Telithromycin: a new ketolide antimicrobial for treatment of respiratory tract infections.

Telithromycin is a new ketolide antimicrobial, specifically developed for the treatment of community-acquired respiratory tract infections. It has a wide spectrum of antibacterial activity against common respiratory pathogens including Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes. It also has activity against atypical pathogens, such as Chlamydia pneumoniae, Legionella pneumophila and Mycoplasma pneumoniae. Telithromycin maintains activity against beta-lactam and macrolide-resistant respiratory tract pathogens and does not appear to induce cross-resistance to other members of the macrolide-lincosamide-streptogramin (MLS) group of antimicrobials. It demonstrates bactericidal activity against S. pneumoniae and H. influenzae and has a prolonged concentration-dependent post-antibiotic effect (PAE) in vitro. The drug has favourable pharmacokinetics following oral administration. It is well absorbed, achieves good plasma levels and is highly concentrated in pulmonary tissues and white blood cells. In clinical trials, telithromycin given orally at a dose of 800 mg once daily for 5 - 10 days was as effective as comparator antimicrobials for the treatment of adults with community-acquired pneumonia, acute exacerbations of chronic bronchitis, acute maxillary sinusitis and group A-beta-haemolytic streptococcal pharyngitis or tonsillitis. The adverse events and safety profile were similar to comparator antimicrobials. The most common adverse events were diarrhoea, nausea, headache and dizziness. Telithromycin should provide an effective, convenient and well-tolerated once-daily oral therapy for treatment of respiratory infections.

Clostridium difficile-associated diarrhea in a VA medical center: clustering of cases, association with antibiotic usage, and impact on HIV-infected patients.

A case-control study of patients with stools assayed for Clostridium difficile toxin over a 24-month period at a Veterans Affairs hospital found that the majority of cases (70.6%) occurred in temporal clusters. Clustering was particularly evident on a designated human immunodeficiency virus (HIV) unit. Thirty-four (75.5%) of 45 HIV-infected patients with C difficile-associated diarrhea (CDAD) died during their hospitalization. Third-generation cephalosporins were the antibiotics most strongly associated with CDAD.

Vancomycin-resistant Enterococcus faecium in a Veterans Affairs Medical Center: association with antibiotic usage.

BACKGROUND: Colonization and infection with vancomycin-resistant Enterococcus faecium (VREF) has been associated with the use of vancomycin and other antibiotics in individual patients. The objective of this study was to determine the association of VREF with the aggregate usage of antibiotics on nursing units in a hospital. METHODS: This was a retrospective correlation study. A usage ratio was calculated for each parenteral antibiotic on each nursing unit as the per-bed usage by weight of that antibiotic divided by its average usage throughout the hospital. An average usage ratio (AUR) for each nursing unit was calculated as the mean of usage ratios of individual antibiotics. The AUR was used to compare the usage of antibiotics among nursing units in the hospital. The incidence of VREF infections on individual nursing units in a Veterans Affairs Medical Center was correlated with the usage of parenteral antibiotics separately and in aggregate in univariate and multivariate regression analyses. RESULTS: The AUR was strongly and positively correlated with the recovery of VREF on individual nursing units. By univariate analyses, increasing use of each antibiotic tested was associated with isolation of VREF but only clindamycin remained significant in the multivariate model. However, usage of various antibiotics was highly interrelated, and only clindamycin usage was significantly correlated with usage of all other antibiotics studied. Intensive care and acute care units and units with fewer patient beds were more likely to have patients with VREF infection than were subacute care units (p < 0.003) or larger units (p < 0.01). CONCLUSIONS: VREF infections were associated with greater aggregate antibiotic use on nursing units. Determination of antibiotic usage ratios may provide a convenient and useful tool for examining the association of antibiotic usage with other nosocomial infections.

Emergence of penicillin resistance in recurrent pneumococcal endocarditis in an HIV-infected patient.

The emergence of antibiotic resistance in Streptococcus pneumoniae poses a particular threat to HIV-infected patients. These patients are at increased risk of invasive pneumococcal disease and may respond poorly to pneumococcal vaccination. We describe an HIV-infected patient with recurrent aortic valve endocarditis due to the same serotype of S. pneumoniae (19A) despite appropriate treatment with penicillin and immunoprophylaxis. The pneumococcus responsible for the second episode of endocarditis was susceptible to cefotaxime (MIC of 0.06 microg/ml), but was no longer susceptible to penicillin (MIC of 0.25 microg/ml). The patient was treated successfully with 4 weeks of intravenous ceftriaxone.

Persistence of vancomycin-resistant Enterococcus faecium gastrointestinal tract colonization in antibiotic-treated mice.

Colonization with vancomycin-resistant Enterococcus faecium (VREF) is strongly associated with previous antimicrobial therapy. The gastrointestinal (GI) tract appears to be the major reservoir for this organism. We used antibiotic-treated Swiss Webster mice to study GI tract colonization with a characterized strain of VREF (E. faecium 228). Mice were pretreated with antibiotics in their daily drinking water and inoculated with 10(9) colony-forming units (CFU) of E. faecium 228 by oral gavage. We were able to establish persistent colonization with high concentrations of E. faecium 228 (> 8.0 log10 CFU/g of feces) in animals treated with 5 mg/ml of streptomycin plus 1 mg/ml of cefotetan. RP 59500, a streptogramin antibiotic with good in vitro activity against VREF, was administered orally in mice (n = 8) colonized with E. faecium 228. After 14 days of treatment VREF was undetectable in feces of all treated mice (< 3.0 CFU/g). Seven days after discontinuation of RP 59500, VREF was present in the feces of all animals. VREF isolates recovered after treatment remained susceptible to RP 59500. Attempts to eradicate E. faecium 228 colonization by oral administration of a vancomycin-sensitive E. faecium strain (SF68) or Lactobacillus spp. were unsuccessful as long as animals continued to receive streptomycin and cefotetan. Recovery of E. faecium 228 from cultures of livers and gallbladders in some animals with persistent GI tract colonization suggests that the organisms may also colonize the hepatobiliary system.

Treatment of vancomycin-resistant Enterococcus faecium infections with an investigational streptogramin antibiotic (quinupristin/dalfopristin): a report of fifteen cases.

New therapies for vancomycin-resistant Enterococcus faecium (VREF) infections are urgently needed. We describe the treatment of 15 patients with VREF infection with quinupristin/dalfopristin (RP 59500), a new injectable streptogramin antibiotic. Primary infections treated were bacteremia (4), urinary tract (4), intraabdominal (5), otitis externa (1), and meningitis (1). Minimum inhibitory concentrations for quinupristin/dalfopristin ranged from 0.5 microgram/ml or less to 2 micrograms/ml, and minimum bactericidal concentrations were greater than 64 micrograms/ml for all VREF isolates tested. Peak serum inhibitory titers following infusion of quinupristin/dalfopristin ranged from 1:8 to 1:64; all bactericidal titers were less than 1:2. Development of resistance to quinupristin/dalfopristin during therapy was not observed. The only drug-related adverse effect noted was phlebitis in 4 patients; all had received quinupristin/dalfopristin by peripheral venous infusion. Three patients had clinical and bacteriologic cures. Relapses occurred in 5 patients with recovery of VREF from infected sites in post-treatment cultures. Ten patients died of severe underlying disease; VREF was believed to contribute directly to the death of only 1 patient. While evaluation of clinical efficacy was complicated by the severity of underlying disease in patients with VREF infection, our experience suggests that quinupristin/dalfopristin is a safe and potentially useful agent for the treatment of VREF infections.

Pneumonia complicating adult respiratory distress syndrome.

Aspiration bronchopneumonia occurs in most patients undergoing prolonged mechanical ventilation. These pneumonias adversely affect lung function and release bacteria into the systemic circulation via the lungs' lymphatics. Through this mechanism, clinically occult pneumonias may initiate activation of systemic inflammation, leading to the syndrome of multiple organ failure.

Seizures associated with ganciclovir therapy.

A 32-year-old man diagnosed with acquired immunodeficiency syndrome and a disseminated cytomegalovirus infection experienced seizures associated with the administration of ganciclovir. Seizures began 1 month after initiation of therapy and worsened with increasing dosages. Despite phenytoin administration, the seizure-like activity subsided only after discontinuing ganciclovir. After rechallenge with ganciclovir the seizures recurred. Although this case was confounded by numerous patient and disease factors, the Naranjo algorithm produced a score of 7, indicating a probable association between ganciclovir and seizure activity.

In vitro activity of vancomycin against the spirochete Borrelia burgdorferi.

Borrelia burgdorferi, a spirochete and the causative agent of Lyme disease, has been reported to be susceptible to a variety of antimicrobial agents. In this investigation, the action of vancomycin, a glycopeptide antibiotic not previously known to have activity against spirochetes, against borrelias was examined. The in vitro activity of vancomycin against a variety of strains of B. burgdorferi and one strain of Borrelia hermsii was determined by use of a microdilution MIC method (L.L. Dever, J.H. Jorgensen, and A.G. Barbour, J. Clin. Microbiol. 30:2692-2697, 1992). MICs ranged from 0.5 to 2 micrograms/ml. MICs of the glycopeptides ristocetin and teicoplanin and the lipopeptide daptomycin against strain B31 of B. burgdorferi were all > or = 8 micrograms/ml. Subsurface plating, time-kill studies, synergy studies, and electron microscopy were used to investigate further the activity of vancomycin against B31. The MBC of vancomycin was 2 micrograms/ml. Time-kill curves demonstrated > or = 3-log10-unit (99.9%) killing of the final inoculum after 72 h by vancomycin concentrations twice the MIC. Synergy between vancomycin and penicillin was demonstrated at concentrations one-fourth the MIC of each drug. In electron microscopy, B31 cells exposed to vancomycin showed a disruption of cellular integrity and were indistinguishable from those exposed to penicillin. These studies demonstrate another class of microorganisms susceptible in vitro to vancomycin.

Comparative in vitro activities of clarithromycin, azithromycin, and erythromycin against Borrelia burgdorferi.

The in vitro activities of the macrolide antibiotics clarithromycin, 14-hydroxy-clarithromycin, azithromycin, and erythromycin against 19 isolates of Borrelia burgdorferi were investigated. MICs ranged from 0.003 to 0.03 microgram of clarithromycin per ml, 0.007 to 0.03 microgram of 14-hydroxyclarithromycin per ml, 0.003 to 0.03 microgram of azithromycin per ml, and 0.007 to 0.06 microgram of erythromycin per ml. Time-kill studies using the B31 strain of B. burgdorferi demonstrated a > or = 3-log10-unit killing after 72 h with each of the macrolide antibiotics tested in concentrations representing twice the respective MICs.

In vitro antimicrobial susceptibility testing of Borrelia burgdorferi: a microdilution MIC method and time-kill studies.

The susceptibility of Borrelia burgdorferi, the causative agent of Lyme borreliosis, to various antimicrobial agents varies widely among published studies. These differences are probably due in part to variations in susceptibility testing techniques and growth endpoint determinations. We developed a microdilution method for determining the MICs of antibiotics against B. burgdorferi. The method incorporated BSK II medium, a final inoculum of 10(6) cells per ml, and a 72-h incubation period and was found to be simple and highly reproducible. A variety of antibiotics and strains of B. burgdorferi and one strain of Borrelia hermsii were examined by this method. MICs of penicillin, ceftriaxone, and erythromycin for the B31 strain of B. burgdorferi were 0.06, 0.03, and 0.03 microgram/ml, respectively. We compared the MICs obtained by the microdilution method with those obtained by a macrodilution method using similar criteria for endpoint determinations and found the values obtained by both methods to be in close agreement. To further investigate the bactericidal activities of penicillin, ceftriaxone, and erythromycin against strain B31, we used subsurface plating to determine MBCs and we also performed time-kill studies. The MBCs of penicillin, ceftriaxone, and erythromycin were 0.125, 0.03, and 0.06 micrograms/ml, respectively. Time-kill curves demonstrated a greater than or equal to 3-log10-unit killing after 72 h with penicillin, ceftriaxone, and erythromycin; ceftriaxone provided the greatest reduction in CFU. The described methods offer a more standardized and objective approach to susceptibility testing of B. burgdorferi.

In vitro activities of the everninomicin SCH 27899 and other newer antimicrobial agents against Borrelia burgdorferi.

The in vitro activity of the everninomicin antibiotic SCH 27899 against 17 isolates of Borrelia spp. was investigated. MICs ranged from 0.06 to 0.5 microg/ml. Time-kill studies with the B31 strain of B. burgdorferi demonstrated >/=3-log10-unit killing after 72 h with concentrations representing four times the MIC. The in vitro activity of four other newer antimicrobial agents, meropenem, cefepime, quinupristin-dalfopristin, and linezolid, was also tested against the B31 strain. Meropenem was the most potent of the latter agents, with an MIC of 0.125 microg/ml.

Activity of quinupristin/dalfopristin against Streptococcus pneumoniae in vitro and in vivo in the rabbit model of experimental meningitis.

We tested the efficacy of quinupristin/dalfopristin, an antibiotic made up of dalfopristin (70%) and quinupristin (30%) against a large panel of Streptococcus pneumoniae strains. The pneumococcal isolates (217) included 200 penicillin-resistant and 17 penicillin-susceptible clinical isolates. Eighty-nine of the 200 resistant bacteria showed an intermediate level and 111/200 showed a high level of resistance to penicillin. Of the highly resistant strains, 56/111 belonged to the multidrug-resistant Spanish/USA epidemic clone of S. pneumoniae, as defined by appropriate genetic techniques. The resistant panel also included six isolates of another multidrug-resistant epidemic clone: isolates with capsular type 6B belonging to the Spanish/Icelandic clone of S. pneumoniae. Quinupristin/dalfopristin had a uniform mean MIC of 0.25 mg/L against all pneumococcal isolates, including 37 strains representing a wide spectrum of erythromycin MICs, from 0.03 up to 8.0 mg/L. Quinupristin/dalfopristin showed powerful bactericidal activity against a penicillin-susceptible test strain in vitro and against representatives of both the Spanish/USA and the Spanish/Icelandic multidrug-resistant clones. The rate of bactericidal activity was independent of drug concentration between 2.5 x and 10 x MIC. Quinupristin/dalfopristin was also tested in a rabbit model of experimental meningitis using 50 mg/kg i.v. bolus injections and a penicillin-susceptible capsular type 3 S. pneumoniae strain as the test organism. Quinupristin/dalfopristin had no effect on the intracisternal growth of bacteria when the drug was injected before CSF inflammation, whereas it caused a 2 log kill in 2 h, after which bacterial growth in the CSF resumed, when injected i.v. at a time of inflammation. When a second dose was given 2 h later, this produced a 3 log loss of viability after 4 h. A single injection of ampicillin 50 mg/kg i.v. caused a similar 3 log kill after 4 h under comparable conditions.

Varied presentations and responses to treatment of infections caused by Mycobacterium haemophilum in patients with AIDS.

We describe three patients with AIDS who developed clinically significant infection with Mycobacterium haemophilum. One patient had skin and bone involvement and suspected laryngeal involvement; the second had extensive abdominal adenopathy with partial bowel obstruction; and the third presented with limited skin involvement. Each patient responded transiently to antimycobacterial therapy, but disease recurred and progressed in all three cases. Recovery of M. haemophilum requires a high level of clinical suspicion and special handling of mycobacterial cultures by the microbiology laboratory, including cultivation on enriched chocolate agar or heme-supplemented media and incubation at 30 degrees C for up to 8 weeks. Characteristic patterns of drug susceptibility for this organism have been only partially defined. Reported responses to antimycobacterial therapy in AIDS patients with M. haemophilum infection have been poor, and the optimal therapeutic regimen is not yet known. The prognosis for recovery appears to depend heavily on host-related factors, particularly the degree of immunosuppression.

Vancomycin-dependent Enterococcus faecium isolated from stool following oral vancomycin therapy.

The isolation of clinical strains of enterococci requiring vancomycin for growth has only recently been reported. We describe the isolation of Enterococcus faecium requiring vancomycin for growth from the stool of a patient who had completed oral vancomycin therapy. Growth of the vancomycin-dependent E. faecium was supported by ristocetin and D-alanyl-D-alanine but not by daptomycin, teicoplanin, or D,L-alanine. Spontaneous revertants not requiring vancomycin occurred at a rate of 1 in 10(6). Both the vancomycin-dependent E. faecium and the revertant hybridized with a vanB gene probe and had identical contour-clamped homogeneous electrophoresis patterns. The majority of revertant colonies were resistant to teicoplanin, suggesting constitutive production of the vanB ligase. We believe the vancomycin-dependent E. faecium evolved from a vancomycin-resistant, vancomycin-independent E. faecium in the presence of high concentrations of vancomycin in the intestine.

In vivo activities of ceftriaxone and vancomycin against Borrelia spp. in the mouse brain and other sites.

Borrelia burgdorferi, the agent of Lyme disease, and B. turicatae, a neurotropic agent of relapsing fever, are susceptible to vancomycin in vitro, with an MIC of 0.5 microgram/ml. To determine the activity of vancomycin in vivo, particularly in the brain, we infected adult immunocompetent BALB/c and immunodeficient CB-17 scid mice with B. burgdorferi or B. turicatae. The mice were then treated with vancomycin, ceftriaxone as a positive control, or normal saline as a negative control. The effectiveness of treatment was assessed by cultures of blood and brain and other tissues. Ceftriaxone at a dose of 25 mg/kg of body weight administered every 12 h for 7 to 10 days eliminated cultivable B. burgdorferi or B. turicatae from all BALB/c or scid mice in the study. Vancomycin at 30 mg/kg administered every 12 h was effective in eliminating infection from immunodeficient mice if treatment was started within 3 days of the onset of infection. If treatment with vancomycin was delayed for 7 days or more, vancomycin failed to eradicate infection with B. burgdorferi or B. turicatae from immunodeficient mice. The failure of vancomycin in eradicating established infections in immunodeficient mice was associated with the persistence of viable spirochetes in the brain during antibiotic treatment.

Hyperglycemia associated with protease inhibitors in an urban HIV-infected minority patient population.

BACKGROUND: Hyperglycemia and new-onset diabetes mellitus have been reported to occur in HIV-infected patients treated with protease inhibitors. OBJECTIVE: To determine the effect of protease inhibitor therapy on serum glucose in a predominantly minority patient population. DESIGN: Retrospective record review. SETTING: Clinical HIV program of an urban Veterans Affairs medical center. PATIENTS: All HIV-infected patients receiving a protease inhibitor over a one-year period from September 1996 through August 1997. RESULTS: One hundred seventeen patients not previously known to be diabetic received protease inhibitors; seven (6%) developed symptomatic diabetes mellitus. Eight other patients had one or more serum glucose values >150 mg/dL. Mean random glucose values for patients who did not develop diabetes were higher during therapy than prior to initiation of protease inhibitors. CONCLUSIONS: Urban minority HIV-infected patients receiving combination antiretroviral therapy including a protease inhibitor may be at increased risk for the development of hyperglycemia and diabetes mellitus. Risk factors for diabetes mellitus should be identified and blood glucose monitored in all patients receiving protease inhibitors.