Circulating mitochondrial N-formyl peptides contribute to secondary nosocomial infection in patients with septic shock.

Secondary infections typically worsen outcomes of patients recovering from septic shock. Neutrophil [polymorphonuclear leukocytes (PMNs)] migration to secondarily inoculated sites may play a key role in inhibiting progression from local bacterial inoculation to secondary infection. Mitochondrial N-formyl peptide (mtFP) occupancy of formyl peptide receptor-1 (FPR1) has been shown to suppress PMN chemotaxis. Therefore, we studied the association between circulating mtFPs and the development of secondary infection in patients with septic shock. We collected clinical data and plasma samples from patients with septic shock admitted to the intensive care unit for longer than 72 h. Impacts of circulating nicotinamide adenine dinucleotide dehydrogenase subunit-6 (ND6) upon clinical outcomes were analyzed. Next, the role of ND6 in PMN chemotaxis was investigated using isolated human PMNs. Studying plasma samples from 97 patients with septic shock, we found that circulating ND6 levels at admission were independently and highly associated with the development of secondary infection (odds ratio = 30.317, 95% CI: 2.904 to 316.407, P = 0.004) and increased 90-d mortality (odds ratio = 1.572, 95% CI: 1.002 to 2.465, P = 0.049). In ex vivo experiments, ND6 pretreatment suppressed FPR1-mediated PMN chemotactic responses to bacterial peptides in the presence of multiple cytokines and chemokines, despite increased nondirectional PMN movements. Circulating mtFPs appear to contribute to the development of secondary infection and increased mortality in patients with septic shock who survive their early hyperinflammatory phase. The increased susceptibility to secondary infection is probably partly mediated by the suppression of FPR1-mediated PMN chemotaxis to secondary infected sites.

The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile.

Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell's cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI.

SAA (Serum Amyloid A): A Novel Predictor of Stroke-Associated Infections.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate and independently validate SAA (serum amyloid A)-a recently discovered blood biomarker-to predict poststroke infections. METHODS: The derivation cohort (A) was composed of 283 acute ischemic stroke patients and the independent validation cohort (B), of 367 patients. The primary outcome measure was any stroke-associated infection, defined by the criteria of the US Centers for Disease Control and Prevention, occurring during hospitalization. To determine the association of SAA levels on admission with the development of infections, logistic regression models were calculated. The discriminatory ability of SAA was assessed, by calculating the area under the receiver operating characteristic curve. RESULTS: After adjusting for all predictors that were significantly associated with any infection in the univariate analysis, SAA remained an independent predictor in study A (adjusted odds ratio, 1.44 [95% CI, 1.16-1.79]; P=0.001) and in study B (adjusted odds ratio, 1.52 [1.05-2.22]; P=0.028). Adding SAA to the best regression model without the biomarker, the discriminatory accuracy improved from 0.76 (0.69-0.83) to 0.79 (0.72-0.86; P<0.001; likelihood ratio test) in study A. These results were externally validated in study B with an improvement in the area under the receiver operating characteristic curve, from 0.75 (0.70-0.81) to 0.76 (0.71-0.82; P<0.038). CONCLUSIONS: Among patients with ischemic stroke, blood SAA measured on admission is a novel independent predictor of infection after stroke. SAA improved the discrimination between patients who developed an infection compared with those who did not in both derivation and validation cohorts. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00390962.

Circulating growth/differentiation factor 15 is associated with human CD56bright natural killer cell dysfunction and nosocomial infection in severe systemic inflammation.

BACKGROUND: Systemic inflammation induced by sterile or infectious insults is associated with an enhanced susceptibility to life-threatening opportunistic, mostly bacterial, infections due to unknown pathogenesis. Natural killer (NK) cells contribute to the defence against bacterial infections through the release of Interferon (IFN) γ in response to Interleukin (IL) 12. Considering the relevance of NK cells in the immune defence we investigated whether the function of NK cells is disturbed in patients suffering from serious systemic inflammation. METHODS: NK cells from severely injured patients were analysed from the first day after the initial inflammatory insult until the day of discharge in terms of IL-12 receptor signalling and IFN-γ synthesis. FINDINGS: During systemic inflammation, the expression of the IL-12 receptor ß2 chain, phosphorylation of signal transducer and activation 4, and IFN-γ production on/in NK cells was impaired upon exposure to Staphylococcus aureus. The profound suppression of NK cells developed within 24 h after the initial insult and persisted for several weeks. NK cells displayed signs of exhaustion. Extrinsic changes were mediated by the early and long-lasting presence of growth/differentiation factor (GDF) 15 in the circulation that signalled through the transforming growth factor ß receptor I and activated Smad1/5. Moreover, the concentration of GDF-15 in the serum inversely correlated with the IL-12 receptor ß2 expression on NK cells and was enhanced in patients who later acquired septic complications. INTERPRETATION: GDF-15 is associated with the development of NK cell dysfunction during systemic inflammation and might represent a novel target to prevent nosocomial infections. FUND: The study was supported by the Department of Orthopaedics and Trauma Surgery, University Hospital Essen.

Virulence profiles and innate immune responses against highly lethal, multidrug-resistant nosocomial isolates of Acinetobacter baumannii from a tertiary care hospital in Mexico.

Virulence profiles and innate immune responses were studied in Acinetobacter baumannii from nosocomial infections collected over one year in a tertiary care hospital in Mexico. A. baumannii were identified by VITEK 2 System followed by susceptibility tests. Carbapenemase genes, active efflux mechanism to imipenem and meropenem and outer membrane proteins profile were analyzed to evaluate their role on the activity of carbapenem resistance. All isolates were genotyped by pulsed field gel electrophoresis. The ability to form biofilm was determined on a polystyrene surface. The resistance to complement was determined with a pooled human normal serum and TNFα release by infected macrophages was determined by ELISA. The 112 isolates from this study were associated with a 52% of mortality. All were resistance to ß-lactams, fluoroquinolones, and trimethroprim-sulfamethoxal, 96 and 90% were resistant to meropenem and imipenem, respectively, but with high susceptibility to polymyxin B, colistin and tigecyclin. Isolates were classified in 11 different clones. Most isolates, 88% (99/112), were metallo-ß-lactamases and carbapenemases producers, associated in 95% with the presence of blaOXA-72 gene. Only 4/99 and 1/99 of the carbapenem-resistant isolates were related to efflux mechanism to meropenem or imipenem resistance, respectively. The loss of expression of 22, 29, and/or 33-36-kDa proteins was detected in 8/11 of the clinical isolates with resistance to carbapenem. More than 96% (108/112) of the isolates were high producers of biofilms on biotic surfaces. Finally, all isolates showed variable resistance to normal human serum activity and were high inductors of TNFα release by macrophages. In summary, these results suggest that multidrug-resistant A. baumannii can persist in the hospital environment through its ability to form biofilms. The high mortality observed was due to their ability to survive normal human serum activity and capability to induce potent inflammatory immune response making this nosocomial pathogen a serious threat to hospitalized patients.

Population pharmacokinetics of telavancin in healthy subjects and patients with infections.

A population pharmacokinetic model of telavancin, a lipoglycopeptide antibiotic, was developed and used to identify sources of interindividual variability. Data were obtained from healthy subjects (seven phase 1 studies), patients with complicated skin and skin structure infections (cSSSI; two phase 2 and two phase 3 studies), and patients with hospital-acquired pneumonia (HAP; two phase 3 studies). A two-compartment open model with zero-order input best fit the telavancin data from healthy individuals and patients with cSSSI or HAP. Telavancin clearance was highly correlated with renal function and, to a lesser extent, with body weight. Other covariates were related to at least one parameter in cSSSI (gender, bacterial eradication, and surgery) or HAP (age of ≥ 75 years) but did not markedly affect exposure. These analyses support current dosing recommendations for telavancin based on patient weight and renal function.

Hospital-acquired pneumonia after lung resection surgery is associated with characteristic cytokine gene expression.

BACKGROUND: Infection in humans has been linked with altered cytokine gene transcription. It is unclear whether this phenomenon is a consequence of an established disease process or precedes the infective process. The primary end point of this study was to determine whether hospital-acquired pneumonia (HAP) was associated with differential gene expression of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and IL-23p19. The secondary end point was to identify whether alteration in gene expression preceded the clinical onset of infection. METHODS: Sixty consecutive patients undergoing elective thoracic surgery were recruited. HAP was diagnosed as per National Nosocomial Infection Surveillance guidelines. Messenger RNA (mRNA) and protein levels were analyzed preoperatively and 24 h and 5 days postoperatively. RESULTS: Forty-one patients had an uncomplicated recovery. Nineteen patients developed HAP. IL-6, IL-10, IL-12p35, IL-23p19, IL-27p28, TNF-α, and IFN-γ mRNA and protein levels of IL-6, IL-23, and IFN-γ in peripheral blood leukocytes were analyzed before surgery and 24 h and 5 days postsurgery. IL-23p19 mRNA levels were reduced in the pneumonia group (median, 4.19; 10th-90th centile range, 3.90-4.71) compared with the nonpneumonia group (4.50; 3.85-5.32) day 1 postsurgery (P=02). IFN-γ mRNA levels were reduced in the pneumonia group (2.48; 1.20-3.20) compared with nonpneumonia group (2.81; 2.10-3.26) (P=03) day 5 postsurgery. Results are expressed as log to base 10 copy numbers of cytokine mRNA per 10 million ß-actin mRNA copy numbers. All values are given as median and 10th to 90th centile range. CONCLUSIONS: Cytokine gene expression is altered immediately following surgery in patients with postoperative HAP.

Novel toxin assays implicate Mycoplasma pneumoniae in prolonged ventilator course and hypoxemia.

BACKGROUND: Community-acquired respiratory distress syndrome (CARDS) toxin is a unique Mycoplasma pneumoniae virulence factor. Molecular assays targeting this toxin are more sensitive than existing diagnostics, but these assays have not been used to investigate the role of M pneumoniae as a nosocomial infection in critical illness. We sought to determine the incidence of M pneumoniae among mechanically ventilated subjects using these novel assays and to investigate the impact of this pathogen on pulmonary outcomes. METHODS: We conducted a prospective observational study enrolling subjects with suspected ventilator-associated pneumonia (VAP) undergoing BAL in the surgical trauma ICU at a level I trauma center. Lavage fluid and serum samples were tested for M pneumoniae using assays to detect CARDS toxin gene sequences, protein, or antitoxin antibodies. RESULTS: We collected samples from 37 subjects, with 41% (15 of 37) testing positive using these assays. The positive and negative groups did not differ significantly in baseline demographic characteristics, including age, sex, injury severity, or number of ventilator days before bronchoscopy. The positive group had significantly fewer ventilator-free days (P = .04) and lower average oxygenation (P = .02). These differences were most pronounced among subjects with ARDS. CONCLUSIONS: Evidence is provided that M pneumoniae is present in a substantial number of subjects with suspected VAP. Subjects testing positive experience a significantly longer ventilator course and worse oxygenation compared with subjects testing negative.

Lysozyme activates Enterococcus faecium to induce necrotic cell death in macrophages.

Enterococci are commensal organisms in the alimentary tract. However, they can cause a variety of life-threatening infections, especially in nosocomial settings. We hypothesized that induction of cell death might enable these facultative pathogenic bacteria to evade the innate immune response and to cause infections of their host. We demonstrate that E. faecium when exposed to lysozyme induces cell death in macrophages in vitro and in vivo. Flow cytometric analyses of J774A.1 macrophages infected with E. faecium revealed loss of cell membrane integrity indicated by uptake of propidium iodide and decrease of the inner mitochondrial transmembrane potential DeltaPsi(m). Inhibition of caspases, treatment of macrophages with cytochalasin D, or rifampicin did not prevent cells from dying, suggesting cell death mechanisms that are independent of caspase activation, bacterial uptake, and intracellular bacterial replication. Characteristics of necrotic cell death were demonstrated by both lack of procaspase 3 activation and cell shrinkage, electron microscopy, and release of lactate dehydrogenase. Pretreatment of E. faecium with lysozyme and subsequently with broad spectrum protease considerably reduced cell death, suggesting that a bacterial surface protein is causative for cell death induction. Moreover, in a mouse peritonitis model we demonstrated that E. faecium induces cell death of peritoneal macrophages in vivo. Altogether, our results show that enterococci, under specific conditions such as exposure to lysozyme, induce necrotic cell death in macrophages, which might contribute to disseminated infections by these facultative pathogenic bacteria.

Prediction of nosocomial infection acquisition in ventilated patients by nasal nitric oxide: proof-of-concept study.

The development of biomarkers able to predict the occurrence of nosocomial infection could help manage preventive strategies, especially in medical patients whose degree of acquired immunosuppression may be variable. We hypothesized that the NO fraction present in the airways (upper and lower) of critically ill patients under mechanical ventilation could constitute such a biomarker. We conducted an observational proof-of-concept study in a medical intensive care unit of a teaching hospital. Forty-five patients (26 men; 72 [25th-75th percentiles] years [56-82]; Simplified Acute Physiology Score II, 63 [50-81], 14 infected) under mechanical ventilation (>3 days) underwent on day 1 and day 3 of their stay: nasal and exhaled (partitioned in bronchial and alveolar sources) bedside NO measurements, determination of urine NO end products and plasma cytokine (IL-6, IL-10) concentrations, and Sequential Organ Failure Assessment score calculation. Nosocomial infection incidence was recorded during the 15 subsequent days. Fifteen patients (33%) acquired a nosocomial infection (16 infections, 15 ventilator-associated pneumonia and 1 bacteremia). Nasal NO was the only marker significantly different between patients with and without subsequent infection (day 1, 52 ppb [20-142] vs. 134 [84-203], P = 0.038; day 3, 98 ppb [22-140] vs. 225 [89-288], P = 0.006, respectively). Nasal NO fraction 148 ppb or less at day 3 had an 80% sensitivity, a 70% specificity, and an odds ratio of 2.7 (95% confidence interval, 1.9-3.8) to predict acquisition of nosocomial infection. Nonsurvivors had a higher IL-6 concentration on day 3 (P = 0.014), whereas their nasal NO fractions were not significantly different. Nasal NO seems to be a relatively sensitive and specific biomarker of subsequent nosocomial infection acquisition (at least for ventilator-associated pneumonia), which warrants confirmation in a multicenter trial.

C-reactive protein and anemia: implications for patients on dialysis.

C-reactive protein (CRP) is an acute-phase reactant protein that increases significantly in the presence of intercurrent (concurrent) events such as infectious and inflammatory processes. Data indicate that CRP levels correlate with anemia parameters, higher levels being associated with an increased comorbidity burden, lower hemoglobin (Hb) levels, and higher Epoetin alfa dose requirements. This article explores the use of CRP monitoring in patients on dialysis, and the relationship to anemia outcomes.

Estudio de un brote debido a aislados de Klebsiella pneumoniae productores de betalactamasas de espectro extendido en un centro asistencial de Rosario - Argentina / An outbreak of extended spectrum beta-lactamase Klebsiella pneumoniae producers in a health care center from Rosario - Argentina

En América Latina (AL) son trascendentes los productores de betalactamasas de espectro extendido (BLEE) en infecciones hospitalarias. Los datos de API y SENTRY revelan una incidencia del 22 a 55. En AL y frecuentemente en el Cono Sur predominan las BLEE de la familia CTX-M contrariamente a EUA y Europa donde prevalecen las derivadas de TEM. Las CTX-M afectan cefotaxima, ceftriaxona y cefepima con más frecuencia que ceftacidima. El tratamiento depende del empleo de carbapenemes con el riesgo de seleccionar resistencia en bacilos gram negativos no fermentadores. El uso de otros betalactámicos particularmente cefepima no es aconsejable por las frecuentes fallas observadas en nuestro medio debido al efecto inóculo por aislados productores de CTX-M-2. Describimos un brote por Klebsiella pneumoniae (Kp) ocurrido entre junio-julio 2004. En el período previo, sólo un paciente presentó una infección debida a Kp productora de BLEE y en el posterior, lo presentaron dos pacientes Se determinó la CIM por microdilución en agar. El fenotipo BLEE se sospechó por ensayo del efecto del clavulanato unido a cefalosporinas de 3ª generación (C3G). Se determinó el punto isoeléctrico (pI) y la detección por PCR del tipo molecular por métodos convencionales. Se comprobaron dos bandas pI 5.4 y 8.2 con ampicilina y ceftriaxona en todas las cepas excepto en dos. Todas las cepas revelaron producción de CTX-M-2 excepto en dos cepas que se identificaron como productoras de SHV-5. Los estudios clonales se correspondieron con los moleculares identificándose dos clones. El brote se resolvió usando dos importantes medidas: 1) lavado de manos y otras medidas de barrera y 2) restringiendo el uso de C3G y ciprofloxacina

Aerosolized antibiotics in mechanically ventilated patients: delivery and response.

OBJECTIVES: To determine whether aerosolized antibiotics can be delivered efficiently to the lower respiratory tract in mechanically ventilated patients and to define possible clinical responses to these agents. DESIGN: Prospective serial study with cases as their own control. SETTING: A 10-bed respiratory care unit for patients with chronic respiratory failure in a tertiary university hospital. PATIENTS: Ventilator dependent patients who are otherwise medically stable. All subjects had a tracheostomy in place, were colonized with gram-negative organisms, and produced purulent secretions which could be sampled daily. INTERVENTIONS: Six patients received nine courses of nebulized therapy, which consisted of treatments every 8 hrs of gentamicin (80 mg) or amikacin (400 mg) for 14 to 21 days. MEASUREMENTS AND MAIN RESULTS: Doses to the lung were measured using radiolabeled aerosols and antibiotic concentrations in sputum. The response was assessed by a) changes in the volume of respiratory secretions; b) effect on bacterial cultures; and c) changes in the inflammatory cells and mediators of inflammation of the respiratory secretions (interleukin-1beta [IL-1beta], tumor necrosis factor-alpha [TNF-alpha], soluble intercellular adhesion molecule-1 [sICAM-1], and human leukocyte elastase). On average, patients inhaled 35.4 +/- 5.08% (SD) of the initial drug placed in the nebulizer (neb-charge). Of this neb-charge, 9.50 +/- 2.78% was found on the respirator tubing and tracheostomy tube and 21.9 +/- 7.15% was actually deposited in the lungs. The remainder of the neb-charge was sequestered in the nebulizer or exhaled. Trough sputum concentrations averaged 4.3 +/- 3.2 microg/mL/mg neb-charge (range 234 to 520 microg/mL) and increased to 16.6 +/- 8.1 microg/mL/mg neb-charge (range 1005 to 5839 microg/mL) immediately after therapy (p = .011). Serum concentrations were undetectable in most determinations except for a single patient who was in renal failure (8.7 microg/mL amikacin). Treatment caused a significant reduction in the volume of secretions (p = .002). Weekly cultures revealed eradication of Pseudomonas species, Serratia marcescens, and Enterobacter aerogenes in most of the trials. Before antibiotic treatment, concentrations of IL-1beta were higher than those reported in acute respiratory distress syndrome. Throughout the duration of the study, IL-1beta correlated significantly with the absolute number of macrophages, neutrophils, and lymphocytes, respectively (r2 = .55, p = .002; r2 = .50, p < .0004, r2 = .36, p = .005). TNF-alpha concentrations correlated with lymphocytes and neutrophils, respectively (r2 =.27, p = .013, r2 = .21, p = .033). sICAM-1 concentrations increased two-fold (p < .001) during treatment and then returned to baseline. The volume of secretions was related to neutrophil and IL-1beta concentrations, respectively (r2 = .25, p = .008, r2= .35, p = .006). CONCLUSIONS: Nebulizer delivery of aerosolized aminoglycosides is efficient and predictable. In our clinical model, aerosolized antibiotics can make a significant impact on respiratory secretions. Their efficacy in treatment of critically ill patients remains to be determined.

Wound tissue oxygen tension predicts the risk of wound infection in surgical patients.

OBJECTIVE: To test the hypothesis that subcutaneous wound oxygen tension (PsqO2) has a predictive relation to the development of wound infection in surgical patients. DESIGN: A noninterventional, prospective study. SETTING: A university department of surgery. PATIENTS: One hundred thirty operative general surgical patients at notable risk of infection as predicted by an anticipated Study on the Effect of Nosocomial Infection Control (SENIC) score of 1 or greater. OUTCOME MEASURES: PsqO2 was measured perioperatively. Its relation to the subsequent incidence of surgical wound infection was then determined and compared with the SENIC score as a criterion standard. RESULTS: Although the SENIC score and PsqO2 are inversely correlated, PsqO2 is the stronger predictor of infection. Low PsqO2 identified patients at risk and concentrated them in a cohort that was about half the size of that identified by the SENIC score. CONCLUSIONS: Subcutaneous perfusion and oxygenation are important components of immunity to wound infections. The SENIC score identifies systemic physiological variables that are important to the development of wound infection. Nevertheless, PsqO2 is the more powerful predictor of wound infection. Moreover, PsqO2 can be manipulated by available clinical means, and thus may direct interventions to prevent infection.

Penetration of ciprofloxacin into bronchial secretions from mechanically ventilated patients with nosocomial bronchopneumonia.

The aim of the study was to evaluate the penetration of ciprofloxacin into bronchial secretions from mechanically ventilated patients with nosocomial bronchopneumonia. For this purpose, in each patient studied, simultaneous serial blood and bronchial secretion samples were obtained over a 12-h period on days 2 and 4. Eight patients were included in the study. Ciprofloxacin was given at a dose of 200 mg over 30 min by using an automatic pump. Ciprofloxacin was measured by high-performance liquid chromatography. Peak levels of drug in serum were 2.95 +/- 1 mg/liter on day 2 and 2.43 +/- 0.7 mg/liter on day 4. Peak and trough levels in bronchial secretions were 0.95 +/- 0.51 and 0.21 +/- 0.12 mg/liter, respectively, on day 2 and 0.76 +/- 0.17 and 0.18 +/- 0.14 mg/liter, respectively, on day 4. The ratios of peak concentrations in bronchial secretions/serum were 0.32 +/- 0.11 and 0.33 +/- 0.06 on days 2 and 4, respectively. The ratios of the area under the concentration-time curve from 0 to 12 h (AUC0-12) for bronchial secretions/those for serum were 0.66 +/- 0.40 and 0.55 +/- 0.30 on days 2 and 4, respectively. A significant positive correlation was found on day 4 between the AUC0-12 for serum and the AUC0-12 for bronchial secretions. No significant correlations were found between peak values in serum and bronchial secretions.

Persistent elastase/proteinase inhibitor imbalance during prolonged ventilation of infants with bronchopulmonary dysplasia: evidence for the role of nosocomial infections.

Acute imbalance between elastase and alpha-1-proteinase inhibitor (alpha 1Pi) may contribute to the development of bronchopulmonary dysplasia (BPD). The question of whether such an imbalance persists in BPD infants still requiring mechanical ventilation after 4 wk of life has not been previously addressed. We studied 14 infants still on mechanical ventilation at 4 wk of age: nine had BPD and five did not. Weekly (4 to 9 wk) serum and bronchoalveolar lavage (BAL) specimens were taken. alpha 1Pi and alpha-2-macroglobulin were measured in serum and BAL by immunoturbidimetric assay. BAL elastase activity was measured by cleavage of a synthetic substrate and expressed as ng of porcine pancreatic elastase equivalent. Infants with BPD had higher levels of serum alpha 1Pi and alpha-2-macroglobulin than those without BPD. In contrast, the corresponding BAL levels were either similar or even decreased (alpha 1Pi). Moreover, there was a 3-fold increase in elastase-1Pi imbalance expressed as the BAL ng of porcine pancreatic elastase equivalent/2 alpha 1Pi ratio. The role of nosocomial infections was evident in a subgroup of 11 infected BAL aspirates in BPD infants. In such cases we found a 3-fold increase in the BAL ng of porcine pancreatic elastase equivalent/alpha 1Pi ratio as compared to 35 noninfected BAL in BPD infants. These data suggest a persistent alveolitis with imbalance between elastase and proteinase inhibitors in prolonged severe BPD. Such an imbalance is, in part, explained by a local destruction and/or inactivation of alpha 1Pi. Our results also emphasize the increase in proteolysis with nosocomial pneumonia.

Efficacy and pharmacokinetics of Timentin in paediatric infections.

Twenty-four children, ten of whom had an infection due to ticarcillin-resistant, Timentin-sensitive bacteria, were treated with Timentin. A full clinical success was obtained in sixteen cases (13 pyelonephritis, nine of them due to ticarcillin-resistant, Timentin-sensitive Escherichia coli, two neonatal infections and one pneumonia). Four children were improved (1 bronchiectasis, 3 leukaemias), three were unassessable and one failure occurred with a staphylococcal urinary tract infection. A pharmacokinetic study was performed in three newborns (under three months) and ten children (mean age 3 years). Timentin was administered as four daily 30-min iv infusions. The mean dosage used in patients under three months was 225 mg/kg/d ticarcillin and 9 mg/kg/d clavulanic acid. In infants older than three months of age the mean dosage was 250 mg/kg/d ticarcillin and 16 mg/kg/d clavulanic acid. The pharmacokinetic results demonstrated similar serum concentrations of ticarcillin to those in earlier studies, and serum concentrations of clavulanic acid of 3.1 +/- 0.63 mg/l and 2.18 +/- 0.17 mg/l at 1 h and 2 h respectively after infusion in newborns. For children, at the same times, the serum levels were respectively 2.3 +/- 0.9 mg/l and 1.4 +/- 0.9 mg/l. The peak serum concentrations of clavulanic acid were the same in the two groups of dosages (4.7 mg/l), but the half-lives of clavulanic acid were 1.1 h in children older than three months and 1.8 h in infants younger than 3 months. The tolerance was good. Timentin may be useful as a first line antibiotic in infections in hospitalized children in the dosage described, as three or four injections daily, according to the age and the severity of the disease.

[In vitro activity, serum, urine and prostatic adenoma concentrations of ofloxacin in urologic patients with complicated urinary tract infections]. / In vitro-Aktivität, Serum-, Urin- und Prostataadenom-Gewebekonzentrationen von Ofloxacin bei urologischen Patienten mit komplizierten Harnwegsinfektionen.

The minimal inhibitory concentrations (MIC) of ofloxacin against 400 isolates cultured from the urine of urological patients with complicated urinary tract infections (UTI) resulted in an inhibition of 94% (99%) of the gram-negative strains at a concentration of 1 mg/l (2 mg/l) and an inhibition of 59% (100%) of the gram-positive strains at a concentration of 1 mg/l (4 mg/l). According to the MIC 90% values, the corresponding grade of activity was as follows: ciprofloxacin, ofloxacin, norfloxacin, pefloxacin, enoxacin, pipemidic acid, enoxacin and nalidixic acid. After an oral dose of 400 mg of ofloxacin, the mean peak serum concentration of ten patients was 5.5 mg/l. The mean renal excretion during 24 hours was 41%. In ten patients undergoing transurethral resection of the prostate, the median serum concentration was 1.87 mg/l and the median prostatic adenoma tissue concentration 1.20 mg/kg 14.5 to 19 hours after oral administration of 400 mg ofloxacin. Due to the in vitro activity and the concentrations obtained in serum, urine and tissue, ofloxacin appears to be well suited for treatment of complicated UTI.