Paul H. Edelstein

Extended-Spectrum β-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae: Risk Factors for Infection and Impact of Resistance on Outcomes

The prevalence of antibiotic resistance among extended-spectrum beta-lactamase (ESBL)--producing Escherichia coli and Klebsiella pneumoniae has increased markedly in recent years. Thirty-three patients with infection due to ESBL-producing E. coli or K. pneumoniae (case patients) were compared with 66 matched controls. Total prior antibiotic use was the only independent risk factor for ESBL-producing E. coli or K. pneumoniae infection (odds ratio, 1.10; 95% confidence interval, 1.03--1.18; P=.006). Case patients were treated with an effective antibiotic a median of 72 hours after infection was suspected, compared with a median of 11.5 hours after infection was suspected for controls (P<.001). ESBL-producing E. coli or K. pneumoniae infection was associated with a significantly longer duration of hospital stay and greater hospital charges (P=.01 and P<.001, respectively). Finally, many ESBL-producing E. coli and K. pneumoniae isolates were closely related. ESBL-producing E. coli and K. pneumoniae infections have a significant impact on several important clinical outcomes, and efforts to control outbreaks of infection with ESBL-producing E. coli and K. pneumoniae should emphasize judicious use of all antibiotics as well as barrier precautions to reduce spread.

Drug Tolerance in Replicating Mycobacteria Mediated by a Macrophage-Induced Efflux Mechanism

Treatment of tuberculosis, a complex granulomatous disease, requires long-term multidrug therapy to overcome tolerance, an epigenetic drug resistance that is widely attributed to nonreplicating bacterial subpopulations. Here, we deploy Mycobacterium marinum-infected zebrafish larvae for in vivo characterization of antitubercular drug activity and tolerance. We describe the existence of multidrug-tolerant organisms that arise within days of infection, are enriched in the replicating intracellular population, and are amplified and disseminated by the tuberculous granuloma. Bacterial efflux pumps that are required for intracellular growth mediate this macrophage-induced tolerance. This tolerant population also develops when Mycobacterium tuberculosis infects cultured macrophages, suggesting that it contributes to the burden of drug tolerance in human tuberculosis. Efflux pump inhibitors like verapamil reduce this tolerance. Thus, the addition of this currently approved drug or more specific efflux pump inhibitors to standard antitubercular therapy should shorten the duration of curative treatment.

Spectrum Bias in the Evaluation of Diagnostic Tests: Lessons from the Rapid Dipstick Test for Urinary Tract Infection

OBJECTIVE To determine if the leukocyte esterase and bacterial nitrite rapid dipstick test for urinary tract infection (UTI) is susceptible to spectrum bias (when a diagnostic test has different sensitivities or specificities in patients with different clinical manifestations of the disease for which the test is intended). DESIGN Cross-sectional study. PATIENTS A total of 366 consecutive adult patients in whom clinicians performed urinalysis to diagnose or exclude UTI. SETTING An urban emergency department and walk-in clinic. MEASUREMENTS After the patient encounter, but before dipstick test or culture was done, clinicians recorded the signs and symptoms that were the basis for suspecting UTI and for performing a urinalysis and an estimate of the probability of UTI based on the clinical evaluation. For all patients who received urinalysis, dipstick tests and culture were done in the clinical microbiology laboratory by medical technologists blinded to clinical evaluation. Sensitivity for the dipstick was calculated using a positive result in either leukocyte esterase or bacterial nitrite, or both, as the criterion for a positive dipstick, and greater than 10(5) CFU/mL for a positive culture. RESULTS In the 107 patients with a high (greater than 50%) prior probability of UTI, who had many characteristic UTI symptoms, the sensitivity of the test was excellent (0.92; 95% CI, 0.82 to 0.98). In the 259 patients with a low (less than or equal to 50%) prior probability of UTI, the sensitivity of the test was poor (0.56; CI, 0.03 to 0.79). CONCLUSIONS The leukocyte esterase and bacterial nitrite dipstick test for UTI is susceptible to spectrum bias, which may be responsible for differences in the tests sensitivity reported in previous studies. As a more general principle, diagnostic tests may have different sensitivities or specificities in different parts of the clinical spectrum of the disease they purport to identify or exclude, but studies evaluating such tests rarely report sensitivity and specificity in subgroups defined by clinical symptoms. When diagnostic tests are evaluated, information about symptoms in the patients recruited for study should be included, and analyses should be done within appropriate clinical subgroups so that clinicians may decide if reported sensitivities and specificities are applicable to their patients.

Epidemiological Investigation of Fluoroquinolone Resistance in Infections Due to Extended-Spectrum β-Lactamase—Producing Escherichia coli and Klebsiella pneumoniae

The incidence of infections due to extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae (ESBL-EK) has increased markedly in recent years. Treatment is difficult because of frequent multidrug resistance. Although fluoroquinolones offer effective therapy for ESBL-EK infections, their usefulness is threatened by increasing fluoroquinolone resistance. To identify risk factors for fluoroquinolone resistance in ESBL-EK infections, a case-control study of all patients with ESBL-EK infections from 1 June 1997 through 30 September 1998 was conducted. Of 77 ESBL-EK infections, 43 (55.8%) were resistant to fluoroquinolones. Independent risk factors for fluoroquinolone resistance were fluoroquinolone use (odds ratio [OR], 11.20; 95% confidence interval [CI], 1.99-63.19), aminoglycoside use (OR, 5.83; 95% CI, 1.12-30.43), and long-term care facility residence (OR, 3.39; 95% CI, 1.06-10.83). The genotypes of fluoroquinolone-resistant ESBL-EK isolates were closely related. Efforts should be directed at modification of these risk factors to preserve the utility of fluoroquinolones in the treatment of ESBL-EK infections.

Risk Factors and Clinical Impact of Klebsiella pneumoniae Carbapenemase–Producing K. pneumoniae

BACKGROUND Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae is an emerging pathogen with serious clinical and infection control implications. To our knowledge, no study has specifically examined risk factors for KPC-producing K. pneumoniae or its impact on mortality. METHODS To identify risk factors for infection or colonization with KPC-producing K. pneumoniae, a case-control study was performed. Case patients with KPC-producing K. pneumoniae were compared with control subjects with carbapenem-susceptible K. pneumoniae. A cohort study evaluated the association between KPC-producing K. pneumoniae and in-hospital mortality. RESULTS Fifty-six case patients and 863 control subjects were identified. In multivariable analysis, independent risk factors for KPC-producing K. pneumoniae were (1) severe illness (adjusted odds ratio [AOR], 4.31; 95% confidence interval [CI], 2.25-8.25), (2) prior fluoroquinolone use (AOR, 3.39; 95% CI, 1.50, 7.66), and (3) prior extended-spectrum cephalosporin use (AOR, 2.55; 95% CI, 1.18, 5.52). Compared with samples from other anatomic locations, K. pneumoniae isolates from blood samples were less likely to harbor KPC (AOR, 0.33; 95% CI, 0.12, 0.86). KPC-producing K. pneumoniae was independently associated with in-hospital mortality (AOR, 3.60; 95% CI, 1.87-6.91). CONCLUSIONS KPC-producing K. pneumoniae is an emerging pathogen associated with significant mortality. Our findings highlight the urgent need to develop strategies for prevention and infection control. Limiting use of certain antimicrobials, specifically fluoroquinolones and cephalosporins, use may be effective strategies.

Clinical and Microbiological Outcomes of Serious Infections with Multidrug-Resistant Gram-Negative Organisms Treated with Tigecycline

Eighteen patients received tigecycline as treatment for infection due to multidrug-resistant gram-negative bacilli, including Acinetobacter baumannii and Klebsiella pneumoniae carbapenemase- and extended-spectrum beta-lactamase-producing Enterobacteriaceae. Pretherapy minimum inhibitory concentration values for tigecycline predicted clinical success. Observed evolution of resistance during therapy raises concern about routine use of tigecycline in treatment of such infections when other therapies are available.

Why Is Long-Term Therapy Required to Cure Tuberculosis?

The authors argue that understanding and countering general bacterial mechanisms of phenotypic antibiotic resistance may hold the key to reducing the duration of treatment of all recalcitrant bacterial infections, including tuberculosis.

The prepilin peptidase is required for protein secretion by and the virulence of the intracellular pathogen Legionella pneumophila

Prepilin peptidases cleave, among other substrates, the leader sequences from prepilin‐like proteins that are required for type II protein secretion in Gram‐negative bacteria. To begin to assess the importance of type II secretion for the virulence of an intracellular pathogen, we examined the effect of inactivating the prepilin peptidase (pilD ) gene of Legionella pneumophila. Although the pilD mutant and its parent grew similarly in bacteriological media, they did differ in colony attributes and recoverability from late stationary phase. Moreover, at least three proteins were absent from the mutants supernatant, indicating that PilD is necessary for the secretion of Legionella proteins. The absence of both the major secreted protein and a haemolytic activity from the mutant signalled that the L. pneumophila zinc metalloprotease is excreted via type II secretion. Most interestingly, the pilD mutant was greatly impaired in its ability to grow within Hartmannella vermiformis amoebae and the human macrophage‐like U937 cells. As reintroduction of pilD into the mutant restored infectivity and as a mutant lacking type IV pilin replicated like wild type, these data suggested that the intracellular growth of L. pneumophila is promoted by proteins secreted via a type II pathway. Intratracheal inoculation of guinea pigs revealed that the LD50 for the pilD mutant is at least 100‐fold greater than that for its parent, and the culturing of bacteria from infected animals showed a rapid clearance of the mutant from the lungs. This is the first study to indicate a role for PilD and type II secretion in intracellular parasitism.

Association between Fluoroquinolone Resistance and Mortality in Escherichia coli and Klebsiella pneumoniae Infections: The Role of Inadequate Empirical Antimicrobial Therapy

BACKGROUND The prevalence of fluoroquinolone (FQ) resistance among Escherichia coli and Klebsiella pneumoniae has increased markedly in recent years. However, the impact of FQ resistance on mortality remains unknown. METHODS To identify the association between FQ resistance and mortality, we conducted a retrospective cohort study of hospitalized patients with infections due to FQ-resistant strains and FQ-susceptible strains of E. coli and K. pneumoniae between 1 January 1998 and 30 June 1999. RESULTS Of 123 patients with FQ-resistant infection, 16 (13.0%) died, compared with 4 (5.7%) of 70 patients with FQ-susceptible infection (odds ratio [OR], 2.47; 95% confidence interval [CI], 0.75-10.53). After adjustment for other significant risk factors and confounders, there remained an independent association between FQ-resistant infection and mortality (adjusted OR, 4.41; 95% CI, 1.03-18.81). Patients with FQ-resistant infection were significantly less likely to have received antimicrobial therapy with activity against the infecting pathogen within the first 24 h and 48 h of infection (P=.002 and P<.001, respectively). The association between FQ resistance and mortality was no longer significant, after adjusting for inadequate empirical therapy. CONCLUSIONS FQ resistance is an independent risk factor for mortality in patients with health care-acquired E. coli and K. pneumoniae infections. This may be explained, at least in part, by a delay in the initiation of appropriate antimicrobial therapy in patients with FQ-resistant infection. These results highlight the grave clinical consequences of FQ resistance and emphasize the importance of efforts designed to curb the increase in the prevalence of resistance to these agents.

Legionella longbeachae Species Nova, Another Etiologic Agent of Human Pneumonia

A new species of bacteria that is an etiologic agent of human pneumonia has been isolated and characterized. Clinical symptoms of infection with this organism are not readily distinguishable from those caused by Legionella pneumophila infection. The organism was isolated from respiratory tract specimens from four patients. Two cases of infection apparently originated in California and one in Georgia, and a fourth was of unknown geographic origin. The name Legionella longbeachae species nova is proposed for this organism. The type strain of L. longbeachae is Long Beach 4 (= American Type Culture Collection 33462).