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New respiratory fluoroquinolones (FQs), such as levofloxacin, offer many improved qualities over older agents, such as ciprofloxacin. These include retaining excellent Gram-negative bacilli activity, with improved Gram-positive activity. New FQ-like levofloxacin possesses greater bioavailabilty and a longer serum half-life compared with ciprofloxacin, allowing for once-daily dosing, which may improve patient adherence. The high bioavailability of levofloxacin allows for rapid step-down from intravenous administration to oral therapy, minimizing unnecessary hospitalization, which may decrease costs and improve patient quality of life. Levofloxacin has been evaluated for the treatment of community-acquired pneumonia (CAP) in numerous randomized clinical trials. Most published studies have used the 500 mg dose, although more recent studies have investigated the 750 mg dose once daily. These trials demonstrate that levofloxacin is effective and safe for the treatment of CAP, displaying relatively mild adverse effects that are more or less comparable with ciprofloxacin. Levofloxacin has much to offer in terms of bacterial eradication, including for resistant respiratory pathogens. However, ciprofloxacin-resistant organisms are becoming more prevalent so prudence must be exercised when prescribing this agent.

The objective of this work was to study the role of mannose-binding lectin (MBL) and C-reactive protein (CRP) in pneumococcal pneumonia, to determine whether MBL acts as an acute-phase reactant and whether the severity of the disease correlates with MBL levels. The study comprised 100 patients with pneumococcal pneumonia. The pneumonia severity score was calculated and graded into a risk class of mortality (Fine scale). The MBL genotypes and the levels of MBL and CRP at the acute and recovery phases were determined. Fifty patients with the wild-type MBL genotype showed higher MBL levels in each phase (P < 0.001) and an increased risk to developing bacteraemia, odds ratio (OR) 2.74, 95% confidence interval (CI) 1.01-7.52) (P = 0.02), but this did not correlate with the pneumonia severity class. CRP levels in the acute phase, 79.53 mg/l [standard deviation (s.d.) 106.93], were higher in the subjects with positive blood cultures (P = 0.003), and remained higher [20.12 mg/l (s.d. 31.90)] in the group of patients with an underlying disease (P = 0.01). No correlation was observed between the levels of MBL and CRP in each phase, or with the pneumonia severity score. We cannot conclude that MBL acts uniformly as an acute-phase reactant in pneumococcal pneumonia. MBL levels do not correlate well with the severity of the pneumonia. The risk of developing bacteraemia could be enhanced in individuals with the wild-type MBL genotype.

Background: This study was designed to investigate the effect of cigarette smoking on hydrogen peroxide (H2O2) and thiobarbituric reactive substances (TBARs) concentrations in exhaled breath condensate (EBC) in patients with community acquired pneumonia (CAP)., Methods: H2O2 and TBARs concentrations in EBC were determined with spectrofluorimetrical assays., Results: Non-smoking CAP patients (n = 24) exhaled 1.4, 1.8 and 1.7 times more H2O2 than the smoking patients with CAP (n = 19) as assessed one (0.73 +/- 0.32 microM v. 0.51 +/- 0.36 microM), three (0.84 +/- 0.31 microM v. 0.47 +/- 0.24 microM) and five (0.66 +/- 0.28 microM v. 0.40 +/- 0.35 microM) days after admission (p < 0.05 in each case). Over 10 days of hospital treatment, mean level of exhaled H2O2 0.45 +/- 0.22 microM in CAP patients with smoking history was decreased if compared with 0.71 +/- 0.19 microM exhaled H2O2 in CAP group (p = 0.005). On the contrary, TBARs concentration evaluated over entire study period was increased in smoking CAP patients (median 0.02 microM, range 0-0.32 microM) compared with non-smoking group (median 0.01 microM, range 0-0.21 microM, p < 0.05). Concurrent, active smoking status was related with the decreased levels of H2O2 exhaled in breath condensate within the course of CAP but it appeared to increase levels of TBARs., Conclusions: The differential alternations of oxidative parameters in EBC with respect to the smoking status might provide evidence of increased H2O2 decomposition and enhanced generation of reactive species in airways of CAP patients.

Background: A reliable prediction of the causative agent of community-acquired pneumonia (CAP) is not possible based on clinical features. Our aim was to test, whether the measurement of the expression of complement receptors or Fcgamma receptors on neutrophils and monocytes would be a useful preliminary test to differentiate between bacterial and viral pneumonia., Methods: Sixty-eight patients with CAP were studied prospectively. Thirteen patients had pneumococcal pneumonia; 13 patients, influenza A pneumonia; 5 patients, atypical pneumonia, and 37 patients, aetiologically undefined pneumonia. Leukocyte receptor expression was measured within 2 days of hospital admission., Results: The mean expression of complement receptor 1 (CR1) on neutrophils was significantly higher in the patients with pneumococcal pneumonia than in those with influenza A pneumonia. The mean expression of CR1 was also significantly higher in aetiologically undefined pneumonia than in influenza A pneumonia, but there was no difference between pneumococcal and undefined pneumonia., Conclusion: Our results suggest that the expression of CR1 is higher in classical bacterial pneumonia than in viral pneumonia. Determination of the expression of CR1 may be of value as an additional rapid tool in the aetiological diagnosis, bacterial or viral infection, of CAP. These results are preliminary and more research is needed to assess the utility of this new method in the diagnostics of pneumonia.

Background: Despite antibiotic treatment, the mortality of severe community-acquired pneumonia (CAP), especially in patients with severe comorbidity, remains high. Innate defense mechanisms including polymorphonuclear neutrophil (PMN) activation and survival, orchestrated by cytokines, are primarily responsible for the elimination of bacterial organisms from the alveolus., Objectives: The aim of this study was to evaluate the effect of granulocyte colony-stimulating factor (G-CSF) on PMN activation, apoptosis and cytokine response in patients with CAP., Methods: Patients received a single dose of G-CSF (1 x 300 or 480 microg s.c.) prior to standard antibiotic treatment (n=8) or standard treatment only (n=8). Apoptosis rate and expression of CD11b, CD66b, CD64 and CD114 surface molecules on systemic PMN were assessed using fluorescence-activated cell sorter analysis. Levels of the interleukin-1 receptor antagonist (IL-1 RA), the soluble tumor necrosis factor receptor inhibitor (sTNF-p55) and G-CSF were measured by ELISA., Results: In the treatment group, 12 h after G-CSF application, neutrophil count increased, neutrophil activation marker CD11b was stimulated (CD11b: 48.6+/-9.7 vs. 71.2+/-17.7, p<0.01), neutrophil apoptosis decreased (apoptosis: 1.36+/-0.27 vs. 0.2+/-0.12%, p <.01) and the concentration of IL-1RA and sTNF-p55 increased (IL-1RA 136.4+/-72.2 vs. 340.1+/-194.6 ng/ml, p<0.01; sTNF-p55,382+/-4,243 vs. 632+/-4,714 ng/ml, p<0.01; control group nonsignificant). These effects were not seen in the control group., Conclusions: The application of a single dose of G-CSF in patients with CAP caused a prolonged survival and increased activation of neutrophils combined with a sustained release of anti-inflammatory cytokines.

Clarithromycin extended-release (ER) is a second-generation macrolide with bactericidal activity against a broad group of pathogens. It allows for convenient once-daily dosing (2 x 500 mg/day), and has less severe adverse effects than the immediate-release (IR) formulation of the drug, which may result in improved patient compliance. Clarithromycin ER has been approved for the treatment of community-acquired pneumonia, acute maxillary sinusitis and acute bacterial exacerbation of chronic bronchitis. In comparison to the IR formulation, clarithromycin ER demonstrates prolonged absorption from the gastrointestinal tract, allowing for once-daily dosing with improved gastrointestinal tolerability. Various double-blind, randomised clinical trials and group studies have found clarithromycin ER to be an efficacious treatment option, comparable with clarithromycin IR, or its other competitors.

Moxifloxacin is a fourth-generation fluoroquinolone that has been shown to be effective against respiratory pathogens, including Gram-positive (Streptococcus pneumoniae), Gram-negative (Haemophilus influenzae, Moraxella catarrhalis), and atypical strains (Chlamydia pneumoniae, Mycoplasma pneumoniae), as well as multi-drug resistant S. pneumoniae, including strains resistant to penicillin, macrolides, tetracyclines, trimethoprim/sulfamethoxazole and some fluoroquinolones. Moxifloxacin is highly concentrated in lung tissue, and has demonstrated rapid eradication rates. The bioavailability and half-life of moxifloxacin provides potent bactericidal effects at a dose of 400mg/day. The ratio of the area under the concentration-time curve to MIC of moxifloxacin is the highest among the fluoroquinolones against S. pneumoniae. The clinical efficacy of moxifloxacin has been shown in controlled studies of community-acquired pneumonia (CAP), exacerbations of chronic bronchitis (CB) and acute bacterial rhinosinusitis. Moxifloxacin has demonstrated a faster resolution of symptoms in CAP and exacerbations of CB patients compared with first-line therapy. It has also demonstrated better eradication in exacerbations of CB compared with standard therapy, in particular the macrolides. Treatment guidelines should take into account the results of clinical trials with moxifloxacin in order to establish the role of this antimicrobial in the therapeutic arsenal against respiratory tract infections.

Garenoxacin (T-3811ME, BMS-284756) is a novel, broad-spectrum des-F(6) quinolone currently under study for the treatment of community-acquired respiratory tract infections. This analysis assessed garenoxacin population pharmacokinetics and exposure-response relationships for safety (adverse effects [AE]) and antimicrobial activity (clinical cure and bacteriologic eradication of Streptococcus pneumoniae and the grouping of Haemophilus influenzae, Haemophilus parainfluenzae, and Moraxella catarrhalis). Data were obtained from three phase II clinical trials of garenoxacin administered orally as 400 mg once daily for 5 to 10 days for the treatment of community-acquired pneumonia, acute exacerbation of chronic bronchitis, and sinusitis. Samples were taken from each patient before drug administration, 2 h following administration of the first dose, and on the day 3 to 5 visit. Individual Bayesian estimates of the fu (fraction unbound), the Cmax, and the fu for the area under the concentration-time curve from 0 to 24 h (fu AUC(0-24)) were calculated as measurements of drug exposure by using an ex vivo assessment of average protein binding. Regression analysis was performed to examine the following relationships: treatment-emergent AE incidence and AUC(0-24), Cmax, or patient factors; clinical response or bacterial eradication and drug exposure (fu Cmax/MIC, fu AUC(0-24)/MIC, and other exposure covariates); or disease and patient factors. Garenoxacin pharmacokinetics were described by a one-compartment model with first-order absorption and elimination. Clearance was dependent on creatinine clearance, ideal body weight, age, obesity, and concomitant use of pseudoephedrine. The volume of distribution was dependent on weight and gender. Patients with mild or moderate renal dysfunction had, on average, approximately a 16 or 26% decrease in clearance, respectively, compared to patients of the same gender and obesity classification with normal renal function. AE occurrence was not related to garenoxacin exposure. Overall, clinical cure and bacterial eradication rates were 91 and 90%, respectively, for S. pneumoniae and 93 and 92%, respectively, for the grouping of H. influenzae, H. parainfluenzae, and M. catarrhalis. The fu AUC(0-24)/MIC ratios were high (>90% were >200), and none of the pharmacokinetic-pharmacodynamic exposure measurements indexed to the MIC or other factors were significant predictors of clinical or bacteriologic response. Garenoxacin clearance was primarily related to creatinine clearance and ideal body weight. Although garenoxacin exposure was approximately 25% higher for patients with moderate renal dysfunction, this increase does not appear to be clinically significant as exposures in this patient population were not significant predictors of AE occurrence. Garenoxacin exposures were at the upper end of the exposure-response curves for measurements of antimicrobial activity, suggesting that 400 mg of garenoxacin once daily is a safe and adequate dose for the treatment of the specified community-acquired respiratory tract infections.

Background: A 1400-bed tertiary medical center in northern Taiwan was used to conduct an epidemiological study of children hospitalized with community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infection during a 5-year period., Methods: Nineteen previously healthy children with predominantly skin and soft-tissue CA-MRSA infections were enrolled into the study. Seventeen CA-MRSA isolates were examined for antimicrobial susceptibility and molecular typing., Results: A comparison of our results with the reported resistance rates among CA-MRSA isolates from other countries showed uniformly high macrolide resistance (100%). Of the 17 MRSA isolates in our study, all had the macrolide-lincosamide-streptogramin-constitutive phenotype and the ermB gene. Moreover, on the basis of molecular typing results, 11 (65%) of 17 CA-MRSA isolates were genetically related (as determined by pulsed-field gel electrophoresis), and multilocus sequence typing revealed a sequence type of 59 in all isolates. Staphylococcal toxin genes lukS-PV and lukF-PV were detected in all isolates. However, staphylococcal cassette chromosome mec type IV was only detected in 3 (17.6%) of 17 isolates; the remaining 14 isolates were untypeable., Conclusions: Analysis of our data suggests the predominance of a single endemic CA-MRSA strain with high macrolide resistance in our community. Clinical improvement with incision and drainage was noted for most patients, despite treatment with an ineffective antibiotic, so the need for a change in treatment guidelines should be addressed.

Background: Bacterial pneumonia involves influx of activated phagocytes into distal airways. These cells release oxidants including H2O2, that may be exhaled or induce peroxidative damage to lung tissues with formation of thiobarbituric reactive substances (TBARs)., Study Objectives: To determine whether concentrations of H2O2 and TBARs in exhaled breath condensate (EBC) is elevated and correlate with systemic response to pneumonia during 10 days of hospital treatment., Design: The concentration of H2O2 and TBARs was measured in EBC of 43 inpatients with community acquired pneumonia (CAP) and 20 healthy never smoked subjects over 10 days and were accompanied by monitoring of WBC count, serum concentration of C-reactive protein (CRP) and peroxyl radical-trapping capacity., Results: Patients with CAP exhaled 4.6-, 3.7-, 3.9-, 3.3-times more H2O2 than healthy controls at 1st, 3rd, 5th and 10th day of treatment (P<0.05), respectively. EBC concentrations of TBARs were elevated at 1st and 3rd day. H2O2 and TBARs levels decreased along with treatment course. Correlation (P<0.05) was found between H2O2 levels and CRP and WBC count (r = 0.31) at 1st day and between TBARs and CRP at 5th (r = 0.34) and 10th day (r = 0.46). The mean H2O2 exhalation estimated over ten days of treatment correlated with pneumonic chest X-ray score (r = 0.42), CRP levels (r = 0.46) and WBC count (r = 0.33) at admission (P<0.05)., Conclusions: Pneumonia is accompanied by oxidative stress in airways that moderately correlates with intensity of systemic inflammatory response. Determination of H2O2 in EBC may be helpful for non-invasive monitoring of oxidants production during lower respiratory tract infection.

For an antibiotic to be active in vivo, the concept of high tissue concentrations at infected sites has been popular for a long time, but has recently been criticised. The measurement of antibiotic tissue levels in humans is restricted by ethical issues, the cost of investigations and doubtful clinical significance. In the respiratory tree (RT), antibiotic concentrations have been studied. It has been shown that the antibiotic concentrations in both the lung tissue and fluids are related to three factors: the frequency of community and severe hospital respiratory infections; the wide prescription of antibiotics in cases of respiratory infections; and the easy access of sampling different areas of the RT. Due to the controversial perception of these studies, new pharmacological approaches have been developed using animal models, in vitro simulation of antibiotic kinetics in human serum and the involvement of pathogens, thus resulting in new pharmacodynamic parameters. This review looks at the concepts in antibiotic concentrations and the pharmacodynamics of the RT.

Protease-antiprotease balance in 17 patients with unilateral community-acquired pneumonia (CAP) was characterized (day 6+/-0.8). Levels and activities of alpha-1 antitrypsin (A1AT), secretory leucoprotease inhibitor (SLPI), and neutrophil elastase (NE) were quantified. Lobes were designated as infected or uninvolved according to the presence of an infiltrate on chest radiograph. NE levels in infected lobes were higher than those in uninvolved lobes, and NE levels were significantly elevated in both, compared with that in control lobes (n=18; P<.01). A1AT and SLPI levels were similar in infected and uninvolved lobes and were significantly elevated, compared with those in control lobes (P<.05 and P<.005, respectively). Anti-NE activity in infected lobes was less than that in control or uninvolved lobes (P<.05); values in the latter 2 were similar. Free NE was detected in 7 of the infected samples, indicating that anti-NE capacity is impaired. Both A1AT and SLPI were cleaved or complexed in infected lobes, and A1AT was oxidized in infected lobes. We conclude that mean elastase levels are increased and that mean anti-elastase capacity is decreased in pneumonic lobes.

SP-D is a lectin involved in the first line of defense against microorganisms. It is primarily found in the lung but also at extrapulmonary sites and in the circulation. An immunoassay for the quantification of SP-D in serum was established and the SP-D concentration was measured in consecutive blood samples from 61 patients hospitalized for community-acquired pneumonia of suspected bacterial origin. On the day of admission to the hospital the serum SP-D concentration was significantly lower than that in healthy subjects. On day 5, the SP-D concentration had increased on average three times the concentration on admission and then slowly declined toward normal levels. CRP was measured simultaneously but no correlation was observed between concentrations of SP-D and CRP. The results show a wide range of serum SP-D concentration in healthy volunteers and indicate that significant changes occur during pulmonary infection.

The prevalence of extended-spectrum beta-lactamases producing Enterobacteriaceae (ESBLPE) among nosocomial and community acquired isolates was studied (September, 1999 - August, 2000). Nosocomial and OPD isolates (200 each) were collected from OPD and different wards of the Pakistan Institute of Medical Sciences (PIMS) Islamabad, Pakistan, and tested for the production of ESBLs using the double disc diffusion technique. The prevalence of ESBL was highest in nosocomial isolates among the patients of age group III (50-60 years) (48%) with Escherichia coli as the most prevalent organism. ESBL positive isolates were mostly reported in males (65.33%) compared to females (34.67%).

Beta-lactam antibiotics have long played a central role in the management of pediatric infections. However, widespread beta-lactam resistance among community- and hospital-acquired pathogens, mainly due to beta-lactamase production, has reduced the usefulness of these trusted and well-tolerated agents. Many regions have reported an increase in beta-lactamase-mediated resistance to cephalosporins and carbapenems as well as penicillins among clinically important Gram-positive and Gram-negative aerobes and anaerobes. For some pathogens such as Moraxella catarrhalis, Klebsiella species and Pseudomonas aeruginosa, virtually all strains worldwide are beta-lactamase producers. The development of beta-lactamase inhibitors for co-administration with a number of established beta-lactam agents has restored their usefulness in pediatric patients. The combination of ampicillin plus sulbactam has broad anti-aerobic and anti-anaerobic activity in vitro and achieves high concentrations in many body tissues and fluids. The availability of a mutual oral prodrug, sultamicillin, has enabled the development of an oral formulation. Excellent clinical response and bacterial eradication rates with ampicillin/sulbactam and sultamicillin have been demonstrated for upper and lower respiratory tract infections, urinary tract infections, osteomyelitis, and meningitis in pediatric patients and neonates. Furthermore, many studies have demonstrated an excellent tolerability profile. Thus, ampicillin/sulbactam has an important role in the management of pediatric infections.

The rationale for achieving an early discharge for patients with CAP is that reduced length of stay can result in lower costs. When hospital discharge is premature, however, use of resources after discharge from the hospital may increase. This situation could increase overall cost and worsen quality of care. The objective should be to achieve a safe and early discharge. Several studies have evaluated methods for achieving this goal. Key findings from these studies are as follows: When a patient achieves clinical stability (e.g., systolic blood pressure, > or = 90 mm Hg; heart rate, < or = 100 beats/min; respiratory rate, < or = 24 breaths/min; temperature, < or = 38.3 degrees C [101 degrees F]; oxygen saturation, > or = 90%; able to eat; and stable mental status) or fulfills appropriate criteria (see Table 2), the patient may be eligible for switch from parenteral to oral antibiotics and early discharge. For many patients, this switch or discharge may occur on day 3 of hospitalization. When a patient is switched from parenteral to oral antibiotics, in many cases there does not appear to be a demonstrable clinical benefit to in-hospital observation. Elimination of in-hospital observation for patients who do not have an obvious reason for continued hospitalization potentially could reduce length of stay by 1 day. Improving efficiency of care reduces length of stay. This reduction may be accomplished by implementing clinical pathways, identifying and correcting causes of medically unnecessary hospital days, initiating early discharge planning, enlisting the services of a discharge coordinator, and organizing outpatient parenteral antibiotic treatment programs. These strategies are effective in many but not all patients, and their application should be tempered with careful clinical judgment.

Over the last decade or so there has been a growing interest in routes of antimicrobial administration other than by the conventional intravenous route for institutionalized patients and for some outpatients. Both oral (PO) and intramuscular (IM) routes of administration are less costly than giving antimicrobial agents by vein (IV). In addition, fewer complications such as catheter-related sepsis and phlebitis are associated with non-IV routes of administration. Furthermore, a reduced-dosage, reduced-volume IM administration of ceftriaxone may provide a tolerable route of administration and equivalent bactericidal activities compared with higher dose IV ceftriaxone. The purpose of this study was to determine the time that the drug concentration remained in excess of the minimum inhibitory concentration (MIC) (T > MIC) and the duration of bactericidal activities of ceftriaxone one gram administered IV, ceftriaxone 250 mg given IM and cefixime 400 mg given orally against clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in adult volunteers. Single doses of each agent were administered and serum concentrations were collected over the standard dosing period of 24 h for all study regimens. Ceftriaxone, regardless of route of administration and dose, resulted in bactericidal activities and T > MIC for 100% of the dosing period for S. pneumoniae, H. influenzae, and M. catarrhalis. Cefixime maintained at least 50% T > MIC and bactericidal activity against both isolates each of H. influenzae and M. catarrhalis. Against both isolates of S. pneumoniae, cefixime achieved T > MIC for at least 50% of the dosing period, but did not maintain bactericidal activity. Reduced dose ceftriaxone given IM seems to be a viable alternative to ceftriaxone IV if the pathogen, susceptibility and infection site are known. Based on T > MIC exceeding 50% of the dosing interval, cefixime would be considered an effective alternative to IV therapy against common respiratory tract pathogens. Clinical studies need to be conducted to confirm these findings.

Gram-positive cocci are important causes of infection both in the community and in the hospital, with repercussions on mortality and increased economic costs. Treatment of these infections is made difficult by the increasing emergence of multi-resistant organisms, primarily among Gram-positive cocci, such as vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci, and penicillin-resistant pneumococci. Linezolid, a member of the new class of synthetic antimicrobials named oxazolidinones, has several favourable characteristics including high activity against multiresistant Gram-positive cocci. In a number of clinical trials, linezolid showed good clinical and microbiologic efficacy in the therapy of infections caused by these organisms. It can be considered a valid option for treating both community- and hospital-acquired infections due to multiresistant Gram-positive cocci.

To distinguish sinusitis from uncomplicated "colds," we examined lactoferrin and eosinophilic cationic protein (ECP) in nasal secretions. Lactoferrin titers were >/=1:400 in 4% of persons with uncomplicated colds and controls but in 79% of persons with sinusitis or purulent sputa. ECP levels were >200 ng/ml in 61% of persons with colds and >3,000 ng/ml in 62% of persons with sinusitis. Nasal lactoferrin helps distinguish sinusitis from colds.

Study Objective: To compare the extent of oral clarithromycin absorption in patients during an illness and in health., Design: Sequential two-phase prospective study including an acutely ill pneumonia phase (PP) and a subsequent convalescent phase (CP)., Study Population: Patients >/= 18 years old with radiographically confirmed community-acquired pneumonia (CAP) who were admitted to the hospital., Methods: During both study phases, patients received one single 500-mg dose of oral clarithromycin. Serial blood samples were drawn over a 24-h period in order to characterize the plasma concentration-time curves. Area under the curve from zero to 24 h (AUC(0-24)), maximum plasma concentration (Cmax), and time to maximum concentration (Tmax) were determined for both clarithromycin and its metabolite, 14-hydroxyclarithromycin, and compared between the two phases., Results: Twelve patients completed both phases of the study. For clarithromycin, there was a significant increase AUC(0-24) (47.37 +/- 8.51 microg/h/mL vs 36.22 +/- 6.09 microg/h/mL) in favor of the PP. There were no significant differences detected with respect to Cmax (4.32 +/- 0.63 microg/mL vs 3.57 +/- 0.46 microg/mL), or Tmax (3.50 +/- 0.50 h vs 2.83 +/- 0.59 h) between PP and CP. For 14-hydroxyclarithromycin, the AUC(0-24) and Cmax were significantly higher (5.84 +/- 1.08 microg/h/mL vs 8.84 +/- 1.92 microg/h/mL; 0.42 +/- 0.08 microg/mL vs 0.76 +/- 0.23 microg/mL) in the CP as compared to the PP. Tmax remained unchanged., Conclusion: The extent of absorption of oral clarithromycin was not diminished during an acute illness with CAP.

It was hypothesized that there would be an upregulation of systemic neutrophil CD11b expression in pneumonia. Expression of CD11b and concentrations of soluble intercellular adhesion molecule (ICAM)-1 and E-selectin were evaluated as potential surrogate markers of the severity of pneumonia. Possible age-related immunosenescence in relation to neutrophil CD11b expression in elderly patients with pneumonia was examined for. In patients with community-acquired pneumonia (n = 36) neutrophil CD11b expression was measured by flow cytometry and soluble ICAM-1 and E-selectin concentrations by enzyme-linked immunosorbent assay. An upregulation of neutrophil CD11b expression and increased soluble adhesion molecule concentrations on admission were confirmed, but the concentrations did not correlate with patient Acute Physiology and Chronic Health Evaluation II scores. Neutrophil CD11b expression was similar between elderly (age range 70-100 yrs) and younger (age range 18-70 yrs) patients with pneumonia. In conclusion, there is evidence of neutrophil and endothelial cell activation in pneumonia as indicated by upregulation of CD11b and increased soluble intercellular adhesion molecule and E-selectin, however, they do not appear to be good surrogate markers of severity of infection. Advanced age does not influence adhesion molecule expression in pneumonia.

Background: Inflammatory cytokine concentrations correlate with severity of sepsis. We hypothesised that patients with community acquired pneumonia (CAP) associated with systemic inflammatory response syndrome (SIRS) would have greater interleukin 6 (IL-6) production due to activation of the inflammatory cytokine cascade, matched by a significant anti-inflammatory cytokine response. Interleukin 10 (IL-10) was evaluated as a potential surrogate marker of severity of sepsis in CAP and age related impairment of the cytokine response was studied in elderly patients with CAP., Methods: Circulating immunoreactive IL-6 and IL-10 levels were measured in 38 patients with CAP subdivided into a group fulfilling the criteria for SIRS (n = 28) and a non-SIRS group (n = 10) in a variety of age groups and correlated with APACHE II scores., Results: 80% had circulating IL-6 levels (median 46.7 pg/ml, range 4.6-27,000) and 60% had circulating IL-10 levels (median 15.5 pg/ml, range 2.5-765). Concentrations of both were significantly increased in patients with SIRS compared with non-SIRS patients. Those with activation of the inflammatory cytokine cascade (IL-6 positive) produced more IL-10 than IL-6 negative patients. Older patients had a similar cytokine response. Both cytokines correlated positively with APACHE II scores., Conclusions: This is the first demonstration of circulating IL-10 in CAP. A greater counter-inflammatory response in patients with SIRS and in IL-6 positive patients suggests a potential immunomodulatory role for IL-10 in controlling the inflammatory cytokine response in CAP. IL-10 concentrations correlate with severity of illness in CAP and may be of prognostic importance. There is no age related impairment in the cytokine response.

Population pharmacokinetic modeling is a useful approach to obtaining estimates of both population and individual pharmacokinetic parameter values. The potential for relating pharmacokinetic parameters to pharmacodynamic outcome variables, such as efficacy and toxicity, exists. A logistic regression relationship between the probability of a successful clinical and microbiological outcome and the peak concentration-to-MIC ratio (and also the area under the plasma concentration-time curve [AUC]/MIC ratio) has previously been developed for levofloxacin; however, levofloxacin assays for determination of the concentration in plasma are not readily available. We attempted to derive and validate demographic variable models to allow prediction of the peak concentration in plasma and clearance (CL) from plasma for levofloxacin. Two hundred seventy-two patients received levofloxacin intravenously for the treatment of community-acquired infection of the respiratory tract, skin or soft tissue, or urinary tract, and concentrations in plasma, guided by optimal sampling theory, were obtained. Patient data were analyzed by the Non-Parametric Expectation Maximization approach. Maximum a posteriori probability Bayesian estimation was used to generate individual parameter values, including CL. Peak concentrations were simulated from these estimates. The first 172 patients were used to produce demographic models for the prediction of CL and the peak concentration. The remaining 100 patients served as the validation group for the model. A median bias and median precision were calculated. A two-compartment model was used for the population pharmacokinetic analysis. The mean CL and the mean volume of distribution of the central compartment (V1) were 9.27 liters/h and 0.836 liter/kg, respectively. The mean values for the intercompartmental rate constants, the rate constant from the central compartment to the peripheral compartment (Kcp) and the rate constant from the peripheral compartment to the central compartment (Kpc), were 0.487 and 0.647 h(-1), respectively. The mean peak concentration and the mean AUC values normalized to a dosage of 500 mg every 24 h were 8.67 microg/ml and 72.53 microg x h/ml, respectively. The variables included in the final model for the prediction of CL were creatinine clearance (CLCR), race, and age. The median bias and median precision were 0.5 and 18.3%, respectively. Peak concentrations were predicted by using the demographic model-predicted parameters of CL, V1, Kcp and Kpc, in the simulation. The median bias and the median precision were 3.3 and 21.8%, respectively. A population model of the disposition of levofloxacin has been developed. Population demographic models for the prediction of peak concentration and CL from plasma have also been successfully developed. However, the performance of the model for the prediction of peak concentration was likely insufficient to be of adequate clinical utility. The model for the prediction of CL was relatively robust, with acceptable bias and precision, and explained a reasonable amount of the variance in the CL of levofloxacin from plasma in the population (r2 = 0.396). Estimated CLCR, age, and race were the final model covariates, with CLCR explaining most of the population variance in the CL of levofloxacin from plasma. This model can potentially optimize the benefit derived from the pharmacodynamic relationships previously developed for levofloxacin.

The aim of the present study was to further characterize the role of alveolar macrophages (AM) in acute human lung inflammation by evaluating their capacity to produce pro-inflammatory cytokines such as tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-8. Patients with severe community-acquired pneumonia (CAP; n=12) and healthy volunteers (n=10) underwent bronchoalveolar lavage (BAL). AM were separated to high purity (>96%) using fluorescence-activated cell sorting. We determined the TNF-alpha, IL-6 and IL-8 cytokine gene expression in AM ex vivo using semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). Moreover, we measured in vitro unstimulated, lipopolysaccharide (LPS)- and LPS/interferon-gamma inducible TNF-alpha, IL-6 and IL-8 cytokine release and evaluated samples of BAL fluids for the same pro-inflammatory cytokines using an enzyme-linked immunosorbent assay (ELISA). We found increased TNF-alpha, IL-6 and IL-8 messenger ribonucleic acid (mRNA) levels in AM from CAP patients that were significantly elevated only for IL-8. When challenged with endotoxin in vitro, AM obtained from CAP patients showed a strongly reduced potential to release TNF-alpha and IL-6 compared to healthy controls, whereas IL-8 secretion did not differ significantly between groups. Moreover, stimulation of AM from CAP patients with LPS plus IFN-gamma augmented TNF-alpha and IL-6 cytokine release to near normal levels. Interestingly, no TNF-alpha protein was measured in BAL samples from CAP patients, whereas IL-6 and IL-8 protein levels were found to be significantly increased. Together, highly purified alveolar macrophages from community-acquired pneumonia patients show relatively low ex vivo tumour necrosis factor-alpha and interleukin-6 but not interleukin-8 messenger ribonucleic acid levels that are associated with a decreased pro-inflammatory cytokine release in vitro which, however, can be restored by concurrent interferon-gamma stimulation.

The use of the broad-spectrum cephalosporin, cefotaxime, in internal medicine is well-established, particularly in the treatment of moderately severe to severe community- and hospital-acquired infections. It is particularly useful for infections of the lower respiratory tract, urinary and biliary systems, skin and soft tissue, and in serious conditions, such as meningitis, particularly in pediatric patients. Knowledge of the pharmacokinetic and pharmacodynamic properties of cefotaxime supports the view that low dose (1-2 g), low frequency (12-hourly) dosage regimens are applicable to many mild-to-moderately severe infections, including community-acquired pneumonia, caused by susceptible organisms.

The in situ inflammatory response developing in the human lung during a localized bacterial infection was studied in 15 patients with unilateral community-acquired pneumonia (CAP). The local response in the involved lung was compared with that in the contralateral, noninvolved lung as well as with the systemic blood response. Eight healthy volunteers served as control subjects. Concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and interleukin-6 (IL-6) were measured by ELISA in bronchoalveolar lavage (BAL) fluids (n = 15), serum (n = 15), and alveolar macrophage and monocyte culture supernatants (n = 8). The concentrations of TNF-alpha, IL-beta and IL-6 in BAL fluid were significantly higher in the involved lung than in the paired noninvolved lung (p < or = 0.01) or in healthy subjects (p < or = 0.02, p < or = 0.01, and p < or = 0.001, respectively). Serum IL-6 concentrations were higher in patients than in control subjects, whereas IL-1 beta and TNF-alpha concentrations did not differ in the two groups. Alveolar macrophages from the involved lung spontaneously released higher concentrations of IL-1 beta, IL-6, and TNF-alpha (p < or = 0.05) than did macrophages from the noninvolved lung, which served as controls. However, macrophages were hyporesponsive in terms of cytokine production to further stimulation by lipopolysaccharide (LPS) in the noninvolved and involved lung compared with controls, whereas peripheral blood monocytes were not.(ABSTRACT TRUNCATED AT 250 WORDS)