David J. Ritchie

Pseudomonas aeruginosa Bloodstream Infection: Importance of Appropriate Initial Antimicrobial Treatment

ABSTRACT Pseudomonas aeruginosa bloodstream infection is a serious infection with significant patient mortality and health-care costs. Nevertheless, the relationship between initial appropriate antimicrobial treatment and clinical outcomes is not well established. This study was a retrospective cohort analysis employing automated patient medical records and the pharmacy database at Barnes-Jewish Hospital. Three hundred five patients with P. aeruginosa bloodstream infection were identified over a 6-year period (January 1997 through December 2002). Sixty-four (21.0%) patients died during hospitalization. Hospital mortality was statistically greater for patients receiving inappropriate initial antimicrobial treatment (n = 75) compared to appropriate initial treatment (n = 230) (30.7% versus 17.8%; P = 0.018). Multiple logistic regression analysis identified inappropriate initial antimicrobial treatment (adjusted odds ratio [AOR], 2.04; 95% confidence interval [CI], 1.42 to 2.92; P = 0.048), respiratory failure (AOR, 5.18; 95% CI, 3.30 to 8.13; P < 0.001), and circulatory shock (AOR, 4.00; 95% CI, 2.71 to 5.91; P < 0.001) as independent determinants of hospital mortality. Appropriate initial antimicrobial treatment was administered statistically more often among patients receiving empirical combination antimicrobial treatment for gram-negative bacteria compared to empirical monotherapy (79.4% versus 65.5%; P = 0.011). Inappropriate initial empirical antimicrobial treatment is associated with greater hospital mortality among patients with P. aeruginosa bloodstream infection. Inappropriate antimicrobial treatment of P. aeruginosa bloodstream infections may be minimized by increased use of combination antimicrobial treatment until susceptibility results become known.

Relationship between Fluoroquinolone Use and Changes in Susceptibility to Fluoroquinolones of Selected Pathogens in 10 United States Teaching Hospitals, 1991-2000

We retrospectively examined the relationship between fluoroquinolone use and the susceptibilities of 11 bacterial pathogens to fluoroquinolones in 10 US teaching hospitals from 1991 through 2000. Statistical significance was determined by 2-way analysis of variance, with the number of isolates tested each year as a weighting factor. The analysis of baseline-to-end point change in the percentage of susceptibility and the slope of the regression line (trend line) for logit percentage of susceptibility showed that the overall percentage of susceptibility to fluoroquinolones decreased significantly during the study period (P<.05) and that change in percentage of susceptibility was significantly related to change in fluoroquinolone use (P<.05). Particularly notable were the decreases in the susceptibilities of Pseudomonas aeruginosa, Proteus mirabilis, and Escherichia coli (decreases of 25.1%, 11.9%, and 6.8%, respectively).

Successful treatment of vancomycin-resistant Enterococcus endocarditis with oral linezolid

We report a case of vancomycin-resistant Enterococcus faecium endocarditis that failed to respond to sequential monotherapy with chloramphenicol and quinupristin/dalfopristin but was successfully treated with oral linezolid.

Tigecycline for treatment of pneumonia and empyema caused by carbapenemase-producing Klebsiella pneumoniae

Strains of Klebsiella pneumoniae that produce one of three possible carbapenemases—KPC—have recently been identified with increasing frequency among isolates recovered from patients residing along the East Coast of the United States, particularly within the New York City metropolitan region. These strains have exhibited resistance to multiple antibiotic classes, including carbapenem agents. We report a case of nosocomial pneumonia and empyema caused by a KPC‐producing isolate of K. pneumoniae at a large midwestern U.S. tertiary care facility in which the patient was treated with tigecycline. Although the pneumonia was treated successfully, the empyema recurred in association with a treatment‐emergent tigecycline minimum inhibitory concentration (MIC) increase from 0.75 to 2 μg/ml. Clinicians should be aware of the potential occurrence of this treatment‐emergent MIC increase, especially in the setting of sustained tigecycline therapy. In addition, the emergence of carbapenem‐resistant Enterobacteriaceae reinforces the importance of antibiotic stewardship and strict infection control practices.

In vitro activities of various beta-lactam antimicrobial agents against clinical isolates of Escherichia coli and Klebsiella spp. resistant to oxyimino cephalosporins.

Broth microdilution testing was used to study the activity of several beta-lactam antimicrobial agents, including piperacillin-tazobactam and cefepime, against 108 clinically derived Escherichia coli and Klebsiella sp. strains resistant to oxyimino cephalosporins (i.e., putative extended-spectrum beta-lactamase producers). On the basis of the percentage of susceptible strains, imipenem (100%), cefotetan (> or = 92%), and piperacillin-tazobactam (> or = 86%) were the most active agents. Cefepime activity (52 to 64% susceptible) was comparable to that of cefotaxime (40 to 63% susceptible) and aztreonam (20 to 63% susceptible). Among all beta-lactams tested, imipenem and cefotetan demonstrated the highest and most consistent level of activity and were the least affected by challenges with increased sizes of inocula of these resistant organisms.

Comparison of outcomes from daptomycin or linezolid treatment for vancomycin-resistant enterococcal bloodstream infection: A retrospective, multicenter, cohort study.

BACKGROUND The optimal treatment for bloodstream infections (BSIs) with vancomycin-resistant enterococci (VRE) is unknown. OBJECTIVE This study examined outcomes in patients treated with daptomycin or linezolid for VRE BSI. METHODS A retrospective, multicenter, cohort study was performed via chart review. Hospitalized patients treated for VRE BSI with daptomycin or linezolid from September 1, 2003, to June 30, 2007, were identified via pharmacy and microbiology reports at each institution. Patients aged <18 years or with polymicrobial bacteremia were excluded from analysis. Linezolid and daptomycin were included because the participating institutions used either of the 2 agents as first-line treatment for VRE BSI. Univariate and multivariate analyses were performed to determine the effect of drug selection on mortality and duration of BSI. Duration of BSI was defined as the amount of time from the draw date of the first positive blood culture to the draw date of the first finalized negative blood culture. Adverse events were not assessed. RESULTS One-hundred one patients from 3 participating US hospitals experiencing VRE BSI were identified. Sixty-seven patients were treated with daptomycin and 34 with linezolid. Baseline characteristics appeared comparable between the daptomycin- and linezolidtreated groups, with the exception of shock (P = 0.049), prior vancomycin treatment (P = 0.002), and prior linezolid treatment (P < 0.001), all of which occurred significantly more often in daptomycin-treated patients. Inpatient mortality occurred in 31 daptomycin- and 10 linezolid-treated patients (46.3% vs 29.4%; P = NS). Linear regression found that shock (P = 0.015), infective endocarditis (P = 0.021), and concurrent rifampin or gentamicin treatment (P = 0.01) were associated with prolonged duration of positive cultures. Logistic regression revealed that shock (odds ratio [OR] = 14.24; P = 0.008), infection with Enterococcus faecium (OR = 53.10; P = 0.024), previous linezolid treatment (OR = 6.63; P = 0.031), concurrent rifampin or gentamicin treatment (OR = 6.48; P = 0.046), and a nonline source of infection (OR = 6.67; P = 0.019) were associated with increased mortality. CONCLUSIONS In this retrospective cohort analysis, there were no significant differences in mortality of VRE BSI between patients receiving daptomycin or linezolid. Underlying comorbidities appeared to best predict outcome; however, given the retrospective nature of this study, larger, prospective, randomized, comparative studies are needed to control for potential biases and determine definitive outcome differences between these 2 antimicrobials.

Early clinical experience with anidulafungin at a large tertiary care medical center.

Study Objective. To evaluate early clinical experience with anidulafungin.

Vancomycin levels after intravitreal injection: Effects of inflammation and surgery

Objective: Vancomycin hydrochloride for intraocular injection is the drug of choice for the treatment of suspected gram‐positive endophthalmitis. To study its intraocular pharmacokinetics, we injected vancomycin into the vitreous cavity of phakic, aphakic, and aphakic‐vitrectomized rabbit eyes and determined its rate of clearance. Inflamed eyes were compared to control eyes in each group. Methods: Three groups of eyes were prepared. The eyes in Group 1 were phakic, the eyes in Group 2 had the lens removed, and the eyes in Group 3 had both the lens and central vitreous removed. Each group was subdivided into a control group and a group made inflamed by injection of heat‐killed Staphylococcus epidermidis. Vancomycin hydrochloride 1 mg in 0.1 cc of diluent was injected into the midvitreous cavity and samples obtained at 2 or 3, 8, 24, and 48 hours after injection. Vancomycin concentrations were measured and clearance rates were calculated for each of the groups. Results: Vancomycin was cleared substantially faster from aphakic‐vitrectomized eyes (half‐life 9.0 hours) and aphakic eyes (half‐life 8.9 hours) than phakic eyes (half‐life 25.1 hours). Inflammation increased the rate of elimination of vancomycin only in the aphakic group. Conclusions: Clearance of vancomycin from the phakic eye is prolonged compared to that of beta‐lactam antibiotics, an important pharmacokinetic advantage in treating endophthalmitis. Its clearance from aphakic‐vitrectomized eyes is dramatically faster than from phakic eyes and is similar to that of other antimicrobial agents.

Enterococcus faecalis Resistant to Linezolid: Case Series and Review of the Literature

Reports of linezolid resistance among Enterococcus faecalis have been relatively rare. We describe three patients with linezolid‐resistant strains of E. faecalis, discovered after the patients had received long courses (> 30 days) of linezolid therapy. All strains contained the G2576U mutation in 23S rRNA. A literature review revealed one other case in the United States and three cases in Europe; all involved patients who had received long courses of therapy. It appears that recent or extended linezolid therapy may be a risk factor for development of resistant E. faecalis. In patients who have recently been treated with linezolid and have an identified new systemic enterococcal isolate, linezolid sensitivity should be verified as soon as possible to guide therapy. This strategy also should be considered for patients with a breakthrough enterococcal isolate during linezolid therapy.

Adefovir dipivoxil: A new antiviral agent for the treatment of hepatitis B virus infection

BACKGROUND Hepatitis B virus (HBV) infection is a major problem worldwide and an important cause of chronic liver disease and cirrhosis. Currently available treatments include interferon alfa-2b, lamivudine, and adefovir dipivoxil. Adefovir dipivoxil is an acyclic nucleotide analogue that was developed in part to improve on the limitations of earlier therapies. OBJECTIVE This article is a review of available data on the clinical pharmacology, virology, efficacy, tolerability, and clinical use of adefovir dipivoxil. METHODS A search of the English-language literature indexed on MEDLINE from 1966 to July 2003 was performed using the terms adefovir, PMEA, and Bis-POM PMEA. Pertinent abstracts from scientific meetings on infectious diseases and hepatology were also included. The manufacturer of adefovir dipivoxil provided additional information. These materials were supplemented by US Food and Drug Administration briefing documents and other unpublished materials. In vitro and preclinical studies were included in the review, as were Phase II and III clinical trials. RESULTS In vitro, adefovir dipivoxil concentrations exceed those necessary to inhibit both wild-type and lamivudine-resistant isolates of HBV. In clinical trials, adefovir dipivoxil was clinically and virologically effective in patients in whom lamivudine therapy had failed due to the presence of lamivudine-resistant HBV. The drug was generally well tolerated. The risk of nephrotoxicity, the most notable adverse effect of adefovir dipivoxil at previously used higher doses, has been substantially reduced at the currently recommended dosage of 10 mg/d. CONCLUSION Based on the data reviewed adefovir dipivoxil is an effective and well-tolerated alternative for the treatment of HBV infection, including disease that is lamivudine resistant.