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PubMed1986

Toxicologic and pharmacologic considerations in the choice of empiric parenteral antibiotics.

The last five years have produced an explosive development of new beta-lactam compounds with extended bacterial spectra to include most of the gram-positive cocci as well as the gram-negative bacilli. With the exception of activity against enterococci, there are now third-generation cephalosporins with a spectrum of activity similar to that of the aminoglycosides. In addition, beta-lactams retain a high level of activity against anaerobes and against aerobes surviving in anaerobic conditions, a capacity that is lacking with the aminoglycoside group of antibiotics. The beta-lactams in general and some specific compounds in particular (moxalactam, ceftriazone) have a good penetration into the cerebrospinal fluid, a capacity that is also lacking with the aminoglycosides. Since there is a wide range of different spectra of activity among penicillins and cephalosporins, it is also possible to choose an antibiotic with a spectrum restricted to the offending microorganisms. Finally, because the potential toxicity of beta-lactams is less than that of the aminoglycosides (with the possible exception of myelotoxicity), the first choice of antibiotic in a patient with suspected severe infection should be a beta-lactam. The addition of an aminoglycoside should be reserved for those situations in which a synergistic action between the beta-lactam and the aminoglycoside antibiotics is expected to increase the efficacy of the beta-lactam alone, e.g., enterococcal infections, Pseudomonas aeruginosa infections, infections in severely neutropenic patients, or bacterial endocarditis.

Aminoglycosides↗
PubMed2004

Reduction in prevalence of chronic Pseudomonas aeruginosa infection at a regional pediatric cystic fibrosis center.

Various management strategies were introduced at the Leeds Regional Cystic Fibrosis (CF) Unit in an attempt to reduce the prevalence of chronic Pseudomonas aeruginosa respiratory infection, previously thought to be inevitable in most children with CF. These included neonatal screening (1975), regular microbiological monitoring (1975), early antibiotic treatment of first isolations of P. aeruginosa (1985), intensive intravenous antibiotic treatment where nebulized antibiotics failed to eradicate P. aeruginosa (1988), and separate clinics for patients chronically infected with P. aeruginosa and uninfected patients (1991). The aim of this study was to assess the impact of these interventions. All 232 patients receiving full-time care at the Leeds Paediatric CF Centre during the period January 1990-December 2000 were categorized into four groups: never grown P. aeruginosa; free of P. aeruginosa for at least 1 year; intermittent grower of P. aeruginosa with </=50% of months with samples positive for P. aeruginosa over the previous 12 months; and chronic P. aeruginosa infection with >50% of months with samples positive for P. aeruginosa over the previous 12 months. The yearly prevalence of patients having chronic P. aeruginosa infection fell significantly during the study, from 24.5% in 1990 to 18.1% in 2000 (P < 0.05), despite an increase in mean age of patients from 7.73 to 9.42 years. The number of patients aged less than 11 years who had chronic P. aeruginosa infection fell from 23.8% in January 1990 to only 4.3% by December 2000. The annual incidence and mean age of first acquisition of P. aeruginosa did not alter significantly. In conclusion, antipseudomonal management strategies were associated with both reduced prevalence, and an increase in the mean age of onset of chronic P. aeruginosa infection.

Adolescent↗
PubMed1995

Clinical evaluation of meropenem versus ceftazidime for the treatment of Pseudomonas spp. infections in cystic fibrosis patients.

Cystic fibrosis patients (children and young adults) with Pseudomonas spp. chest infections were treated with meropenem or ceftazidime. This study was the first to investigate the use of meropenem in cystic fibrosis. Meropenem was well tolerated with only transient elevations of serum transaminases. No patient experienced nausea and vomiting, even when meropenem was administered as a bolus injection. This allowed home therapy to be used. Meropenem appeared to be at least as active as ceftazidime even at the low doses used. Patients showed a greater improvement in respiratory function on meropenem than ceftazidime. Only one patient (out of 60 courses) failed to respond to meropenem (98% success rate) compared with two failures out of 21 episodes with ceftazidime (90% success rate). There was little emergence of resistance to meropenem even though some patients were treated up to eight times over a 2 year period.

Adolescent↗
PubMed1993

Resting energy expenditure before and after treatment for Pseudomonas aeruginosa infection in patients with cystic fibrosis.

To investigate whether metabolic rates change after antipseudomonal treatment, resting energy expenditure (REE) was measured in 29 patients with cystic fibrosis (CF) aged 5-27 y before and after a 2-wk course of intravenous antibiotics for the treatment of chronic Pseudomonas aeruginosa infection. Before therapy, mean (+/- SD) REE was increased to 119.0 +/- 11.4% of the predicted normal value (REE%). Seventeen of the 29 patients were classified as having increased baseline REE% (> 115% of predicted, group I), whereas 12 patients had resting energy expenditures within the normal range (group N). After antipseudomonal therapy, mean REE% decreased significantly by 6.2% of predicted. This decline was negatively correlated with the baseline REE% (r = 0.70, P < 0.001). It was most pronounced (-11.3%) in group I whereas patients of group N showed no major changes. These results suggest that antipseudomonal therapy can reduce increased energy requirements of moderately ill CF patients with chronic Pseudomonas aeruginosa infection.

Adolescent↗
PubMed2000

Mouse models of chronic lung infection with Pseudomonas aeruginosa: models for the study of cystic fibrosis.

The discovery of the CFTR gene in 1989 has lead to rapid progress in understanding the molecular basis of cystic fibrosis (CF) and the biological properties of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. However, more than 10 years later, recurrent lung infections with Pseudomonas aeruginosa, which lead to chronic lung disease and eventual respiratory failure, remain the major cause of morbidity and mortality among CF patients. A distinguishing feature of lung disease in CF is an exaggerated and persistent inflammatory response, characterized by the accumulation of excessive numbers of neutrophils and dysregulated cytokine production. The events leading to the establishment of lung infection with P. aeruginosa, especially the inflammatory and immunological events, and the relation between the CF defect and infection, remain largely undefined. Progress in this area has been hampered by the lack of a suitable animal model. An exciting achievement in the past few years has been the development of a number of variants of CFTR-deficient mice which exhibit defective cAMP-mediated Cl(-) conductance and have a range of clinical phenotypes from mild to severe. In parallel, a model of chronic P. aeruginosa lung infection has been established in genetically and immunologically well-defined inbred mouse strains which differ in susceptibility to this infection in the lung. BALB/c mice are resistant, while DBA/2 mice are extremely susceptible, with high mortality within 3 days of infection. C57BL/6 and A/J mice are relatively susceptible and experience low mortality. Furthermore, the bacterial load correlates with the magnitude and quality of the inflammatory response in the infected lungs of BALB/c and C57BL/6 mice. Although results of infection studies in CFTR-deficient mice have been variable, C57BL/6-Cftr(m1UNC)/Cftr(m1UNC) knockout mice compared to littermate control mice are highly susceptible to chronic P. aeruginosa infection in the lung. The availability of CFTR knockout mice and non-CF inbred mice differing in susceptibility to chronic P. aeruginosa infection offers useful tools for progress in understanding the genesis of chronic P. aeruginosa infection and the ensuing inflammation in the CF lung, as well as the relation between the CF defect and infection. Information generated from these studies will provide the rationale for the development of novel immunomodulatory measures capable of ameliorating or modulating the chronic inflammation associated with CF lung disease.

Animals↗
PubMed1978

The role of OEP-antibodies in Pseudomonas aeruginosa infection.

When mice were challenged intraperitoneally with 2.2 X 10(4) Pseudomonas aeruginosa in 0.5 ml of 2.7% mucin solution, the bacteria markedly increased in the peritoneal cavity, rapidly entered the blood stream, and the mice died, probably of bacteremia, within a short time. However, when mice were injected subcutaneously 4 hours prior to the challenge with 0.2 ml of 0.75% IgG (OEP-HA = 12.8) or IgM (OEP-HA = 64) separated from human plasma or 3% S-IgA EP-HA = 19.2) from fresh human milk, the bacteria were inhibited from propagating and were eliminated from the cavity so that they could not enter the blood stream. As a result, the mice tolerated the challenge and survived. When 3% IgA (OEP-HA less than 0.8) from human plasma was given, a complete cure was not effected in a few mice despite a general tendency of healing. Determination of the number of viable intra- and extracellular bacteria in the peritoneal cavity revealed that the infecting bacteria were rapidly phagocytized and killed by the peritoneal phagocytes in the presence of OEP-antibodies. These findings indicate that the effect of bacterial clearance from the cavity results from the cooperative action of OEP-antibodies and peritoneal phagocytes. Marked enhancement of phagocytosis by the antibodies was observed in an in vitro study in the presence of a heat-labile, complement-like substance(s). This finding is interpreted as evidence of the cooperative activity.

Animals↗
PubMed2005

Longitudinal development of mucoid Pseudomonas aeruginosa infection and lung disease progression in children with cystic fibrosis.

CONTEXT: Although Pseudomonas aeruginosa is the most common virulent respiratory pathogen in cystic fibrosis (CF), the longitudinal development of P aeruginosa infection and its effect on antibody responses and lung disease progression in children with CF remain unclear. OBJECTIVE: To prospectively examine the epidemiology of P aeruginosa infection and its impact on CF pulmonary morbidity. DESIGN, SETTING, AND PATIENTS: We prospectively evaluated 56 CF patients at 2 CF centers in Madison and Milwaukee, Wis, from birth up to age 16 years between April 15, 1985, and April 15, 2004, with diagnoses made through the Wisconsin CF Neonatal Screening Project. MAIN OUTCOME MEASURES: Timing of nonmucoid P aeruginosa and mucoid P aeruginosa acquisition was assessed by first positive result. Longitudinal development from no P aeruginosa to nonmucoid P aeruginosa and from nonmucoid P aeruginosa to mucoid P aeruginosa was examined. Outcome measurements included antibody titers, respiratory symptoms, quantitative chest radiography, and pulmonary function tests. RESULTS: Sixteen patients (29%) acquired nonmucoid P aeruginosa in the first 6 months of life. The age-specific prevalence of mucoid P aeruginosa increased markedly from age 4 to 16 years. Nonmucoid and mucoid P aeruginosa were acquired at median ages of 1.0 and 13.0 years, respectively. In contrast with the short transition time from no P aeruginosa to nonmucoid P aeruginosa, the transition time from nonmucoid to mucoid P aeruginosa was relatively long (median, 10.9 years) and could be slightly extended by brief/low anti-P aeruginosa antibiotic treatment. Antibody titers increased with both transitions, but the deterioration in cough scores, chest radiograph scores, and pulmonary function correlated best with transition from nonmucoid to mucoid P aeruginosa. CONCLUSIONS: Early prevention and detection of nonmucoid and mucoid P aeruginosa are critical because of early acquisition and prevalence. There is a window of opportunity for suppression and possible eradication (by aggressive anti-P aeruginosa treatment) of initial nonmucoid P aeruginosa. Mucoid P aeruginosa plays a much greater role in CF lung disease progression than nonmucoid P aeruginosa. Antibody titers, cough scores, and chest radiographs are early signs of nonmucoid P aeruginosa and especially mucoid P aeruginosa stages.

Adolescent↗
PubMed1998

Allograft colonization and infections with pseudomonas in cystic fibrosis lung transplant recipients.

OBJECTIVE: To assess the incidence of pseudomonal infection, colonization, and inflammation in the allograft of lung transplant recipients with cystic fibrosis (CF) as compared with recipients with other end-stage lung disease. DESIGN: Retrospective review. SETTING: University medical center transplant service. PATIENTS: All patients with CF and chronic pseudomonal infection (n=62) and patients with nonseptic end-stage lung disease (n=52) receiving a double lung transplant between October 1983 and March 1996. RESULTS: Fifty lung transplant recipients with CF survived beyond postoperative day (POD) 15 and were subject to sequential bronchoscopy with BAL. Forty-four CF lung transplant recipients had Pseudomonas isolated from the allograft by median POD 15 as compared with 21 non-CF lung transplant recipients (p<0.001) with isolation at median POD 158 (p<0.0001). Thirteen CF lung transplant recipients had histologic evidence of infection when Pseudomonas was isolated as compared with only three of the non-CF lung transplant recipients (p<0.01). These infections occurred earlier in the CF lung transplant recipients (median POD 10 vs 261) (p<0.01). When compared with non-CF lung transplant recipients, CF lung transplant recipients with Pseudomonas isolated but without concomitant histologic infection (colonized) were demonstrated to have increased number of polymorphonuclear cells (PMNs) in the BAL fluid recovered from the allograft (17.66+/-24.94 x 10(6) cells vs 3.46+/-4.73 x 10(6)) (p<0.05). Non-CF lung transplant recipients who became colonized with Pseudomonas also had a greater number of PMNs recovered when compared with non-CF lung transplant recipients who did not have Pseudomonas (22.32+/-34.00 x 10(6) cells vs 0.21+/-0.18 x 10(6)) (p<0.01). Nine of 32 (28%) lung transplant recipients with CF have died from pseudomonal allograft infections, but this is no greater than 4 of 21 (19%) deaths related to Pseudomonas infection in recipients without CF (p=0.34). CONCLUSIONS: Isolation of Pseudomonas from the lung allograft occurs more frequently and earlier after transplantation in recipients with CF. While infections related to Pseudomonas also occur more frequently in recipients with CF, there is no increase in mortality. There is an intense inflammatory response in the lung allograft associated with the isolation of Pseudomonas in recipients with and without CF.

Adult↗
PubMed1989

N-acetylcysteine in cystic fibrosis and Pseudomonas aeruginosa infection: clinical score, spirometry and ciliary motility.

The effect of peroral N-acetylcysteine (NAC) in patients with cystic fibrosis (CF) and chronic pulmonary Pseudomonas aeruginosa infection was studied in 52 patients in a double-blind, placebo-controlled, cross-over trial of two, 3 month durations. Active treatment consisted of NAC, 200 mg x 3 daily (patients weighing less than 30 kg) or 400 mg x 2 daily (greater than 30 kg). The effect was evaluated by a subjective clinical score, weight, sputum bacteriology, blood leucocyte count, sedimentation rate, titres of specific antimicrobial antibodies, lung function parameters and measurement of nasal ciliary function in vitro. 31 patients completed the study. No significant differences in lung function or subjective clinical scores were seen between NAC and placebo for the study group as a whole. Patients with peak expiratory flow rate (PEFR) below 70% of predicted normal values showed a satisfactory significant increase in PEFR, forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) during NAC treatment. No effect of NAC on ciliary activity was observed.

Acetylcysteine↗
PubMed1982

A tracheal culture model of respiratory tract infection with Pseudomonas aeruginosa.

The pathogenesis of Pseudomonas aeruginosa for the respiratory tract has been examined using hamster tracheal organ cultures. Tracheal rings prepared from male Syrian hamsters, strain LSH/LAK, were infected with P. aeruginosa for 4 h and processed at 4-h intervals for 24 h for examination by light- and electron microscopy. Tissue destruction was observed within 8 h after infection with 10(8) colony-forming units (cfu)/ml and within 12 h after infection with 10(4) or 10(6) cfu/ml. Ciliated cells that contained abnormal subcellular organelles were expelled from the epithelium. By 20 h the epithelial borders were composed primarily of nonciliated cells. Transmission- and scanning electron microscopy revealed details of the cellular destruction and attachment of P. aeruginosa to the ciliated epithelium. Pseudomonas aeruginosa causes a rapid destruction of the epithelium of hamster trachea in cultures. Hamster tracheal organ cultures have been shown to be useful in studying the pathogenesis of P. aeruginosa for the respiratory tract.

Animals↗
PubMed2006

Restoration of natural IgM production from liver B cells by exogenous IL-18 improves the survival of burn-injured mice infected with Pseudomonas aeruginosa.

Pseudomonas aeruginosa is the most common bacterium of postburn infection. In the present study we investigated the immune mechanism of susceptibility to this type of postburn infection and also examined the efficacy of IL-18 treatment. C57BL/6 mice were challenged with P. aeruginosa on day 7 after burn injury. Although the burn-injured mice showed a poor survival rate after bacterial challenge, they retained their IFN-gamma production. The burned mice showed lower serum IgM levels and a poor IgM response following P. aeruginosa challenge in comparison with the sham mice, whereas IL-18 treatment after burn injury (alternate day injections for 1 wk) greatly improved the serum IgM levels, which are P. aeruginosa-independent natural IgM before bacterial challenge, thereby increasing the survival rate after the challenge. IL-18 treatment also induced specific IgM to P. aeruginosa in the sera 5 days after bacterial challenge in the burned mice. Interestingly, CD43(+)CD5(-)CD23(-)B220(dim) cells, namely B-1b cells, increased in the liver after the IL-18 treatment and were found to actively produce IgM in vitro without any additional stimulation. Furthermore, the IL-18 treatment up-regulated the neutrophil count and the C3a levels in the blood as a result of the increased IgM level, which may thus play a critical role in the opsonization and elimination of any invading bacteria. IL-18 treatment for the burned mice and their resultant natural IgM production were thus found to strengthen the host defense against P. aeruginosa infection.

Animals↗
PubMedDate not supplied

Combined host and specific anti-Pseudomonas-directed therapy for Pseudomonas aeruginosa infections in burned mice: experimental results and theoretic considerations.

Four strains of Pseudomonas aeruginosa showed significant variation in the elaboration of the virulence-associated exoproducts, exotoxin A and proteases. These variations appeared to affect the mortality observed when these strains were used to infect burned mice. Further, these variations seemed to influence the efficacy of individual after sepsis treatments designed to (1) reduce total microbial load in the host (HIg treatment), (2) reduce total circulating protease load in the host (alpha 1-PI treatment), or (3) neutralize the specific effects of exotoxin A (antitoxin treatment). Combined treatment, using all of these approaches, was significantly better than individual treatment.

ADP Ribose Transferases↗