Emerging therapies for serious gram-positive bacterial infections: a focus on linezolid.

Respiratory tract infections and skin and soft-tissue infections frequently are caused by gram-positive cocci, and treating these infections with standard antibiotics has recently become problematic. Many of the primary pathogens causing these infections are now resistant to current standard treatment regimens. In addition, the frequency of these infections is increasing, particularly among patients with complex medical conditions. Thus, new and effective antimicrobial agents are needed, and many are currently in various stages of development. Linezolid, the first approved oxazolidinone, has enhanced activity against gram-positive organisms. Recent results of 5 large, randomized, phase 3 trials evaluating linezolid for the treatment of community-acquired pneumonia, nosocomial pneumonia, and uncomplicated and complicated skin and soft-tissue infections are encouraging and indicate that linezolid is as effective as standard comparator agents as therapy for these infections. Thus, the recent availability of linezolid offers clinicians a promising new agent for the treatment of serious gram-positive bacterial infections.

Potential importance of Legionella species as etiologies in community acquired pneumonia (CAP).

Large percentages of patients with community acquired pneumonia (CAP) do not have a defined etiology. Between 1992-1993, 99 acute and convalescent sera were collected from patients with CAP of unknown etiology. The sera were tested using an indirect immunofluorescence antibody assay (IFA) against the following antigens: Legionella pneumophila, serogroups 3,5,6 and 7 and L. longbeachae, L. anisa, L. bozemanii and Legionella-Like Amoebal Pathogens (LLAP). A four-fold rise in titer to at least one of the antigens tested, was seen in 14% of patients; 8% to L. bozemanii, 4% to L. anisa, 2% to S. lyticum, 2% to LLAP 10 and 1% each to LLAP 1, 6 and 9. Two patients reacted to several antigens. These results indicate that other species of legionella may be important in the etiology of CAP. L. bozemanii was the organism identified in the majority of these infections. Better diagnostic studies i.e. cultures, serologies and urinary antigen testing, which recognize legionella isolates other than L. pneumophila serogroup 1 need to be developed.

Importance of atypical pathogens of community-acquired pneumonia.

The atypical clinical presentation of patients with community-acquired pneumonia (CAP) was first recognized and reported by astute clinicians 50 years ago. The cause of pneumonia in this group eventually was shown to be Mycoplasma pneumoniae. More recently, Chlamydia pneumoniae also has been recognized as a cause of CAP. Legionella has been lumped together with M. pneumoniae and C. pneumoniae because of its antimicrobial susceptibility pattern. This group of organisms is susceptible to the macrolides, tetracycline, and the newer fluoroquinolones. However, Legionnaires' disease frequently presents a more acute clinical picture than either mycoplasmal or chlamydial infections. Recent data suggest that in the Medicare population hospitalized with pneumonia, morbidity and mortality can be decreased if initial therapy includes coverage for atypical pathogens (i.e., macrolides or fluoroquinolones). Unfortunately, few studies use culture methodology for atypical pathogens. Future studies of the efficacy of macrolide or fluoroquinolone therapy for CAP should include aggressive diagnostic studies for M. pneumoniae, C. pneumoniae, and Legionella species.

Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group.

OBJECTIVE: To provide recommendations for the management of community-acquired pneumonia and the surveillance of drug-resistant Streptococcus pneumoniae (DRSP). METHODS: We addressed the following questions: (1) Should pneumococcal resistance to beta-lactam antimicrobial agents influence pneumonia treatment? (2) What are suitable empirical antimicrobial regimens for outpatient treatment of community-acquired pneumonia in the DRSP era? (3) What are suitable empirical antimicrobial regimens for treatment of hospitalized patients with community-acquired pneumonia in the DRSP era? and (4) How should clinical laboratories report antibiotic susceptibility patterns for S pneumoniae, and what drugs should be included in surveillance if community-acquired pneumonia is the syndrome of interest? Experts in the management of pneumonia and the DRSP Therapeutic Working Group, which includes clinicians, academicians, and public health practitioners, met at the Centers for Disease Control and Prevention in March 1998 to discuss the management of pneumonia in the era of DRSP. Published and unpublished data were summarized from the scientific literature and experience of participants. After group presentations and review of background materials, subgroup chairs prepared draft responses, which were discussed as a group. CONCLUSIONS: When implicated in cases of pneumonia, S pneumoniae should be considered susceptible if penicillin minimum inhibitory concentration (MIC) is no greater than 1 microg/mL, of intermediate susceptibility if MIC is 2 microg/ mL, and resistant if MIC is no less than 4 microg/mL. For outpatient treatment of community-acquired pneumonia, suitable empirical oral antimicrobial agents include a macrolide (eg, erythromycin, clarithromycin, azithromycin), doxycycline (or tetracycline) for children aged 8 years or older, or an oral beta-lactam with good activity against pneumococci (eg, cefuroxime axetil, amoxicillin, or a combination of amoxicillin and clavulanate potassium). Suitable empirical antimicrobial regimens for inpatient pneumonia include an intravenous beta-lactam, such as cefuroxime, ceftriaxone sodium, cefotaxime sodium, or a combination of ampicillin sodium and sulbactam sodium plus a macrolide. New fluoroquinolones with improved activity against S pneumoniae can also be used to treat adults with community-acquired pneumonia. To limit the emergence of fluoroquinolone-resistant strains, the new fluoroquinolones should be limited to adults (1) for whom one of the above regimens has already failed, (2) who are allergic to alternative agents, or (3) who have a documented infection with highly drug-resistant pneumococci (eg, penicillin MIC > or =4 microg/mL). Vancomycin hydrochloride is not routinely indicated for the treatment of community-acquired pneumonia or pneumonia caused by DRSP.

Clinical characteristics of Chlamydia pneumoniae infection as the sole cause of community-acquired pneumonia.

The clinical characteristics of 26 patients with community-acquired pneumonia due to Chlamydia pneumoniae as the only identified pathogen who required hospitalization were evaluated. Most patients (18) had reinfection based on serological results. The mean age of the patients was 55 years (38 years, patients with primary infection; 63 years, patients with reinfection), and the gender representation was equal. Generally, illness was mild and associated with limited temperature elevation and nonspecific symptoms. The presence of comorbid illnesses and the requirement of supplemental oxygen therapy were the most common criteria for hospital admission.

Parainfluenza virus infection among adults hospitalized for lower respiratory tract infection.

To better define the contribution of human parainfluenza viruses (HPIVs) to lower respiratory tract infection in adults, we tested acute- and convalescent-phase serum specimens from hospitalized adults participating in a population-based prospective study of lower respiratory tract infection during 1991-1992. We tested all available specimens from the epidemic seasons for each virus and approximately 300 randomly selected specimens from the corresponding off-seasons for antibodies to HPIV-1, HPIV-2, or HPIV-3. During the respective epidemic season, HPIV-1 infection was detected in 18 (2.5%) of 721 and HPIV-3 infection in 22 (3.1%) of 705 patients with lower respiratory tract infection. Only 2 (0.2%) of 1,057 patients tested positive for HPIV-2 infection. No HPIV-1 infections and only 2 (0.7% of 281 patients tested) HPIV-3 infections were detected during the off-seasons. HPIV-1 and HPIV-3 were among the four most frequently identified infections associated with lower respiratory tract infection during their respective outbreak seasons.

An emergency department-based pneumococcal vaccination program could save money and lives.

STUDY OBJECTIVE: Pneumococcal vaccination (PV) rates for eligible emergency department patients are less than 25%. This study determines the potential effect of an ED-based pneumococcal vaccination program in preventing pneumococcal bacteremia (PB) in high-risk patients. METHODS: In a retrospective observational study, hospital records of 188 consecutive adults (>/=18 years old) with PB were reviewed to determine how many were treated in the ED from 1 to 72 months before their admission for bacteremia. Potential cost savings and mortality reductions from an ED-based PV program were calculated assuming PV prevents 65% of bacteremic episodes. A retrospective review of 10,650 ED charts determined the percentage of patients with PV indications and the relative frequency of indications. RESULTS: One hundred four (55%) of the 188 patients with PB were seen in the ED less than or equal to 72 months before their admission for PB, and 91 (88%) of the 104 had indications for PV. These 91 patients had been evaluated in the ED an average of 3.4 times per patient during this 72-month period. Nine patients (10%) died before discharge. Mean hospital stay for the 82 survivors was 11.2 days. Of 10,650 ED charts reviewed, 2,011 (19%) had documented PV indications. Most prevalent PV indications were age 65 years or older (851 patients, 42%), diabetes mellitus (697, 35%), malignancy (248, 12%), chronic renal failure (228, 11%), and immunosuppression (221, 11%). Estimated cost savings ranged from $168,940 to $427,380. CONCLUSION: ED-based PV programs would result in considerable cost savings and decreased mortality.

Accuracy of ICD-9-CM codes in detecting community-acquired pneumococcal pneumonia for incidence and vaccine efficacy studies.

Studies have used medical record discharge data as coded by the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) to estimate pneumococcal pneumonia incidence and vaccine efficacy. However, the accuracy of coding data to identify laboratory-confirmed pneumococcal pneumonia is not known. With the use of information collected in Ohio for a community-based pneumonia incidence study, the authors calculated the sensitivities, specificities, positive predictive values (PPV), and negative predictive values (NPV) of specific codes for pneumococcal pneumonia among hospitalized patients with community-acquired pneumonia. Sensitivities of the most common ICD-9-CM codes listed in the first five positions for patients with laboratory-confirmed pneumococcal pneumonia were 58.3% (code 481.0, pneumococcal pneumonia), 20.4% (38.0, streptococcal septicemia), 19.2% (38.2, pneumococcal septicemia), 15.0% (518.81, respiratory failure), 14.2% (486.0, pneumonia, organism unspecified), and 11.3% (482.3, streptococcal pneumonia). Using the first five listed ICD-9-CM codes rather than just the first listed code increased sensitivity without causing substantial change in specificity, PPV, and NPV. Sensitivity, PPV, and NPV of individual and groups of codes varied with different case definitions of pneumococcal pneumonia. Incidence and vaccine efficacy studies with the ability to validate diagnoses by medical chart review can use a combination of many ICD-9-CM codes to maximize sensitivity. However, without the ability to review medical charts, researchers must carefully decide which codes would best suit their studies.

Update of Legionella infections.

Legionella spp. are significant causes of both community-acquired pneumonia and nosocomial pneumonia. More than 40 species of Legionella have now been identified. The spectrum of disease ranges from asymptomatic infection to serious disease, with two specific syndromes identified: Legionnaire's disease and Pontiac fever. Hospital-acquired infection arises from the presence of Legionella in the hospital water supply. The optimal approach for the detection and prevention of nosocomial infection is debatable-whether or not periodic sampling of hospital water systems should be carried out in the absence of clinical cases is controversial. Newer macrolides or newer fluoroquinolone agents are the preferred therapy for serious diseases caused by Legionella.

The role of atypical pathogens: Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila in respiratory infection.

Infections caused by M. pneumoniae, C. pneumoniae, and Legionella spp. are important causes of community-acquired pneumonia (CAP). In the past decade, considerable new information has come to light concerning these organisms. Despite this, debate continues concerning the syndromic approach to CAP and the scientific merit of lumping these pathogens together. Because the etiologic diagnosis of these pathogens is established only in a minority of cases, the true prevalence tends to be underestimated. In clinical practice, these pathogens are often empirically treated. More rapid and cost-effective diagnostic techniques are needed so that the clinical course of patients with these infections can be better characterized.

Value of noninvasive studies in community-acquired pneumonia.

Noninvasive diagnostic studies, i.e., sputum gram stain, sputum culture, blood culture and antigen detection assays will assist the clinician in the selection of initial antimicrobial therapy in some patients. These tests may be even more valuable in adjusting treatment regimens to prevent the use of broad spectrum antimicrobial agents as routine therapy.

Cost-effectiveness of vaccination against pneumococcal bacteremia among elderly people.

CONTEXT: Clinical, epidemiologic, and policy considerations support updating the cost-effectiveness of pneumococcal vaccination for elderly people and targeting the evaluation only to prevention of pneumococcal bacteremia. OBJECTIVE: To assess the implications for medical costs and health effects of vaccination against pneumococcal bacteremia in elderly people. DESIGN: Cost-effectiveness analysis of pneumococcal vaccination compared with no vaccination, from a societal perspective. SETTING AND PARTICIPANTS: The elderly population aged 65 years and older in the United States in 3 geographic areas: metropolitan Atlanta, Ga; Franklin County, Ohio; and Monroe County, New York. MAIN OUTCOME MEASURES: Incremental medical costs and health effects, expressed in quality-adjusted life-years per person vaccinated. RESULTS: Vaccination was cost saving, ie, it both reduced medical expenses and improved health, for all age groups and geographic areas analyzed in the base case. For people aged 65 years and older, vaccination saved $8.27 and gained 1.21 quality-adjusted days of life per person vaccinated. Vaccination of the 23 million elderly people unvaccinated in 1993 would have gained about 78000 years of healthy life and saved $194 million. In univariate sensitivity analysis, the results remained cost saving except for doubling vaccination costs, including future medical costs of survivors, and lowering vaccination effectiveness. With assumptions most unfavorable to vaccination, cost per quality-adjusted life-year ranged from $35 822 for ages 65 to 74 years to $598 487 for ages 85 years and older. In probabilistic sensitivity analysis, probability intervals were more narrow, with less than 5% probability that the ratio for ages 85 years and older would exceed $100000. CONCLUSIONS: Pneumococcal vaccination saves costs in the prevention of bacteremia alone and is greatly underused among the elderly population, on both health and economic grounds. These results support recent recommendations of the Advisory Committee on Immunization Practices and public and private efforts under way to improve vaccination rates.

Incidence of community-acquired pneumonia requiring hospitalization. Results of a population-based active surveillance Study in Ohio. The Community-Based Pneumonia Incidence Study Group.

BACKGROUND: Pneumonia is the leading cause of death due to infectious diseases in the United States; however, the incidence of most infections causing community-acquired pneumonia in adults is not well defined. METHODS: We evaluated all adults, residing in 2 counties in Ohio, who were hospitalized in 1991 because of community-acquired pneumonia. Information about risk factors, symptoms, and outcome was collected through interview and medical chart review. Serum samples were collected from consenting individuals during the acute and convalescent phases, and specific etiologic diagnoses were assigned based on results of bacteriologic and immunologic tests. RESULTS: The incidence of community-acquired pneumonia requiring hospitalization in the study counties in 1991 was 266.8 per 100,000 population; the overall case-fatality rate was 8.8%. Pneumonia incidence was higher among blacks than whites (337.7/100,000 vs 253.9/ 100,000; P < .001), was higher among males than females (291.4 vs 244.8; P < .001), and increased with age (91.6/100,000 for persons aged < 45 years, 277.2/ 100,000 for persons aged 45-64 years, and 1012.3/ 100,000 for persons aged > or = 65 years; P < .001). Extrapolation from study incidence data showed the projected annual number of cases of community-acquired pneumonia requiring hospitalization in the United States to be 485,000. These data provide previously unavailable estimates of the annual number of cases that are due to Legionella species (8000-18,000), Mycoplasma pneumoniae (18,700-108,000), and Chlamydia pneumoniae (5890-49,700). CONCLUSIONS: These data provide information about the importance of community-acquired pneumonia and the relative and overall impact of specific causes of pneumonia. The study provides a basis for choosing optimal empiric pneumonia therapy, and allows interventions for prevention of pneumonia to be targeted at groups at greatest risk for serious illness and death.

Susceptibility of ninety-eight clinical isolates of Legionella to macrolides and quinolones using the Etest.

Isolates of Legionella from 98 patients with Legionnaires' disease hospitalized in Columbus, Ohio, USA between 1991 through 1995 were tested for antimicrobial susceptibility to macrolides and quinolones using the Etest. Most (87%) isolates were Legionella pneumophila serogroup 1. All isolates tested remain susceptible to erythromycin, azithromycin, clarithromycin, ciprofloxacin, ofloxacin, and levofloxacin. In vitro susceptibility testing of Legionella to representative macrolides and quinolones should be considered to detect the emergence of resistant isolates.

Stability of Legionella urinary antigens over time.

Twenty-two urine samples positive for Legionella pneumophila serogroup 1 antigen by EQUATE radioimmunoassay (RIA) (Binax, Portland, ME, USA) were stored at various temperatures and the RIA repeated at 1, 7, 30, 90, and 120 days to evaluate stability of the urinary antigens. The mean ratios of patient/negative control remained stable. Although there was a 10% decrease in the mean ratios after 1 month, changes were not significant. However, individual samples with ratios close to 3 may fall to < 3.

Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults.

Respiratory syncytial virus (RSV), the most important cause of lower respiratory disease in infants and young children, is rarely considered among the causes for community-acquired lower respiratory infection in adults. All noninstitutionalized adults hospitalized with community-acquired pneumonia in two Ohio counties were evaluated between December 1990 and May 1992. Fifty-three (4.4%) of 1195 adults admitted during the RSV seasons and 4 (1.0%) of 390 in the off-season had serologic evidence of RSV infection, making RSV one of the four most common pathogens identified. RSV-infected patients had clinical features (e.g., wheezing and rhonchi) that distinguished them from all non-RSV-infected patients and other features (e.g., nonelevated white blood cell counts) that distinguished them from those infected with bacterial or atypical agents. However, RSV infection was not diagnosed during hospitalization for any of the 57 RSV-infected patients. RSV should be considered in the differential diagnosis for adults hospitalized between November and April with community-acquired lower respiratory infection.

Risk factors for domestic acquisition of legionnaires disease. Ohio legionnaires Disease Group.

BACKGROUND: Legionnaires disease is a common cause of adult pneumonia. Outbreaks of legionnaires disease have been well described, but little is known about sporadically occurring legionnaires disease, which accounts for most infections. Exposure to contaminated residential water sources is I plausible means of disease acquisition. METHODS: Employing a matched case-control study design in 15 hospitals in 2 Ohio counties, we prospectively enrolled 146 adults diagnosed as having nonepidemic, community-acquired legionnaires disease and compared each with 2 hospital-based control patients, matched for age, sex, and underlying illness category. An interview regarding potential exposures was followed by a home survey that included sampling residential sources for Legionella. Interview and home survey data were analyzed to estimate the risk of acquiring legionnaires disease associated with various exposures. RESULTS: Multivariate analysis showed that a nonmunicipal water supply (odds ratio [OR], 2.26; 95% confidence interval [CI], 1.17-4.37), recent residential plumbing repair (OR, 2.39; 95% CI, 1.10-5.18), and smoking (OR, 3.48; 95% CI, 2.09-5.79) were independent risk factors for legionnaires disease. Univariate analysis suggested that electric (vs gas) water heaters (OR, 1.97; 95% CI, 1.10-3.52), working more than 40 hours weekly (OR, 2.13; 95% CI, 1.12-4.07), and spending nights away from home before illness (OR, 1.68; 95% CI, 1.03-2.74) were additional possible risk factors. Lower chlorine concentrations in potable water and lower water heater temperatures were associated with residential Legionella colonization. CONCLUSIONS: A proportion of sporadic cases of legionnaires disease may be residentially acquired and are associated with domestic potable water and disruptions in residential plumbing systems. Potential strategies to reduce legionnaires disease risk include consistent chlorination of potable water, increasing water heater temperatures, and limiting exposure to aerosols after domestic plumbing repairs.

Comparison of Binax Legionella Urinary Antigen EIA kit with Binax RIA Urinary Antigen kit for detection of Legionella pneumophila serogroup 1 antigen.

The Legionella Urinary Antigen EIA kit (Binax, Portland, Maine) was compared with the EQUATE RIA Legionella Urinary Antigen kit (Binax) for its ability to detect the presence of urinary antigens to Legionella pneumophila serogroup 1. Urine specimens from patients without Legionnaires' disease (n = 33) were negative by both methods (specificity, 100%). Twenty (77%) of 26 urine specimens from patients with Legionnaires' disease positive by the radioimmunoassay kit were also positive by the enzyme immunoassay (EIA) kit. If the cutoff for a positive EIA result were lowered to a ration of > or = 2.5, 23 of 26 (88%) urine specimens would have been positive by EIA and the specificity would remain 100%. Use of the EIA kit is an acceptable method for detecting L. pneumophila serogroup 1 urinary antigens by laboratories that do not want to handle radioactive materials.

Levofloxacin in vitro activity against bacteremic isolates of Streptococcus pneumoniae. Franklin County Pneumonia Study Group.

Levofloxacin had excellent activity in vitro against bacteremic isolates of Streptococcus pneumoniae with 495 (99.2%) of 499 isolates being susceptible. A total of 38 (97.4%) of 39 isolates with minimal inhibitory concentrations > or = 0.12 micrograms/ml of penicillin were susceptible to levofloxacin. There was excellent correlation between the disk diffusion and broth microdilution methods for determining susceptibility. Resistant isolates belonged to four different serotypes. There was no increase in proportion of isolates of S. pneumoniae resistant between 1991 and 1994.