Early administration of hydrocortisone replacement after the advent of septic shock: impact on survival and immune response*.

OBJECTIVES: To investigate the impact of early initiation of hydrocortisone therapy on the clinical course of septic shock and on cytokine release. DESIGN: Prospective study in patients with septic shock treated with low doses of hydrocortisone. SETTING: ICUs and general wards. PATIENTS: Over a 2-year period, 170 patients with septic shock treated with low doses of hydrocortisone were enrolled. Blood was sampled from 34 patients for isolation of peripheral blood mononuclear cells and cytokine stimulation before and 24 hours after the start of hydrocortisone. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After quartile analysis, patients were divided into those with early initiation of hydrocortisone (< 9 hr after vasopressors, n = 46) and those with late initiation of hydrocortisone (> 9 hr after vasopressors, n = 124). After adjusting for disease severity and type of infection, a protective effect of early hydrocortisone administration against unfavorable outcome was found (hazard ratio, 0.20; p = 0.012). Time of discontinuation of vasopressors was earlier among patients with initiation of hydrocortisone within 9 hours. Production of tumor necrosis factor-α was lower among patients who had had hydrocortisone early. CONCLUSIONS: In patients receiving hydrocortisone for septic shock, early initiation of treatment was associated with improved survival. This treatment was also associated with attenuated stimulation of tumor necrosis factor-α.

Effect of clarithromycin in patients with suspected Gram-negative sepsis: results of a randomized controlled trial.

BACKGROUND: A previous randomized study showed that clarithromycin decreases the risk of death due to ventilator-associated pneumonia and shortens the time until infection resolution. The efficacy of clarithromycin was tested in a larger population with sepsis. METHODS: Six hundred patients with systemic inflammatory response syndrome due to acute pyelonephritis, acute intra-abdominal infections or primary Gram-negative bacteraemia were enrolled in a double-blind, randomized, multicentre trial. Clarithromycin (1 g) was administered intravenously once daily for 4 days consecutively in 302 patients; another 298 patients were treated with placebo. Mortality was the primary outcome; resolution of infection and hospitalization costs were the secondary outcomes. RESULTS: The groups were well matched for demographics, disease severity, microbiology and appropriateness of the administered antimicrobials. Overall 28 day mortality was 17.1% (51 deaths) in the placebo arm and 18.5% (56 deaths) in the clarithromycin arm (P = 0.671). Nineteen out of 26 placebo-treated patients with septic shock and multiple organ dysfunctions died (73.1%) compared with 15 out of 28 clarithromycin-treated patients (53.6%, P = 0.020). The median time until resolution of infection was 5 days in both arms. In the subgroup with severe sepsis/shock, this was 10 days in the placebo arm and 6 days in the clarithromycin arm (P = 0.037). The cost of hospitalization was lower after treatment with clarithromycin (P = 0.044). Serious adverse events were observed in 1.3% and 0.7% of placebo- and clarithromycin-treated patients, respectively (P = 0.502). CONCLUSIONS: Intravenous clarithromycin did not affect overall mortality; however, administration shortened the time to resolution of infection and decreased the hospitalization costs.

Intravenous paracetamol as an antipyretic and analgesic medication: the significance of drug metabolism.

One prospective, open-label, non-randomized study was conducted in 100 patients to define the antipyretic and analgesic effect of a new intravenous formulation of 1 g of paracetamol; 71 received paracetamol for the management of fever and 29 received paracetamol for pain relief after abdominal surgery or for neoplastic pain. Serial follow-up measurements of core temperature and of pain intensity were done for 6 h. Additional rescue medications were recorded for 5 days. Blood was sampled for the measurement of free paracetamol (APAP) and of glucuronide-APAP and N-sulfate-APAP by an HPLC assay. Defervescence, defined as core temperature below or equal to 37.1°C, was achieved in 52 patients (73.2%) within a median time of 3 h. Patients failing to become afebrile with the first dose of paracetamol became afebrile when administered other agents as rescue medications. Analgesia was achieved in 25 patients (86.4%) within a median time of 2 h. Serum levels of glucuronide-APAP were greater among non-responders to paracetamol. The presented results suggest that the intravenous formulation of paracetamol is clinically effective depending on drug metabolism.

An algorithm for the management of Staphylococcus aureus carriage within patients with recurrent staphylococcal skin infections.

Recurrent skin infections of staphylococcal origin raise the question of probable skin colonization by Staphylococcus aureus and the need for eradication. Available evidence does not exist for such settings. A management algorithm was developed by a group of experts that was implemented prospectively in 125 patients admitted for recurrent staphylococcal skin infections. Patients were tested for skin carriage of S. aureus in seven body surfaces. In the event of carriage, therapy was administered consisting of hair and body washing with antiseptics for 60 days and parallel oral treatment according to the antibiogram for 30 days. Patients were followed up for 3 years. Seventy-nine patients were colonized by S. aureus, 49 by methicillin-susceptible (MSSA) and 30 by methicillin-resistant (MRSA) isolates. The eradication rate following the algorithm was 83.7% for patients colonized by MSSA and 90.0% for patients colonized by MRSA. The greater eradication rates were achieved after treatment with one antistaphylococcal penicillin or clindamycin in the case of MSSA carriage and with clindamycin or a fluoroquinolone in the case of MRSA carriage. Of the 79 treated cases, 18 relapsed. Time to relapse did not differ between MSSA carriers and MRSA carriers. It is concluded that the suggested algorithm may be clinically efficacious and achieve high decolonization and low relapse within patients with recurrent staphylococcal skin infections colonized by either MSSA or MRSA.

Effect of clarithromycin in inflammatory markers of patients with ventilator-associated pneumonia and sepsis caused by Gram-negative bacteria: results from a randomized clinical study.

One recent, double-blind, randomized clinical trial with 200 patients showed that clarithromycin administered intravenously for 3 days in patients with ventilator-associated pneumonia (VAP) accelerated the resolution of pneumonia and decreased the risk of death from septic shock and multiple organ dysfunctions (MODS). The present study focused on the effect of clarithromycin on markers of inflammation in these patients. Blood was drawn immediately before the administration of the allocated treatment and on six consecutive days after the start of treatment. The concentrations of circulating markers were measured. Monocytes and neutrophils were isolated for immunophenotyping analysis and for cytokine stimulation. The ratio of serum interleukin-10 (IL-10) to serum tumor necrosis factor alpha (TNF-α) was decreased in the clarithromycin group compared with the results in the placebo group. Apoptosis of monocytes was significantly increased on day 4 in the clarithromycin group compared with the rate of apoptosis in the placebo group. On the same day, the expression of CD86 was increased and the ratio of soluble CD40 ligand (sCD40L) to CD86 in serum was unchanged. The release of TNF-α, IL-6, and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) by circulating monocytes after stimulation was greater in the clarithromycin group than in the placebo group. The expression of TREM-1 on monocytes was also increased in the former group. These effects were pronounced in patients with septic shock and MODS. These results suggest that the administration of clarithromycin restored the balance between proinflammatory versus anti-inflammatory mediators in patients with sepsis; this was accompanied by more efficient antigen presentation and increased apoptosis. These effects render new perspectives for the immunotherapy of sepsis.

Genetic polymorphisms within tumor necrosis factor gene promoter region: a role for susceptibility to ventilator-associated pneumonia.

Debatable findings exist among various studies regarding the impact of single nucleotide polymorphisms (SNPs) within the promoter region of the tumor necrosis factor (TNF) gene for susceptibility to infections. Their impact was investigated in a cohort of mechanically ventilated patients who developed ventilator-associated pneumonia (VAP). Two-hundred and thirteen mechanically ventilated patients who developed VAP were enrolled. Genomic DNA was extracted and SNPs at the -376, -308 and -238 position of the promoter region of the TNF gene were assessed by restriction fragment length polymorphisms. Monocytes were isolated from 47 patients when they developed sepsis and stimulated by bacterial endotoxin for the production of TNFα and of interleukin-6 (IL-6). Patients were divided into two groups; 166 patients bearing only wild-type alleles of all three studied polymorphisms; and 47 patients carrying at least one A allele of the three studied SNPs. Time between start of mechanical ventilation and advent of VAP was significantly shorter in the second group than in the first group (log-rank: 4.416, p: 0.041). When VAP supervened, disease severity did not differ between groups. Stimulation of TNFα and of IL-6 was much greater by monocytes for patients carrying A alleles. Carriage of at least one A allele of the three studied SNPs at the promoter region of the TNF-gene is associated with shorter time to development of VAP but it is not associated with disease severity. Findings may be related with a role of the studied SNPs in the production of pro-inflammatory cytokines.

Risk assessment in sepsis: a new prognostication rule by APACHE II score and serum soluble urokinase plasminogen activator receptor.

INTRODUCTION: Early risk assessment is the mainstay of management of patients with sepsis. APACHE II is the gold standard prognostic stratification system. A prediction rule that aimed to improve prognostication by APACHE II with the application of serum suPAR (soluble urokinase plasminogen activator receptor) is developed. METHODS: A prospective study cohort enrolled 1914 patients with sepsis including 62.2% with sepsis and 37.8% with severe sepsis/septic shock. Serum suPAR was measured in samples drawn after diagnosis by an enzyme-immunoabsorbent assay; in 367 patients sequential measurements were performed. After ROC analysis and multivariate logistic regression analysis a prediction rule for risk was developed. The rule was validated in a double-blind fashion by an independent confirmation cohort of 196 sepsis patients, predominantly severe sepsis/septic shock patients, from Sweden. RESULTS: Serum suPAR remained stable within survivors and non-survivors for 10 days. Regression analysis showed that APACHE II ≥ 17 and suPAR ≥ 12 ng/ml were independently associated with unfavorable outcome. Four strata of risk were identified: i) APACHE II <17 and suPAR <12 ng/ml with mortality 5.5%; ii) APACHE II < 17 and suPAR ≥ 12 ng/ml with mortality 17.4%; iii) APACHE II ≥ 17 and suPAR <12 ng/ml with mortality 37.4%; and iv) APACHE II ≥ 17 and suPAR ≥ 12 ng/ml with mortality 51.7%. This prediction rule was confirmed by the Swedish cohort. CONCLUSIONS: A novel prediction rule with four levels of risk in sepsis based on APACHE II score and serum suPAR is proposed. Prognostication by this rule is confirmed by an independent cohort.

Detrimental effect of apoptosis of lymphocytes at an early time point of experimental abdominal sepsis.

BACKGROUND: Apoptosis of lymphocytes is considered a late sequelum in the sepsis cascade. The role of apoptosis of lymphocytes as a driver of final outcome was investigated. METHODS: Abdominal sepsis was induced after cecal ligation and puncture (CLP) in 31 rabbits. Blood was sampled at serial time intervals and peripheral blood mononuclear cells (PBMCs) were isolated. Apoptosis of lymphocytes and monocytes was measured through flow cytometric analysis. PBMCs were stimulated with LPS and Pam3Cys for the release of tumor necrosis factor-alpha (TNFα). Tissue bacterial growth was quantitatively measured. In a second set of experiments, CLP was performed in another 40 rabbits; 20 received single intravenous infusions of ciprofloxacin and of metronidazole 4 hours after surgery. RESULTS: Animals were divided into two groups based on the percentage of lymphocyte apoptosis at 4 hours after surgery; less than or equal to 32% and more than 32%. Survival of the former was shorter than the latter (p: 0.017). Tissue growth was similar between groups. Apoptosis of lymphocytes and of monocytes was lower in the former group over follow-up. Release of ΤNFα did not differ. The above findings on survival were repeated in the second set of experiments. Administration of antimicrobials prolonged survival of the former group (p: 0.039) but not of the latter group (pNS). CONCLUSIONS: Lymphocyte apoptosis at an early time point of experimental peritonitis is a major driver for death. A lower percentage of apoptosis leads earlier to death. Antimicrobials were beneficial even at that disease state.

Inhibition of caspase-1 activation in Gram-negative sepsis and experimental endotoxemia.

INTRODUCTION: Down-regulation of ex-vivo cytokine production is a specific feature in patients with sepsis. Cytokine downregulation was studied focusing on caspase-1 activation and conversion of pro-interleukin-1ß into interleukin-1ß (IL-1ß). METHODS: Peripheral blood mononuclear cells were isolated from a) 92 patients with sepsis mainly of Gram-negative etiology; b) 34 healthy volunteers; and c) 5 healthy individuals enrolled in an experimental endotoxemia study. Cytokine stimulation was assessed in vitro after stimulation with a variety of microbial stimuli. RESULTS: Inhibition of IL-1ß in sepsis was more profound than tumour necrosis factor (TNF). Down-regulation of IL-1ß response could not be entirely explained by the moderate inhibition of transcription. We investigated inflammasome activation and found that in patients with sepsis, both pro-caspase-1 and activated caspase-1 were markedly decreased. Blocking caspase-1 inhibited the release of IL-1ß in healthy volunteers, an effect that was lost in septic patients. Finally, urate crystals, which specifically induce the NLPR3 inflammasome activation, induced significant IL-1ß production in healthy controls but not in patients with sepsis. These findings were complemented by inhibition of caspase-1 autocleavage as early as two hours after lipopolysaccharide exposure in volunteers. CONCLUSIONS: These data demonstrate that the inhibition of caspase-1 and defective IL-1 ß production is an important immunological feature in sepsis.

Early alterations of the innate and adaptive immune statuses in sepsis according to the type of underlying infection.

INTRODUCTION: Although major changes of the immune system have been described in sepsis, it has never been studied whether these may differ in relation to the type of underlying infection or not. This was studied for the first time. METHODS: The statuses of the innate and adaptive immune systems were prospectively compared in 505 patients. Whole blood was sampled within less than 24 hours of advent of sepsis; white blood cells were stained with monoclonal antibodies and analyzed though a flow cytometer. RESULTS: Expression of HLA-DR was significantly decreased among patients with severe sepsis/shock due to acute pyelonephritis and intraabdominal infections compared with sepsis. The rate of apoptosis of natural killer (NK) cells differed significantly among patients with severe sepsis/shock due to ventilator-associated pneumonia (VAP) and hospital-acquired pneumonia (HAP) compared with sepsis. The rate of apoptosis of NKT cells differed significantly among patients with severe sepsis/shock due to acute pyelonephritis, primary bacteremia and VAP/HAP compared with sepsis. Regarding adaptive immunity, absolute counts of CD4-lymphocytes were significantly decreased among patients with severe sepsis/shock due to community-acquired pneumonia (CAP) and intraabdominal infections compared with sepsis. Absolute counts of B-lymphocytes were significantly decreased among patients with severe sepsis/shock due to CAP compared with sepsis. CONCLUSIONS: Major differences of the early statuses of the innate and adaptive immune systems exist between sepsis and severe sepsis/shock in relation to the underlying type of infection. These results may have a major impact on therapeutics.

Effect of clarithromycin in patients with sepsis and ventilator-associated pneumonia.

BACKGROUND: Because clarithromycin provided beneficiary nonantibiotic effects in experimental studies, its efficacy was tested in patients with sepsis and ventilator-associated pneumonia (VAP). METHODS: Two hundred patients with sepsis and VAP were enrolled in a double-blind, randomized, multicenter trial from June 2004 until November 2005. Clarithromycin (1 g) was administered intravenously once daily for 3 consecutive days in 100 patients; another 100 patients were treated with placebo. Main outcomes were resolution of VAP, duration of mechanical ventilation, and sepsis-related mortality within 28 days. RESULTS: The groups were well matched with regard to demographic characteristics, disease severity, pathogens, and adequacy of the administered antimicrobials. Analysis comprising 141 patients who survived revealed that the median time for resolution of VAP was 15.5 days and 10.0 days among placebo- and clarithromycin-treated patients, respectively (P = .011); median times for weaning from mechanical ventilation were 22.5 days and 16.0 days, respectively (p = .049). Analysis comprising all enrolled patients showed a more rapid decrease of the clinical pulmonary infection score and a delay for advent of multiple organ dysfunction in clarithromycin-treated patients, compared with those of placebo-treated patients (p = .047). Among the 45 patients who died of sepsis, time to death was significantly prolonged in clarithromycin-treated compared with placebo-treated patients (p = .004). Serious adverse events were observed in 0% and 3% of placebo- and clarithromycin-treated patients, respectively (P = .25). CONCLUSIONS: Clarithromycin accelerated the resolution of VAP and weaning from mechanical ventilation in surviving patients and delayed death in those who died of sepsis. The mortality rate at day 28 was not altered. Results are encouraging and render new perspectives on the management of sepsis and VAP.

The impact of multidrug resistance on the pathogenicity of Escherichia coli: an experimental study.

Based on the controversial findings of clinical studies regarding the influence of multidrug resistance on mortality, 10 susceptible and 10 multidrug-resistant (MDR) and extended-spectrum beta-lactamase-producing isolates of Escherichia coli were applied to stimulate monocytes isolated from healthy donors. Immune mediators were estimated in supernatants. Four susceptible isolates (Group A) and four MDR isolates (Group B) were used to initiate acute pyelonephritis in 48 rabbits following inoculation of the pathogen into the right renal pelvis. Survival was recorded and blood monocytes were isolated and incubated to estimate the ex vivo release of tumour necrosis factor-alpha (TNFalpha). Release of TNFalpha, interleukin (IL)-6 and IL-8 was higher after 2 h and 4 h of stimulation by MDR isolates compared with susceptible isolates. The opposite occurred for the release of IL-12. Death occurred in 22 rabbits in Group A (91.7%) compared with 12 in Group B (50.0%) (P=0.003). Monocytes isolated at 24 h from Group A rabbits released significantly higher TNFalpha than monocytes from Group B. Tissue bacterial load after animal death was significantly higher in the kidneys of Group A rabbits. It is concluded that susceptible and MDR E. coli stimulate monocytes resulting in a different pattern of release of pro-inflammatory cytokines, which is accompanied by prolonged survival following experimental sepsis by MDR isolates.

The importance of fever as a predictive symptom for the potency of host's monocytes to release pro- and anti-inflammatory mediators.

OBJECTIVE: To clarify whether time lapsing from advent of fever as a first sign of sepsis may be indicative of the potency of monocytes for the release of pro- and anti-inflammatory mediators. METHODS: Monocytes were isolated from blood of 51 septic patients and 9 healthy donors. Monocytes were incubated in the absence and presence of patients' serum and concentrations of tumour necrosis factor-alpha (TNF alpha), interleukin (IL)-6, IL-10, and malondialdehyde (MDA) were estimated in supernatants. Patients were divided into three groups: group A: <12 hours; group B: 12-24 hours, and group C: >24 hours between initiation of fever and blood sampling. RESULTS: TNF alpha of supernatants of groups B and C was higher than controls, as also were IL-6 of A and C, IL-10 of A and B, and MDA of A. IL-6 of group A was increased after addition of patients serum. A negative correlation was found between time from initiation of symptoms and IL-6 of monocyte supernatants incubated in the presence of patients serum. Median IL-6 of survivors was higher than nonsurvivors. CONCLUSION: Monocytes are potent for the release of pro- and anti-inflammatory mediators within the first 24 hours upon advent of fever related to sepsis; serum stimulates further release of IL-6 within the first 12 hours.

Multidrug resistance to antimicrobials as a predominant factor influencing patient survival.

The impact of multidrug resistance to antimicrobials was assessed in a cohort of 243 patients with microbiologically documented infections by a variety of susceptible and multidrug-resistant (MDR) species. Multidrug resistance was defined as resistance to more than two antimicrobial agents of different chemical structure. Cox regression analysis was performed to define differences and the significance of any predisposing factors. Overall survival of patients infected by susceptible isolates was prolonged compared with patients infected by MDR isolates (P=0.013). Mortality rates of infections caused by susceptible and MDR isolates were 4.87% and 16.15%, respectively (P=0.013); the higher mortality rate for MDR isolates was more pronounced for infections by Klebsiella pneumoniae and Pseudomonas aeruginosa. Mean (+/-standard error (S.E.)) survival of patients infected by susceptible and MDR isolates in patients without signs of severe sepsis was 28 days and 27.29+/-0.35 days, respectively (P=not significant). Mean (+/-S.E.) survival of patients with severe sepsis caused by susceptible and MDR isolates was 7.70+/-4.62 days and 10.45+/-2.18 days, respectively (P=0.048). Diabetes mellitus type 2, the presence of severe sepsis and any underlying malignancy were the most important risk factors affecting survival. It is concluded that infections by MDR isolates were accompanied by higher mortality rates and decreased survival compared with infections by susceptible isolates. Diabetes mellitus type 2 and underlying malignancies were significant co-morbid conditions, whereas survival after infection by susceptible isolates was particularly decreased in the event of severe sepsis.

Clarithromycin is an effective immunomodulator when administered late in experimental pyelonephritis by multidrug-resistant Pseudomonas aeruginosa.

BACKGROUND: To apply clarithromycin as an immunomodulatory treatment in experimental urosepsis by multidrug-resistant Pseudomonas aeruginosa. METHODS: Acute pyelonephritis was induced in 40 rabbits after inoculation of the test isolate in the renal pelvis. Therapy was administered upon signs of sepsis in four groups: A, controls; B, intravenous clarithromycin; C, amikacin; and D, both agents. Survival and vital signs were recorded; blood was sampled for culture and estimation of pro-inflammatory mediators; monocytes were isolated for determination of apoptotic rate and ex vivo TNFalpha secretion. Quantitative cultures and biopsies of organs were performed after death. RESULTS: Increased rectal temperature and oxygen saturation were found in groups B and D compared to A and C. Mean survival of groups A, B, C and D was 2.65, 7.15, 4.25 and 8.70 days respectively. No differences were noted between groups concerning bacterial load in blood and tissues and serum endotoxins. Serum MDA and total caspase-3 activity of monocytes of group D decreased following treatment compared to other groups. Negative correlation was detected between cytoplasmic caspase-3 and ex vivo secretion of TNFalpha of blood monocytes of group A; similar correlation was not found for any other group. Pathology scores of liver and lung of group B were lower than group A. CONCLUSION: Clarithromycin administered late in experimental urosepsis by multidrug-resistant P. aeruginosa prolonged survival and ameliorated clinical findings. Its effect is probably attributed to immunomodulatory intervention on blood monocytes.

Early changes of CD4-positive lymphocytes and NK cells in patients with severe Gram-negative sepsis.

INTRODUCTION: Our aim was to define early changes of lymphocytes and of NK cells in severe sepsis and to correlate them with serum levels of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1). METHODS: Blood was sampled from 49 patients with proven highly suspected infection by Gram-negative pathogens, within 12 hours of the advent of severe sepsis, and was also sampled from six healthy volunteers. White blood cells were targeted with monoclonal antibodies and were analyzed by flow cytometry. The concentrations of sTREM-1 were estimated by ELISA. RESULTS: The presence of CD3/CD4 cells was significantly lower (P < 0.0001) and that of NK cells significantly higher among patients with sepsis compared with controls (P = 0.011). The proportions (median +/- standard error) of ANNEXIN-V/CD4/CD3-positive cells, of ANNEXIN-V/CD8/CD3-positive cells and of ANNEXIN-V/CD14-positive cells of the patient population were 7.41 +/- 2.26%, 7.69 +/- 3.42% and 1.96 +/- 4.22%, respectively. Patients with NK cells >20% survived longer compared with those patients with NK cells < or =20% (P = 0.041), and patients with sTREM-1 concentrations >180 pg/ml survived longer compared with those patients with sTREM-1 concentrations < or =180 pg/ml (P = 0.042). A negative correlation was found between the percentages of ANNEXIN-V/CD4/CD3-positive cells and of CD3/CD4 cells (rs = -0.305, P = 0.049), and a positive correlation was found between the serum sTREM-1 concentration and the percentage of NK cells (rs = +0.395, P = 0.014). NK cells isolated from two healthy volunteers released sTREM-1 upon triggering with endotoxins. CONCLUSION: Early severe sepsis is characterized by CD4-lymphopenia and increased NK cells, providing a survival benefit for the septic patient at percentages >20%. The survival benefit resulting from elevated NK cells might be connected to elevated serum levels of sTREM-1.

Postantibiotic effect of antimicrobial combinations on multidrug-resistant Pseudomonas aeruginosa.

The application of antimicrobial combinations on multidrug-resistant Pseudomonas aeruginosa might be of clinical relevance if they possess a significant postantibiotic effect (PAE). Twenty-two nosocomial isolates were exposed over time to ceftazidime, imipenem, or ciprofloxacin, and to their interaction with amikacin; all were applied at concentrations equal to their average serum level. After 24 h of exposure, live cells were washed and resuspended into fresh broth, and bacterial growth was monitored. PAE was found only for isolates subjected to the synergistic effect of the applied interactions. For these isolates, the mean PAEs (+/-SE) were 3.10 +/- 0.71 h for ceftazidime and amikacin, 4.38 +/- 0.83 h for imipenem and amikacin, and 3.33 +/- 2.83 h for ciprofloxacin and amikacin. The prolonged PAE documented after exposure to the interactions of the studied drugs strengthens the application of their combination for the management of infections by multidrug-resistant P. aeruginosa.

Clarithromycin co-administered with amikacin attenuates systemic inflammation in experimental sepsis with Escherichia coli.

To assess the efficacy of clarithromycin as an immunomodulator in experimental sepsis with Escherichia coli, acute pyelonephritis was induced after ligation of the right ureter and injection of the test isolate into the renal pelvis in 40 rabbits. Four groups of treatment were applied with administration of therapy on advent of sepsis-associated pulmonary oedema, as follows: A: controls; B: clarithromycin; C: amikacin, D: both agents. Survival was recorded along with estimation of serum levels of endotoxins (LPS), of tumour necrosis factor-alpha (TNFalpha), malondialdehyde (MDA) and of bacterial counts. Mean survival of groups A, B, C and D was 2.51, 7.60, 10.25 and 11.40 days, respectively. Serum levels of TNFalpha and of MDA of group A increased over-time. Pulmonary oedema at 6 h after bacterial challenge was accompanied by increase of TNFalpha and MDA; administration of clarithromycin decreased their values. It is concluded that intravenous clarithromycin might constitute a promising immunomodulatory agent for the management of sepsis since its efficacy was proved after administration on presentation of sepsis-associated pulmonary oedema. The presented findings emphasise the need for further clinical research of the use of clarithromycin for the therapy of Gram-negative sepsis.

Comparative efficacy of tigecycline VERSUS vancomycin in an experimental model of soft tissue infection by methicillin-resistant Staphylococcus aureus producing Panton-Valentine leukocidin.

Methicillin-resistant Staphylococcus aureus (MRSA) producing Panton-Valentine leukocidin (PVL) is highly virulent. This study aimed to compare the efficacy of tigecycline versus vancomycin in experimental thigh abscess by a PVL-producing MRSA isolate. One hundred and ninety-six Wistar rats were divided into five groups: group A, controls; groups B and C, administered vancomycin starting 1 and 6 h after bacterial challenge respectively; groups D and E, administered tigecycline starting 1 and 6 h after bacterial challenge respectively. Treatment was continued every 12 hours for three consecutive days. Survival was recorded; separate animals were killed for quantitative cultures. Serum samples were collected for estimation of malondialdehyde (MDA). Survival of group D was prolonged compared to all other groups. The bacterial load of blood, liver, spleen and lung was significantly decreased within group D compared to group B at 36 hours. Treatment with tigecycline was accompanied by significant reduction of serum MDA at 24 hours. Tigecycline is comparable to vancomycin for the treatment of soft tissue infections by PVL-producing MRSA.

Yeast central nervous system infection in a critically ill patient: a case report.

INTRODUCTION: Invasive fungal infections are alarmingly common in intensive care unit patients; invasive fungal infections are associated with increased morbidity and mortality. Risk factors are the increased use of indwelling central venous catheters, the use of broad spectrum antibiotics, parenteral nutrition, renal replacement therapy and immunosuppression. Diagnosis of these infections might be complicated, requiring tissue cultures. In addition, therapy of invasive fungal infections might be difficult, given the rising resistance of fungi to antifungal agents. CASE PRESENTATION: We describe the case of a 28-year-old Greek man with yeast central nervous system infection. CONCLUSIONS: Difficult-to-treat fungal infections may complicate the clinical course of critically ill patients and render their prognosis unfavorable. This report presents a case that was rare and difficult to treat, along with a thorough review of the investigation and treatment of these kinds of fungal infections in critically ill patients.