study compared the in vitro activities of the new long-half-life carbapenem ertapenem (also known as MK-0826 and L-749,345) with those of imipenem, amoxicillin-clavulanate, and ciprofloxacin against 5,558 recent clinical isolates from 11 North American medical centers. We confirmed the greater activity of ertapenem than of imipenem against the Enterobacteriaceae and the greater activity of imipenem against pseudomonads and gram-positive bacteria.

In vitro activity of ticarcillin plus clavulanic acid against 632 clinical isolates.

A total of 632 clinical bacterial isolates were tested for susceptibility to twofold dilutions of ticarcillin alone and in combination with 1, 2, and 4 micrograms of clavulanic acid (CA) (Timentin) per ml by a reference microdilution method. With the addition of CA, ticarcillin MICs were reduced eightfold or greater with 54 of 59 (92%) strains of the family Enterobacteriaceae with ticarcillin MICs of greater than or equal to 64 micrograms/ml. The inhibitory effect of CA on pseudomonads was minimal. Ticarcillin MICs for beta-lactamase-producing Haemophilus influenzae, Neisseria gonorrhoeae, and most Staphylococcus aureus were reduced to less than or equal to 0.5 micrograms/ml when CA was added. For dilution susceptibility testing of ticarcillin-clavulanic acid, dilutions of ticarcillin combined with 2 micrograms of CA per ml is suggested.

Evaluation of the in vitro activity of BMY-28142, a new broad-spectrum cephalosporin.

The in vitro activity of BMY-28142, a new cephalosporin, was tested by a broth microdilution system and compared with those of cefotaxime, ceftazidime, cefoperazone, moxalactam, and HR 810 against 747 bacterial isolates, one-third of which were resistant to one or more third-generation cephalosporins. BMY-28142 was the most active drug tested against 326 Enterobacteriaceae with an MIC for 90% of the organisms tested (MIC90) of 1.0 micrograms/ml. Against these Enterobacteriaceae the relative activities were: BMY-28142 greater than HR 810 greater than moxalactam and ceftazidime greater than cefotaxime greater than cefoperazone. For cefotaxime- and cefoperazone-resistant strains, the MIC90 of BMY-28142 was 4.0 micrograms/ml (compared with 0.13 micrograms/ml for susceptible strains). BMY-28142, with an MIC90 of 8.0 micrograms/ml for Pseudomonas aeruginosa, was about half as active as ceftazidime. The relative activities against P. aeruginosa were: ceftazidime greater than BMY-28142 greater than HR 810 greater than cefoperazone greater than moxalactam and cefotaxime. The MIC90 of BMY-28142 against staphylococci was 2.0 micrograms/ml, which was fourfold less active than HR 810, slightly less active than cefotaxime and cefoperazone, and fourfold more active than ceftazidime and moxalactam. BMY-28142 was very active against beta-lactamase-positive and -negative Haemophilus influenzae (MIC90, 0.06 micrograms/ml), Neisseria gonorrhoeae (MIC90, 0.015 micrograms/ml),aand nonenterococcal streptococci. Its activity against Streptococcus faecalis was poor (MIC90, 64 micrograms/ml). BMY-28142 was stable against the several beta-lactamases tested but exhibited little beta-lactamase inhibitory effect.

Piperacillin/tazobactam (YTR 830) combination: Comparative antimicrobial activity against 5889 recent aerobic clinical isolates and 60 Bacteroides fragilis group strains

Piperacillin combined with tazobactam (formerly YTR 830) was tested at a ratio of 8:1 against 5889 aerobic isolates and 50 strains from the Bacteroides fragilis group. Imipenem was the most active agent tested against Enterobacteriaceae (99.3% at less than or equal to 4 micrograms/ml), ceftazidime was most effective against nonenteric Gram-negative bacilli (80.7% at less than or equal to 8 micrograms/ml), and piperacillin/tazobactam possessed a superior spectrum against Gram-positive cocci (92.2% at less than or equal to 16/2 micrograms/ml). Against all aerobic strains, piperacillin/tazobactam had a spectrum (90.3% at less than or equal to 16/2 micrograms/ml) comparable to imipenem (93.6% at less than or equal to 4 micrograms/ml) and was distinctly greater than that of ticarcillin/clavulanic acid (73.3% at less than or equal to 16/2 micrograms/ml) and ceftazidime (75.5% at less than or equal to 8 micrograms/ml). Against the B. fragilis group isolates, all piperacillin/tazobactam MICs were less than or equal to 64/8 micrograms/ml. This activity was superior to piperacillin alone (MIC:50, 8-64 micrograms/ml) and cefoxitin (MIC50, 4-64 micrograms/ml). Piperacillin/tazobactam appears to be a promising parenteral antimicrobial combination, with a spectrum effective against a wide variety of clinical pathogens.

Assessment of Catheter-Associated Infection Risk with the Hickman Right Atrial Catheter

One hundred fifty Hickman right atrial catheters were inserted into 143 patients and were followed prospectively until removal. Primary indications for their use were: cancer chemotherapy (45), parenteral nutrition (35), antibiotic therapy (63), and miscellaneous (7). The overall catheter-associated infection rate was 12.0%. Since the mean duration of catheterization was 125 days, the infection/duration rate was 1.0/1,000 days of use. The risk of infection differed significantly according to the primary indication for catheterization: parenteral nutrition greater than antibiotic therapy greater than cancer chemotherapy. The increased risk of catheter-associated infection attributable to duration of catheterization was additive, and the per day risk of such infections remained constant regardless of duration. Nearly two-thirds of patients were discharged home with catheters in place, without adversely affecting infection risk.