Association of serotypes of Streptococcus pneumoniae with disease severity and outcome in adults: an international study.

BACKGROUND: The introduction of conjugate pneumococcal vaccination for children has reduced the burden of invasive disease due to pneumococcal conjugate vaccine (PCV) types (i.e., serotypes 9V, 14, 6B, 18C, 23F, 19F, and 4) in adults. As nonvaccine serotypes become predominant causes of invasive disease among adults, it is necessary to evaluate the disease severity and mortality associated with infection due to nonvaccine serotypes, compared with PCV serotypes, in adults. METHODS: The association of pneumococcal serotype and host-related variables with disease severity and mortality was statistically examined (with multivariable analysis) in 796 prospectively enrolled, hospitalized adult patients with bacteremia due to Streptococcus pneumoniae. RESULTS: In multivariate analyses of risk in patients with invasive pneumococcal disease, older age (age, > or = 65 years; P = .004), underlying chronic disease (P = .025), immunosuppression (P = .035), and severity of disease (P < .001) were significantly associated with mortality; no association was found between nosocomial infection with invasive serotypes 1, 5, and 7 and mortality. The risk factors meningitis (P = .001), suppurative lung complications (P < or = .001), and preexisting lung disease (P = .051) were significantly associated with disease severity, independent of infecting serotype. No differences were seen in disease severity or associated mortality among patients infected with PCV serotypes, compared with patients infected with nonvaccine serotypes. CONCLUSIONS: Our data support the notion that host factors are more important than isolate serotype in determining the severity and outcome of invasive pneumococcal disease and that these outcomes are unlikely to change in association with nonvaccine serotype infection in the post-conjugate vaccine era.

Discovery and hit-to-lead evaluation of piperazine amides as selective, state-dependent NaV1.7 inhibitors.

NaV1.7 is a particularly compelling target for the treatment of pain. Herein, we report the discovery and evaluation of a series of piperazine amides that exhibit state-dependent inhibition of NaV1.7. After demonstrating significant pharmacodynamic activity with early lead compound 14 in a NaV1.7-dependent behavioural mouse model, we systematically established SAR trends throughout each sector of the scaffold. The information gleaned from this modular analysis was then applied additively to quickly access analogues that encompass an optimal balance of properties, including NaV1.7 potency, selectivity over NaV1.5, aqueous solubility, and microsomal stability.

Legionella: macrolides or quinolones?

Following the first outbreaks of legionnaire's disease, erythromycin emerged as the treatment of choice without the foundation of rigorous clinical trials. The number of therapeutic failures with erythromycin, as well as the side-effects and drug interactions, led to the consideration of other drugs such as the new macrolides and quinolones for the treatment of legionnaire's disease in the 1990s. In this article, 19 studies in in-vitro intracellular models and seven animal studies that compared macrolides to quinolones were reviewed. Quinolones were found to have greater activity in intracellular models and improved efficacy in animal models compared with macrolides. No randomised trials comparing the clinical efficacy of the new macrolides and new quinolones have ever been performed. Three observational studies totalling 458 patients with legionnaire's disease have compared the clinical efficacy of macrolides (not including azithromycin) and quinolones (mainly levofloxacin). The results suggested that quinolones may produce a superior clinical response compared with the macrolides (erythromycin and clarithromycin) with regard to defervescence, complications, and length of hospital stay. Little data exist for direct comparison of quinolones and azithromycin.

Endocarditis and pericarditis complicating pneumococcal bacteraemia, with special reference to the adhesive abilities of pneumococci: results from a prospective study.

The incidence of pneumococcal cardiac infections is unknown and the pathogenicity of such complications is poorly understood. In a prospective, international, observational study, eight of 844 patients hospitalised with Streptococcus pneumoniae bacteraemia developed endocarditis (n = 5) or pericarditis (n = 3). The clinical and microbiological characteristics of these patients were compared with those of control patients. The corresponding incidence of pneumococcal endocarditis was c. 1-3/1 million inhabitants/year. There was no common pattern in the medical history of patients with an infectious cardiac complication. The severity of illness upon admission was comparable with that for patients without infectious cardiac complications, as was the 14-day mortality rate (25% and 17%, respectively). For encapsulated S. pneumoniae, no significant differences were found between patients with infectious cardiac complications and controls in adherence assays. However, non-encapsulated S. pneumoniae showed higher hydrophobicity and increased adherence to human epithelial cells.

Staphylococcus aureus nasal carriage in hemodialysis patients. Its role in infection and approaches to prophylaxis.

Staphylococcus aureus infections remain a major cause of morbidity in hemodialysis patients. Chronic dialysis patients are more prone to staphylococcal infections because of their decreased immunity, increased skin colonization by staphylococci, and the multiple needle punctures required for dialysis. The source of the staphylococci is the anterior nares. Elimination of staphylococcal nasal carriage results in a significantly lower infection rate. Selected clinical studies of topical and oral therapy for eradication of staphylococcal nasal carriage are reviewed. Rifampin has been the most consistently efficacious agent, although emergence of resistance is a potential problem. Trials utilizing newer topical and oral agents for prophylactic eradication of S aureus from the nose are indicated. Promising antibiotics include topical mupirocin, the oral quinolones, and clindamycin.

Pneumococcal pericarditis. Diagnostic usefulness of counterimmunoelectrophoresis and computed tomographic scanning.

Although counterimmunoelectrophoresis (CIE) analysis of cerebrospinal fluid has proved useful in the diagnosis of meningitis, there has been little experience with its use in analyzing pericardial fluid. We describe two patients with pneumococcal pneumonia whose hospital course was complicated by purulent pericarditis. In one patient, results of a computed tomographic scan were important in suggesting the diagnosis. Results of a Gram's stain and culture of pericardial fluid failed to yield any organisms, presumably because both patients had received nine days of beta-lactam antibiotic therapy. However, the results from CIE analysis of pericardial fluid in both cases were positive for Streptococcus pneumoniae. In one patient, for whom capsular typing of the organism was performed, the pneumococcus type isolated from pericardial fluid matched the type isolated previously from a blood sample. The results of CIE can allow focused antibiotic therapy by establishing the correct diagnosis.

Pseudomonas stutzeri bacteremia associated with hemodialysis.

Pseudomonas stutzeri bacteremia developed in six patients undergoing hemodialysis. Fever, shaking chills, nausea, and vomiting were observed. All patients recovered, although only two received specific antibiotic therapy. The infections occurred sporadically over a period of nine months. Pseudomonas stutzeri was subsequently isolated from the dialysate that circulates within the hemodialysis machine. The ultimate source was the deionized water that is combined with the liquid concentrate to form the dialysate. Pseudomonas stutzeri could be localized to the top cannister of the dialysis machine but was also isolated throughout the machine, including the bottom reservoir and the recirculating pump. The emphasis on handwashing, strict compliance with disinfection procedures, and elimination of prolonged sitting times for the filled machine after disinfection resulted in no further cases of P stutzeri infection.

Determinants of nontraditional therapy use in patients with HIV infection. A prospective study.

BACKGROUND: The popularity and use of nontraditional therapies among patients with human immunodeficiency virus (HIV) infection has grown enormously. DESIGN: A prospective, longitudinal cohort study of 56 patients aged 23 through 68 years with HIV infection followed up at the HIV clinic at a university-affiliated Veterans Affairs Medical Center. OBJECTIVE: To assess the demographic and psychologic characteristics of patients who seek nontraditional remedies, and their impact on disease progression and mortality from HIV. METHODS: A standardized, self-administered questionnaire to assess the incidence and type of nontraditional therapies used by patients with HIV. Data on demographics, medical status, physical functioning (Karnofsky performance score), CD4 lymphocyte counts, depression (Beck Depression Inventory), coping (inventory of coping with illness scale), psychological and/or emotional stress (Profile of Mood States scores), and compliance with prescribed therapy were prospectively assessed on all patients at baseline and every 6 months. RESULTS: Thirty percent of patients reported using nontraditional therapies. Nontraditional therapy users were significantly older than patients who did not use such therapies (44 vs 38 years, P = .03); with 94% of patients who used nontraditional therapy being older than 35 years compared with 56% of conventional therapy users (P = .005). Alternative therapy use did not correlate with race, education, HIV-risk group affiliation, duration of HIV seropositivity, stage of HIV disease, CD4 cell count, or Karnofsky performance scores. Nontraditional therapy users reported greater community-based acquired immunodeficiency syndrome group support (P = .06), greater perceived social support (P = .08), and significantly higher recreational or "street drugs" use (P = .02). Depression, adaptive coping, and emotional stress were not different between nontraditional and conventional therapy users; however, nontraditional therapy users were significantly more assertive (P = .04). On follow-up, CD4 cell count, HIV disease progression, physical functioning, or mortality were similar between the two groups. CONCLUSIONS: Recourse to nontraditional therapy is common among patients with HIV. Because of the possibility of untoward effects and potential adverse drug interactions associated with nontraditional therapy, HIV care givers should be aware of its use in their patients and take a history of nontraditional therapy first. Patients who choose nontraditional remedies do so not because they are depressed or emotionally disturbed, but rather because they seek greater control of the outcome of their disease. However, no beneficial effect on disease progression, CD4 cell count, or mortality was observed in these patients when compared with patients receiving only conventional medical therapy.

Infections caused by Pseudomonas maltophilia. Expanding clinical spectrum.

Pseudomonas maltophilia (Xanthomonas maltophilia) is a frequently isolated commensal that is gaining increasing recognition as an opportunistic pathogen in debilitated hosts. We report three unusual infections due to P maltophilia that illustrate the ability of the organism to cause life-threatening illness. We describe a case of postoperative meningitis, a case of recurrent bacteremia complicated by ecthyma gangrenosum, and a case of native valve endocarditis in a drug addict. Because of frequent isolation from noninfected sites, the pathogenic potential of P maltophilia may be overlooked. The notable resistance of this organism is commonly used beta-lactam and aminoglycoside antibiotics may complicate therapy.

A pink-pigmented, oxidative, nonmotile bacterium as a cause of opportunistic infections.

We describe two cases of bacteremia due to a pink-pigmented, oxidative, nonmotile, gram-negative, rod-shaped organism. One case occurred in a febrile neutropenic patient and another in a chronically debilitated patient with pancreatic abscess. The first patient was cured with gentamicin and ticarcillin, but the second patient died while receiving cefamandole therapy. The organisms described here are similar to Methylobacterium mesophilicum (Pseudomonas mesophilica) and the "unnamed taxon" organisms. A major difference from M mesophilicum is the lack of methanol utilization. Further distinctions between our isolates and M mesophilicum are the lack of flagella in our organisms, growth at 42 degrees C, growth on MacConkey's agar, lack of acetamide assimilation, and citrate utilization. The lack of flagella is the principle difference between our isolates and those in the unnamed taxon. Both of the isolates were resistant to the cephalosporins, but susceptible to the aminoglycosides, ticarcillin-clavulanic acid, sulfamethoxazole and trimethoprim, and imipenem. With the growing population of immunocompromised and chronically ill patients, these organisms may emerge as important pathogens.

Therapeutic approaches in patients with candidemia. Evaluation in a multicenter, prospective, observational study.

OBJECTIVES: To evaluate the morbidity and mortality of Candida fungemia and to assess the efficacy of low- vs high-dose amphotericin B and fluconazole vs amphotericin B in patients with candidemia. METHODS: Multicenter, prospective, observational study of 427 consecutive patients with candidemia. RESULTS: The mortality rate for patients with candidemia was 34%. The mortality rate for patients with catheter-related candidemia in whom the catheters were retained was significantly higher than that of patients in whom the catheters were removed (41% vs 21%, P < .001). We found no overall difference in mortality in patients treated with low-dose (total amphotericin B dose of < or = 500 mg) (13%) vs high-dose amphotericin B (total amphotericin B dose of > 500 mg) (15%), but the group treated with a low dose had fewer side effects (40%) than those treated with a high dose (55%) (P = .03). Fluconazole was as efficacious as amphotericin B in the therapy of candidemia, even when stratified by risk factors for mortality. Fewer side effects were seen with fluconazole (12%) compared with amphotericin B (44%) (P < .001). CONCLUSIONS: In selected patients with candidemia, low-dose amphotericin B was as efficacious as high-dose amphotericin B. Based on other studies and ours, fluconazole seems to be an alternative therapeutic option to amphotericin B in selected patients.

Azithromycin vs cefuroxime plus erythromycin for empirical treatment of community-acquired pneumonia in hospitalized patients: a prospective, randomized, multicenter trial.

OBJECTIVE: To compare the efficacy and safety of azithromycin dihydrate monotherapy with those of a combination of cefuroxime axetil plus erythromycin as empirical therapy for community-acquired pneumonia in hospitalized patients. METHODS: Patients were enrolled in a prospective, randomized, multicenter study. The standard therapy of cefuroxime plus erythromycin was consistent with the American Thoracic Society, Canadian Community-Acquired Pneumonia Consensus Group, and Infectious Disease Society of America consensus guidelines. The doses were intravenous azithromycin (500 mg once daily) followed by oral azithromycin (500 mg once daily), intravenous cefuroxime (750 mg every 8 hours), followed by oral cefuroxime axetil (500 mg twice daily), and erythromycin (500-1000 mg) intravenously or orally every 6 hours. Randomization was stratified by severity of illness and age. Patients who were immunosuppressed or residing in nursing homes were excluded. RESULTS: Data from 145 patients (67 received azithromycin and 78 received cefuroxime plus erythromycin) were evaluable. Streptococcus pneumoniae and Haemophilus influenzae were isolated in 19% (28/145) and 13% (19/145), respectively. The atypical pathogens accounted for 33% (48/145) of the etiologic diagnoses; Legionella pneumophila, Chlamydia pneumoniae, and Mycoplasma pneumoniae were identified in 14% (20/ 145), 10% (15/145), and 9% (13/145), respectively. Clinical cure was achieved in 91% (61/67) of the patients in the azithromycin group and 91% (71/78) in the cefuroxime plus erythromycin group. Adverse events (intravenous catheter site reactions, gastrointestinal tract disturbances) were significantly more common in patients who received cefuroxime plus erythromycin (49% [30/78]) than in patients who received azithromycin (12% [8/67]) (P<.001). CONCLUSIONS: Treatment with azithromycin was as effective as cefuroxime plus erythromycin in the empirical management of community-acquired pneumonia in immunocompetent patients who were hospitalized. Azithromycin was well tolerated.

Pseudomonas maltophilia causing heroin-associated infective endocarditis.

The association of Pseudomonas maltophilia endocarditis in three patients with recent history of intravenous drug abuse is reported. All three patients had abnormal heart valves (two prosthetic and one rheumatic). A prominent characteristic of this uncommon pathogen is its in vitro resistance to the commonly used antimicrobials. Cure was achieved in all three cases. In two cases, synergistic antibiotic combinations were used. In one case, plasmid-mediated resistance to amikacin sulfate (Amikan, British; no comparable US product) emerged during therapy. The two patients with prosthetic valves received combined surgical and antibiotic therapy.

Steady-state moxalactam kinetics: comparisons with other cephalosporins.

Moxalactam is a new beta-lactam antimicrobial with an extended spectrum. Serum concentrations were determined in 14 patients at steady state using bioassay and high-pressure liquid chromatography methods. Mean peak and trough serum concentrations were 195 and 29.5 micrograms/ml for the 20-gm dose and 214 and 28.8 micrograms/ml for the 3-gm dose. Peak and trough levels exceeded the minimum inhibitory concentration of the infecting bacteria in 100% and 67% of the patients. The 3-gm dose is recommended for infections caused by Pseudomonas aeruginosa and other organisms with higher minimum inhibitory concentrations. Half-lifes ranged from 1.7 to 5.7 hr and reflected the varying renal functions of the patients. A relationship (r = 0.878, p less than 0.001) between creatinine clearance and elimination rate constant was established by bivariant linear regression analysis.

Central nervous system lesions in adult liver transplant recipients: clinical review with implications for management.

Our review shows that a wide array of neurologic complications can occur after liver transplantation. Clinical correlation of the neuropathologic lesions may be difficult, as multiple lesions of variable etiologies may coexist, and significant systemic and metabolic complications may obscure the symptoms related to an underlying lesion in the central nervous system. Nevertheless, a reasoned approach to the recognition and diagnosis of these lesions is offered. In the early post-transplantation period, noninfectious lesions predominated. Of these, anoxic-ischemic changes and vascular events (hemorrhages and/or infarcts) occurred most frequently. Anoxic events occurred a mean of 10 days after transplantation and were often preceded by transient or varying degrees of hypotension. Hemorrhagic events and infarcts occurred a median of 27 and 5 days, respectively, after transplantation. It should be noted, however, that the projected onset of these events may vary somewhat, e.g., a brain infarct developed 47 days after liver transplantation in case 2. Although defects in coagulation may predispose to hemorrhagic lesions, a source for the infarct is usually not apparent. Central pontine myelinolysis is also an early-occurring lesion: most cases are seen within 10 days of transplantation. Extrapontine involvement frequently coexisted with or was present without pontine lesions. Hyponatremia or wide variations in serum sodium generally preceded the CNS lesion. Focal areas of high signal density by CT scan in the pons was highly suggestive of central pontine myelinolysis. Cyclosporine may cause white matter changes in the brain despite normal serum cyclosporine levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Pneumonia due to the Pittsburgh pneumonia agent: new clinical perspective with a review of the literature.

We review the current knowledge concerning this newly recognized pathogen, Pittsburgh pneumonia agent (PPA), and present a new, comprehensive perspective of PPA based on our extensive clinical experience: 1) PPA pneumonia is more common and affects a broader range of patients than previously appreciated. 2) In the general population, the disease is not distinguishable from acute pneumonia due to other causes. Because specialized diagnostic tests are required for detection, it is likely that many cases in other hospitals go unrecognized. 3) Diagnosis is important, as erythromycin appears to improve outcome, whereas beta-lactam antibiotics and aminoglycosides, frequently used as empiric therapy for nosocomial bacterial pneumonias, do not. 4) The presence of both PPA and L. pneumophila in the same environmental sites, and the discovery of seven cases of simultaneous infection by both organisms suggest that both organisms are likely to share a common reservoir within the hospital and a common mode of transmission. 5) PPA infection occurs in a more debilitated population than does Legionnaires' disease. This may represent differences in intensity of exposure to the two organisms or may reflect inherent differences in virulence.

Disease due to the Legionellaceae (other than Legionella pneumophila). Historical, microbiological, clinical, and epidemiological review.

More than 20 species of the Legionellaceae family of bacteria have been discovered since the discovery of Legionella pneumophila. Thirteen have been implicated as causative agents of pneumonia including the Pittsburgh pneumonia agent (Tatlockia micdadei, Legionella micdadei). Although outbreaks of nosocomial pneumonia in immunosuppressed hosts have been well-described, most cases have occurred sporadically in the community. The spectrum of disease ranges from severe life-threatening pneumonia to a self-limiting febrile illness (Pontiac fever). Isolation from the natural aquatic environment has preceded its discovery as agents of human disease in 6 species, while environmental isolation has not yet been obtained for 3 species implicated in disease. The mode of transmission is uncertain, but cases of dual infection by L. pneumophila and the newer species suggests that the epidemiology of these new organisms will be similar to that of L. pneumophila. The antibiotic of choice appears to be erythromycin. The historical background, epidemiology, microbiology, and clinical manifestations of these newly-discovered organisms are reviewed in comparative fashion.

New and emerging etiologies for community-acquired pneumonia with implications for therapy. A prospective multicenter study of 359 cases.

Three hundred fifty-nine consecutive patients with community-acquired pneumonia admitted to university, community, and VA hospitals underwent a standardized evaluation, including specialized tests for Legionella spp. and Chlamydia pneumoniae (TWAR). The most common underlying illnesses were immunosuppression (36.3%), chronic obstructive pulmonary disease (32.4%), and malignancy (28.4%). The most frequent etiologic agents were Streptococcus pneumoniae (15.3%) and Hemophilus influenzae (10.9%). Surprisingly, Legionella spp. and C. pneumoniae were the third and fourth most frequent etiologies at 6.7% and 6.1%, respectively. Aerobic gram-negative pneumonias were relatively uncommon causes of pneumonia despite the fact that empiric broad-spectrum combination antibiotic therapy is so often directed at this subgroup. In 32.9%, the etiology was undetermined. Antibiotic administration before admission was significantly associated with undetermined etiology (p = 0.0003). There were no distinctive clinical features found to be diagnostic for any etiologic agent, although high fever occurred more frequently in Legionnaires' disease. Clinical manifestations for C. pneumoniae were generally mild, although 38% of patients had mental status changes. Mortality was highest for Staphylococcus aureus (50%) and lowest for C. pneumoniae (4.5%) and Mycoplasma pneumoniae (0%). We document that specialized laboratory testing for C. pneumoniae and Legionella spp. should be more widely used rather than reserved for cases not responding to standard therapy. Furthermore, realization that C. pneumoniae and Legionella spp. are common etiologies for community-acquired pneumonia should affect empiric antibiotic prescription.

Malignant external otitis: insights into pathogenesis, clinical manifestations, diagnosis, and therapy.

Malignant external otitis is an infection of the external ear canal, mastoid, and base of the skull caused by Pseudomonas aeruginosa. The condition occurs primarily in elderly patients with diabetes mellitus. Current theories on pathogenesis and anatomic correlations are reviewed. Severe, unrelenting otalgia and persistent otorrhea are the symptomatic hallmarks of the disease, whereas an elevated erythrocyte sedimentation rate is the only distinctive laboratory abnormality. Iatrogenic causes such as administration of broad-spectrum antibiotics and aural irrigation may play a predisposing role in high-risk populations. The disease can result in cranial polyneuropathies (with facial nerve [VII] paralysis being the most common) and death. The mainstay of treatment is administration of antipseudomonal antibiotics for four to eight weeks. Recurrence is common, and mortality remains at about 20 percent despite antibiotic therapy. Given the increasing longevity of diabetic patients, the frequency of this disease is increasing. Internists, family practitioners, and ambulatory care physicians must now be cognizant of the presenting symptoms, while infectious disease specialists and otolaryngologists need to be appraised of strides in diagnosis and therapy. The role of surgery should be minimized. Use of new diagnostic radiologic modalities and new antipseudomonal antibiotics discussed in this review should lead to improved outcome.

Significance of isolation of Aspergillus from the respiratory tract in diagnosis of invasive pulmonary aspergillosis. Results from a three-year prospective study.

The isolation of Aspergillus species from respiratory secretions has been regarded as being of limited usefulness in the antemortem diagnosis of invasive pulmonary aspergillosis. One hundred and eight consecutive patients were evaluated in whom Aspergillus species were isolated from respiratory secretions. Invasive aspergillosis was not demonstrated in non-immunosuppressed patients or in patients with solid tumors in the absence of neutropenia. Lung tissue was examined in 17 patients with leukemia and/or neutropenia; all had invasive aspergillosis. Tissue examination was not performed in 20 neutropenic patients; of 17 not receiving antifungal therapy, 16 died. Multivariate statistical analysis showed that neutropenia and absence of cigarette smoking were significant predictors of invasive aspergillosis in patients with respiratory tract cultures yielding Aspergillus. All cases of invasive aspergillosis were associated with A. fumigatus or A. flavus. The isolation of A. fumigatus or A. flavus from the respiratory tract of a patient with leukemia and/or neutropenia is highly predictive of invasive infection. Empiric amphotericin B therapy, without the necessity for tissue diagnosis, should be considered in this patient subgroup.