New approaches to Pseudomonas aeruginosa lower respiratory tract infections

Since 1973, the occurrence of respiratory tract infections due to P. aeruginosa has increased associated with the development of broad-spectrum penicillins. A clinical entity, diffuse panbronchiolitis (DPB) is a representative disease of chronic P. aeruginosa infections in Japan. In this paper, recent advances of research on pathogenesis and treatments of chronic P. aeruginosa lower respiratory tract infections in our department are reported. We examined sputum from patients with chronic P. aeruginosa infections under the electron microscope. Mucoid type of microcolonies were observed with fibrous matrix of exopolysaccharide. Neutrophils were found to be partially surrounding the microcolony in an attempt to defense. Debris was formed mainly by the destruction of the neutrophils. Most neutrophils were found full of phagocytized debris. These data support that instead of phagocytizing bacteria, neutrophils phagocytized debris and bacteria were not completely eradicated. This might be a factor in the pathogenesis of persistent colonization of P. aeruginosa. In the airways of patients with chronic airway diseases (CAD), neutrophils enhance the recruitment of more neutrophils through the production of neutrophil chemotactic factors such as interleukin-8 (IL-8) and LTB4, perpetuating a cycle of inflammation in the lung. We demonstrated increased levels of IL-8, a chemotactic cytokine, in bronchoalveolar lavage (BAL) fluid from patients with CAD associated with P. aeruginosa infections. We also documented a significant correlation between neutrophil numbers and IL-8 levels or IL-1 beta levels or neutrophil elastase levels in BAL fluids from patients with CAD. By immunohistochemical studies and in vitro data, three major sources of IL-8 in the airways of CAD patients were found to be alveolar macrophages, bronchial epithelial cells, and migrated neutrophils. In Japan, the clinical effectiveness of oral erythromycin (EM) for CAD, including DPB seems to be established, but its pharmacological mechanism remains unclear. In addition, we found a marked decrease of IL-8 levels in BAL fluid from two patients with CAD after treatment with EM. Therefore, we postulated that EM inhibited IL-8 production by stimulated respiratory cells. EM and Roxythromycin, suppressed IL-8 production in Pseudomonas-stimulated neutrophils in a dose-dependent manner. 1 alpha, 25-dihydroxy vitamin D3 also inhibited neutrophil-derived IL-8. Our data encourage the development of new anti-IL-8 agents against persistent P. aeruginosa lower respiratory tract infections.     

Fluoroquinolones as treatment for patients with lower respiratory tract infections caused by Streptococcus pneumoniae

BACKGROUND: Mycophenolate mofetil (MMF) has been previously shown to prevent functional deterioration in an experimental model of chronic renal allograft rejection. METHODS: In this retrospective case-control study, patients with chronic rejection who were receiving cyclosporine or tacrolimus and who had MMF added to their immunosuppressive regimen were compared with patients with chronic rejection who were not receiving MMF. Patients were matched for serum creatinine levels and transplant duration at the time MMF was begun. RESULTS: In the MMF group, the average dose of MMF was 1482 mg/day with an average duration of 19.3 months. Over 36 months, including 12 months before MMF and up to 24 months on MMF, there was no difference in serum creatinine levels between the two groups. Cyclosporine levels and dose were no different. CONCLUSIONS: In this small, retrospective, preliminary study, adding MMF to maintenance immunosuppression provided no clear benefit to renal allograft recipients with established chronic rejection. Larger prospective randomized studies are needed.     

Long term follow-up of children hospitalized with respiratory syncytial virus lower respiratory tract infection and randomly treated with ribavirin or placebo

PURPOSE: To determine how many cases of breast cancer might be found if women not known to have the disease were thoroughly examined (the disease "reservoir"). DATA SOURCES: MEDLINE search from 1966 to the present. STUDY SELECTION: Hospital-based and forensic autopsy series examining women not known to have had breast cancer during life. DATA EXTRACTION: Observed prevalence of occult invasive breast cancer or ductal carcinoma in situ (DCIS) in which the number of women who were given a diagnosis was the numerator and the number of women examined was the denominator. For each autopsy series, we attempted to ascertain the level of scrutiny (sampling method, number of slides examined) given to the pathologic specimens. DATA SYNTHESIS: Among seven autopsy series of women not known to have had breast cancer during life, the median prevalence of invasive breast cancer was 1.3% (range, 0% to 1.8%) and the median prevalence of DCIS was 8.9% (range, 0% to 14.7%). Prevalences were higher among women likely to have been screened (that is, women 40 to 70 years of age). The mean number of slides examined per breast ranged from 9 to 275; series that reported higher levels of scrutiny tended to discover more cases of cancer. CONCLUSIONS: A substantial reservoir of DCIS is undetected during life. How hard pathologists look for the disease and, perhaps, their threshold for making the diagnosis are potentially important factors in determining how many cases of DCIS are diagnosed. The latter has important implications for what it means to have the disease.     

Neutrophil response to Pseudomonas aeruginosa in respiratory infection

The antiviral effect of natural interferon (IFN)-alpha on chronic hepatitis C virus (HCV) infection was estimated by determining quantitative changes in serum HCV-RNA compared with the serum alanine aminotransferase (sALT) improvement; the relationships of responses to IFN according to the dose and period of IFN therapy were defined to determine an appropriate IFN therapy protocol. Twenty-two patients with chronic hepatitis C were given natural IFN-alpha and in 16 (72.7%) patients the viraemia was suppressed during therapy. Five (27.7%) of them sustained the disappearance of HCV-RNA for more than 6 months after therapy accompanied with a prolonged sALT improvement. Pre-treatment viraemia levels in 5 complete responders with "complete suppression" of viraemia were significantly lower than in 11 patients with a transient loss or a decline of HCV-RNA. A favorable antiviral response was closely associated with a high total dose of IFN-alpha and a long duration of IFN therapy.     

Colonization with Pseudomonas aeruginosa in patients developing ventilator-associated pneumonia

To determine routes of colonization and genotypic variation of Pseudomonas aeruginosa leading to ventilator-associated pneumonia, colonization of the rectum, stomach, oropharynx, and trachea was studied chronologically in 10 patients. Ninety-one isolates of P aeruginosa were genotyped; seven different genotypes were identified. Patients developing ventilator-associated pneumonia caused by P aeruginosa were colonized at multiple body sites and may be colonized with multiple genotypes. The upper respiratory tract is the predominant initial site of colonization with P aeruginosa.     

Bacterial colonization of the upper respiratory tract of patients with primary lung cancer and nonmalignant lung disease

We examined the bacterial colonization of the upper respiratory tract of 110 patients with primary lung cancer (PLC), 75 patients with nonmalignant lung diseases (NMLD) and 45 healthy volunteers (HV), comparing the sensitivity of expectorated sputum, and throat and nasal swabs. The frequency of bacterial colonization of the upper respiratory tract was significantly higher in the PLC patients (59.1%) than in NMLD patients (37.3%, p < 0.01) and HV (37.8%, p < 0.01). The frequency of gram-negative colonization was significantly higher in PLC patients than in the other subjects (p < 0.01). Expectorated sputum and nasal swab were the most sensitive for detection of whole bacteria and methicillin-resistant Staphylococcus aureus in the patients with PLC. Our results showed that PLC patients are significantly more frequently colonized by bacteria in their upper respiratory tracts and that a combination culture of expectorated sputum and nasal swab is suitable to estimate the bacterial colonization of the upper respiratory tract in the patients.     

Activation of NF-kappaB by adherent Pseudomonas aeruginosa in normal and cystic fibrosis respiratory epithelial cells

We have generated proliferating cell nuclear antigen (PCNA) mutants by low fidelity PCR and screened for lethal mutations by testing for lack of complementation of a Schizosaccharomyces pombe strain disrupted for the pcn1 + gene. We thus identified eight lethal mutants out of the 50 cDNAs tested. Six were truncated in their C-terminal region due to the introduction of a stop codon within their coding sequences. Two were full-length with a single point mutation at amino acid 68 or 69. The two latter mutants were overexpressed in insect cells via a recombinant baculovirus and were purified. They were unable to stimulate DNA polymerase delta DNA replication activity on a poly(dA).oligo(dT) template. Cross-linking experiments showed that this was due to their inability to form trimers. Since these two mutations are adjacent and not located in a domain of the protein putatively involved in inter-monomer interactions, our results show that the beta-sheet betaF1 to which they belong must play an essential role in maintaining the 3-dimensional structure of S.pombe PCNA.     

Bacteriology of the lower respiratory tract as determined by fiber-optic bronchoscopy and transtracheal aspiration

For assessment of the validity of cultures of tracheobronchial secretions and exudates (TBSE) obtained by fiber-optic bronchoscopy, the aerobic and anaerobic flora of expectorated saliva and TBSE obtained by fiber-optic bronchoscopy from nine healthy volunteers and eight patients were compared with those obtained by fiber-optic bronchoscopy as well). Normal volunteers yielded both aerobic and anaerobic bacteria in amounts usually less than 104.5 colony-forming units (cfu)/ml in TBSE obtained by fiberoptic bronchoscopy. In patients with chronic bronchitis, 42 isolates of aerobic bacteria (104-105.5 cfu/ml) and only 10 isolates of anaerobes (usually less than 104 cfu/ml) were reovered from 15 samples obtained by trantracheal aspiration. The data lead to the conclusion that low-level contamination (less than or equal to 104 cfu/ml) with oral flora is common in TBSE obtained by fiber-optic bronchoscopy. A single potential pathogen in numbers of greater than or equal to 105 cfu/ml may be of etiologic significance, particularly if recovered from purulent drainage material from a localized portion of the lung. Under circumstances in which quantitative bacteriology cannot be done, TBSE obtained by transtracheal aspiration will most reliably reflect the bacterial flora present in the lung.     

The problem of lower respiratory tract foreign bodies in children

The authors treat the problem of lower respiratory tract foreign bodies in children on the basis of their own longterm experience. In the years 1972-1991 in the Pediatric E.N.T. Clinic of the Pediatric Institute, Academy of Medicine in Poznań, 147 foreign bodies were removed. A positive history of foreign body aspiration was obtained in 45.7% of the cases. 44.7% of the foreign bodies were removed during the first 24 hours after their aspiration. Broncho-pulmonary complications occurred in 59.1% of the cases.     

Evaluation of the efficacy of sequential intravenous-oral administration of pefloxacin in community-acquired lower respiratory tract infections in patients with underlying conditions

We studied the efficacy of sequential intravenous-oral pefloxacin therapy in community-acquired lower respiratory tract infection in 24 patients with one or more underlying conditions. Twenty-eight patients were enrolled into the study but only 24 patients were evaluated. There were 16 males and 8 females with a mean age of 66.9 +/- 11.2 years (mean +/- SD, range 46 to 87 years). The underlying conditions present were bronchiectasis, chronic obstructive lung disease and diabetes mellitus. Patients who were older than 70 years but without any underlying condition were also enrolled. All received 4 days of intravenous pefloxacin 400 mg twice a day followed by oral pefloxacin 400 mg twice a day for another 10 days. Assessment of success was based on clinical, microbiological and radiological improvement. Pefloxacin produced 79.2% clinical cure rate. Another 8.3% showed improvement. Pefloxacin was well tolerated. There were few adverse effects and none of the patients required a change of antibiotic. Pefloxacin was an effective and well tolerated treatment for respiratory tract infection and had the advantage of broad in-vitro antibacterial activity, twice daily dosing and sequential availability in an intravenous and oral formulation.     

Pharmacologic management of common lower respiratory tract disorders in women

In a primary care setting, nurse-midwives will collaboratively manage common lower respiratory conditions that require pharmacologic therapy. As such, they must maintain up-to-date knowledge about the indications, use, and potential side effects of these medications. This article reviews the drugs most commonly used for the out-patient treatment of pneumonia, asthma, tuberculosis, and bronchitis (both acute and chronic). Differences among common oral antibiotics recommended by the American Thoracic Society are described. Inhaled bronchodilator and anti-inflammatory medications are covered, as well as systemic corticosteroids. The use of isoniazid preventive therapy for latent tuberculous infection is described in detail, with brief mention made of other drugs used for active tuberculosis. Adjunct treatments including immunotherapy, vaccines, oxygen supplementation, and nicotine replacement for smoking cessation also are discussed.     

Role of the microbiology laboratory in the diagnosis of lower respiratory tract infections

A randomized, double-blind trial was undertaken to measure the effects of zinc supplementation on catch-up growth in severe protein-energy malnutrition, with particular reference to linear growth. One hundred forty-one children between the ages of 6 mo and 3 y were enrolled after admission to a nutritional rehabilitation unit in Dhaka, Bangladesh, and randomly assigned to receive elemental zinc by mouth, 1.5 mg/kg for 15 d, 6.0 mg/kg for 15 d, or 6.0 mg/kg for 30 d, and thereafter they were followed for a total of 90 d. Anthropometric outcome measures included change in knee-heel length, midupper arm circumference, subscapular and triceps skinfold thicknesses, and change in height-for-age, weight-for-age, and weight-for-height z scores. Higher zinc doses were not associated with significant change in any anthropometric measurement, but mortality was significantly greater in children who received high-dose zinc (6.0 mg/kg) initially as opposed to those who received low-dose zinc supplementation (1.5 mg/kg) (Yates-corrected chi-square P value of 0.033 and a risk ratio of 4.53; 95% CI: 1.09 < risk ratio < 18.8). We conclude that there is no benefit to using high-dose zinc supplementation regimens and that they could contribute to increased mortality in severely malnourished children.     

Immunohistologic quantification of Pseudomonas aeruginosa in the tracheobronchial tree from patients with cystic fibrosis

Pseudomonas aeruginosa has been recognized as a pathogen of major importance in the patient with cystic fibrosis (CF). However, no information is available regarding the histologic quantification of P. aeruginosa organisms in the CF tracheobronchial tree. We retrieved all formalin-fixed paraffin-embedded lung blocks from 20 consecutive autopsies of cystic fibrosis patients. Serial histologic sections were made and stained by three methods: hematoxylin and eosin, immunoperoxidase with anti-P. aeruginosa rabbit serum as the primary antibody, and immunoperoxidase with normal rabbit serum as the primary antibody. By studying the hematoxylin and eosin section, we classified five areas in the lung as bronchi, large bronchioles, small bronchioles, bronchioloectatic areas, and abscess/airways with destroyed epithelium. The areas stained by an anti-P. aeruginosa immunoperoxidase method were examined under high-power magnification, and the bacteria within random fields were counted. Pseudomonas aeruginosa organisms were identified in 14 of 20 cases, including 13 of 16 cases in which P. aeruginosa was specifically cultured at autopsy. Quantification of organisms within the lumens of all five airway types showed that the bacterial density in cystic fibrosis airways is highest in bronchi.     

Urinary tract infections in children due to Pseudomonas aeruginosa in Enugu, Nigeria

Ileal duplication cysts within a giant omphalocele are very rare. Only a few cases have been reported in the English literature (4). We report one case of giant omphalocele, which included a huge ileal duplication cyst, detected by prenatal US, and diagnosed at surgery after birth. This case illustrates the diagnostic and therapeutic problems occurring during pregnancy and the neonatal period.