Aldona L. Baltch

Efficacy of pneumococcal vaccine in high-risk patients. Results of a Veterans Administration Cooperative Study.

We conducted a randomized, double-blind, placebo-controlled trial to test the efficacy of the 14-valent pneumococcal capsular polysaccharide vaccine in 2295 high-risk patients (patients with one or more of the following: age above 55 years and the presence of chronic cardiac, pulmonary, renal, or hepatic disease, alcoholism, or diabetes mellitus). Seventy-one episodes of proved or probable pneumococcal pneumonia or bronchitis occurred among 63 of the patients (27 placebo recipients and 36 vaccine recipients). Vaccine-serotype Streptococcus pneumoniae strains were recovered in association with 11 infections in the placebo group and 14 infections in the vaccine group. Pneumococcal infections occurred most frequently among patients with chronic pulmonary, cardiac, or renal diseases. Among vaccine recipients who subsequently had vaccine-type pneumonia or bronchitis, the majority did not make or sustain serum antibodies against their infecting organism in concentrations that were twice as high as the base-line values, or more than 400 ng of antibody nitrogen per milliliter, although their base-line levels were higher than those in subjects in whom infection did not develop. We were unable to demonstrate any efficacy of the pneumococcal vaccine in preventing pneumonia or bronchitis in this population. Our data suggest that chronically ill patients, who are most susceptible to infection, may have an impaired immune response to the pneumococcal vaccine.

Epidemics of Diarrhea Caused by a Clindamycin-Resistant Strain of Clostridium difficile in Four Hospitals

BACKGROUND Large outbreaks of diarrhea caused by a newly recognized strain of Clostridium difficile occurred in four hospitals located in different parts of the United States between 1989 and 1992. Since frequent use of clindamycin was associated with the outbreak in one of the hospitals, we examined the resistance genes of the epidemic-strain isolates and studied the role of clindamycin use in these outbreaks. METHODS Case-control studies were performed at three of the four hospitals to assess the relation of the use of clindamycin to C. difficile-associated diarrhea. All isolates of the epidemic strain and representative isolates of other strains identified during each outbreak were tested for susceptibility to clindamycin. Chromosomal DNA from these representative isolates was also analyzed by dot blot hybridization and amplification with the polymerase chain reaction (PCR) with the use of probes and primers from a previously described determinant of erythromycin resistance - the erythromycin ribosomal methylase B (ermB) gene - found in C. perfringens and C. difficile. RESULTS In a stratified analysis of the case-control studies with pooling of the results according to the Mantel-Haenszel method, we found that the use of clindamycin was significantly increased among patients with diarrhea due to the epidemic strain of C. difficile, as compared with patients whose diarrhea was due to nonepidemic strains (pooled odds ratio, 4.35; 95 percent confidence interval, 2.02 to 9.38; P<0.001). Exposure to other types of antibiotics or hospitalization in a surgical ward was not significantly associated with the risk of C. difficile-associated diarrhea due to the epidemic strain. All epidemic-strain isolates were highly resistant to clindamycin (minimal inhibitory concentration, >256 microg per milliliter). DNA hybridization and PCR analysis showed that all these isolates had an ermB gene, which encodes a 23S ribosomal RNA methylase that mediates resistance to macrolide, lincosamide, and streptogramin antibiotics. Only 15 percent of the nonepidemic strains were resistant to clindamycin. CONCLUSIONS A strain of C. difficile that is highly resistant to clindamycin was responsible for large outbreaks of diarrhea in four hospitals in different states. The use of clindamycin is a specific risk factor for diarrhea due to this strain. Resistance to clindamycin further increases the risk of C. difficile-associated diarrhea, an established complication of antimicrobial use.

EPIDEMIC CLOSTRIDIUM DIFFICILE-ASSOCIATED DIARRHEA : ROLE OF SECOND- AND THIRD-GENERATION CEPHALOSPORINS

OBJECTIVE To better define the role of multiple risk factors for cytotoxic Clostridium difficile-associated diarrhea. DESIGN Case-control study. SETTING A Veterans Affairs Medical Center. PATIENTS Thirty-three case patients with C difficile-associated diarrhea. Two control groups were used: one group consisted of 32 patients from the same ward as the case patients, and one group consisted of 34 patients with nosocomial diarrhea and negative C difficile toxin assays. INTERVENTION None. RESULTS Multivariate analyses revealed that exposure to second- or third-generation cephalosporins was the most important independent risk factor, even after controlling for other antimicrobial use (odds ratio [OR] = 8.3, 95% confidence interval [CI95] = 1.4 to 48.9 compared to ward controls; OR = 9.6, CI95 = 2.1 to 44.1 compared with diarrhea controls). Persons exposed to two or more antimicrobials simultaneously were at substantially elevated risk (OR = 18.7, CI95 = 4.1 to 85.8 compared with ward controls; OR = 21.5, CI95 = 3.2 to 141.9 compared with diarrhea controls). CONCLUSION Physicians should consider carefully the appropriateness of second- and third-generation cephalosporin use and combination antimicrobial therapy, especially during nosocomial C difficile-associated diarrhea outbreaks (Infect Control Hosp Epidemiol 1994;15:88-94).

Bacteremia following dental cleaning in patients with and without penicillin prophylaxis

The rate, type, and magnitude of bacteremia were studied in 56 patients undergoing dental cleaning with and without penicillin prophylaxis. Sixty-one percent of patients without penicillin prophylaxis were bacteremic 5 minutes following the procedure. Although a significant decrease in detectable bacteremia occurred in patients receiving penicillin prophylaxis, the recovery of streptococci was not significantly different in the two groups. Using the present sample of patients as a basis for statistical inference, the true rate of bacteremia in such patients could be between 41% and 79% with 95% certainty. The magnitude of bacteremia was low and positive quantitative pour plates occurred at 5 minutes and only in patients without penicillin prophylaxis. Of the 71 total bacterial isolates, 53 (74.6%) were anaerobes and 18 (25.4%) were aerobes. This study indicates that parenteral penicillin prophylaxis for dental cleaning decreased detectable bacteremia rates significantly and could be recommended for patients with valvular heart disease who are known to be vulnerable to endocarditis.

Pseudomonas aeruginosa bacteremia: a clinical study of 75 patients.

AbstractA 3–1/2 year study of Pseudomonas aeruginosa (P. aeruginosa) bacteremia was conducted in two large hospitals. The average age of the 75 patients was 59 years, and only five pediatric patients were seen (6.6 percent). Neoplastic disease was present in 34 percent; the remaining patients had complex medical-surgical problems. The urinary and respiratory tracts were the most frequent sources of the bacteremia. Polymicrobial bacteremia occurred in 20 percent. Typically, the patients were febrile (> 102 F), had leukocytosis, anemia, thrombocytopenia, uremia and abnormal findings on chest roentgenograms. Ecthyma gangrenosum occurred in only one patient. Two thirds of the patients had received one or two antibiotics, most commonly cephalosporins, before bacteremia occurred. Overall mortality was 63 percent and in 31 percent death occurred. Overall mortality was 63 percent and in 31 percent death occurred within 36 hours. Appropriate therapy, gentamicin and/or carbenicillin, was similar in patients receiving one or both drugs. All 20 autopsied patients had bronchopneumonia. In four the pneumonia was homorrhagic and exudative with microabscesses and vascular thromboses. No invasion of the blood vessel walls was detected. Control of the patients primary disease process combined with prevention of P. aeruginosa colonization appears to be critical to the control of the frequently fatal bacteremia.

The effect of diabetes mellitus on chemotactic and bactericidal activity of human polymorphonuclear leukocytes

We studied the bactericidal activity (against P. aeruginosa) and chemotactic ability of polymorphonuclear leukocytes from 26 diabetic patients in three treatment groups (oral hypoglycemic, daily insulin, and continuous insulin infusion). Patients were studied before entry into intensified management protocols, and after intensified management in 11 of the 26 patients. Diabetic serum had a persistent inhibitory effect on both diabetic and normal white cells, but normal serum was unable to fully correct diabetic white cell killing to control values. After intensified management of diabetes, there was an improvement in bactericidal function of diabetic patient white cells, but not in the effect of diabetic serum. Diabetic serum, and to a lesser extent diabetic white blood cells, are defective mediators of killing of P. aeruginosa. Chemotaxis was normal in all patient groups. These findings confirm the earlier work of others showing that some patients with diabetes mellitus have a defect in host defense against infection with bacteria.

Inhibitory and bactericidal activities of levofloxacin, ofloxacin, erythromycin, and rifampin used singly and in combination against Legionella pneumophila

The susceptibilities of 56 Legionella pneumophila isolates (43 clinical and 15 environmental isolates) to levofloxacin, ofloxacin, erythromycin, and rifampin were studied with buffered charcoal yeast extract (BCYE) agar (inoculum, 10(4) CFU per spot), and the susceptibilities of five isolates were studied with buffered yeast extract (BYE) broth (inoculum, 10(5) CFU/ml). The MICs inhibiting 90% of strains tested on BCYE agar were 0.125, 0.25, 1.0, and < or = 0.004 micrograms/ml for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively. The MICs by the BYE broth dilution method were 1 to 3, 2, 1 to 2, and 1 tube lower than those by the agar dilution method for levofloxacin, ofloxacin, erythromycin, and rifampin, respectively. The MBCs were 1 to 2 tubes higher than the broth dilution MICs for levofloxacin, 1 to 3 tubes higher than the broth dilution MICs for ofloxacin, 1 to 3 tubes higher than the broth dilution MICs for erythromycin, and the same as the broth dilution MICs for rifampin. In kinetic time-kill curve studies, at drug concentrations of 1.0 and 2.0 times the MIC, the most active drugs were levofloxacin and rifampin. At 72 h, concentrations of levofloxacin and rifampin of 2.0 times the MIC demonstrated a bactericidal effect against L. pneumophila. In contrast, at concentrations of 1.0 and 2.0 times the MICs regrowth was observed with ofloxacin and only a gradual decrease in the numbers of CFU per milliliter was observed with erythromycin. Only a minor inhibitory effect was observed with 0.25 or 0.5 time the MICs of all drugs at 24 to 48 h, with regrowth occurring at 72 h. In contrast to erythromycin or ofloxacin plus rifampin at 0.25 time the MICs, only levofloxacin plus rifampin demonstrated synergy. Thus, levofloxacin demonstrated the best inhibitory and bactericidal effects against L. pneumophila when it was studied alone or in a combination with rifampin.

Combinations of antibiotics against Pseudomonas aeruginosa

Pseudomonas aeruginosa continues to cause serious infections, especially bacteremias, in hospitalized and immunocompromised patients. During the past 10 years, bacteremia due to this organism has increased in frequency in many institutions, and mortality rates in patients with rapidly fatal disease remain as high as 85 percent despite antibiotic therapy. Available data do not allow firm conclusions regarding the in vivo predictive value of in vitro synergy testing for P. aeruginosa, but in vitro demonstration of synergy appears important in selecting therapy for patients with P. aeruginosa infections. Combinations of aminoglycosides (amikacin or tobramycin) with highly active antipseudomonal beta-lactam antibiotics are most likely to be associated with in vitro synergy. Experimental studies in animals models support the use of combination therapy for local and bacteremic infections. Similarly, the retrospective and prospective studies in humans suggest better survival with combinations of antimicrobials, usually including aminoglycosides and beta-lactams, in immunocompromised hosts. At present, the use of newer penicillins, piperacillin, azlocillin, or selected antipseudomonal cephalosporins, in combination with amikacin or tobramycin, appears to be the preferable antimicrobial therapy for serious P. aeruginosa infections.

Activities of Daptomycin and Comparative Antimicrobials, Singly and in Combination, against Extracellular and Intracellular Staphylococcus aureus and Its Stable Small-Colony Variant in Human Monocyte-Derived Macrophages and in Broth

ABSTRACT We investigated the antistaphylococcal activities of daptomycin, gentamicin, and rifampin against two Staphylococcus aureus strains and their stable small-colony variants, singly and in combination, in human monocyte-derived macrophages and in broth. Intracellularly, the three-drug combination and two-drug combinations with rifampin were most effective. Extracellularly, daptomycin, daptomycin plus gentamicin, gentamicin plus rifampin, and the three-drug combination had similar activities.

Antimicrobial Activities of Daptomycin, Vancomycin, and Oxacillin in Human Monocytes and of Daptomycin in Combination with Gentamicin and/or Rifampin in Human Monocytes and in Broth against Staphylococcus aureus

ABSTRACT We investigated the antistaphylococcal activity of daptomycin, vancomycin, oxacillin, gentamicin, and rifampin in human monocyte-derived macrophages. Compared with vancomycin and oxacillin, daptomycin had the most rapid and greatest antibacterial activity, but that of oxacillin was most sustained. The combination of daptomycin, gentamicin, and rifampin was most effective intracellularly, while daptomycin plus gentamicin and the three-drug combination were most effective extracellularly, completely eliminating viable Staphylococcus aureus.