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 TNFα 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 TNFα 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

Novel immunotherapeutic strategies for pyelonephritis

Acute pyelonephritis is an infection of the renal parenchyma and renal pelvis. When it is caused by a typical pathogen in an immunocompetent female patient with normal urinary tract, it is considered uncomplicated. In all other cases, sepsis is the most worrisome complication. In the event of sepsis, patients should be hospitalized and treated aggressively with antibiotics, intravenous fluids and agents that enhance the immune response of the host. In this review, we summarize findings from immunomodulatory interventions in experimental studies of acute pyelonephritis and the application of these interventions into clinical practice. Vaccine against bacterial virulence factors and agents aiming to modulate the immune response of the host belong to these interventions and they are discussed. © 2015 Future Medicine Ltd

In Vitro Activity of Oral Cephalosporins (Cefprozil and Cefixime) Against Ciprofloxacin-Resistant Enterobacteriaceae from Community-Acquired Urinary-Tract Infections

Introduction: The global emergence of pathogens of urinary-tract infections resistant to ciprofloxacin or producing extended-spectrum β-lactamases (ESBL) led us to investigate the activity of older antimicrobials such as cefprozil and cefixime against a recent broad collection of urine enterobacteria from 2012 and 2013. Methods: Minimum inhibitory concentrations and minimum bactericidal concentrations of cefprozil, cefixime and ciprofloxacin were determined against 293 Escherichia coli (40 ESBL producers), 54 Klebsiella pneumoniae (10 ESBL producers) and 53 Proteus mirabilis isolates. Results: Cefprozil was more active than ciprofloxacin against non-ESBL-producing E. coli (93.7% vs 80.2%, p < 0.0001); this was not the case for cefixime (85.7% vs 80.2%, p: 0.125). Overall, cefprozil and cefixime inhibited 80–90% of ciprofloxacin-resistant isolates of all studied species. However, they were active against less than 20% of ESBL-producing isolates. Conclusion: Results suggest that cefprozil and cefixime remain a good therapeutic alternative against urine enterobacteria particularly in case of ciprofloxacin-resistant pathogens. Their activity against ESBL-producing pathogens is limited. © 2015, The Author(s)

Differences in cytokine stimulation between methicillin-susceptible and methicillin-resistant Staphylococcus aureus in an experimental endocarditis model

The present study focused on the impact of methicillin resistance of Staphylococcus aureus on cytokine production by monocytes. Cytokine stimulation was studied by 20 heat-killed isolates, 10 methicillin-susceptible Staphylococcus aureus (MSSA) and 10 methicillin-resistant Staphylococcus aureus (MRSA). Bacterial endocarditis was induced in 27 male rabbits by challenge with 1 MSSA isolate and 1 MRSA isolate. Blood was sampled for estimation of tumor necrosis factor-alpha (TNF-α) and malondialdehyde (MDA) and stimulation of monocytes. MSSA induced greater stimulation of TNF-α than MRSA, as shown after addition of a Toll-like receptor-4 (TLR4) antagonist. Survival of rabbits challenged by MRSA was prolonged compared to those challenged by MSSA. Serum MDA was greater after MSSA stimulation. Serum of animals challenged by MRSA stimulated greater release of interleukin (IL)-8 and IL-10 compared with MSSA: the opposite was observed for TNF-α. It is concluded that MSSA and MRSA induce a different pattern of TNF-α stimulation through a TLR4-independent mechanism, leading to shorter survival in experimental endocarditis. © 2012 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases

In vitro release of fusidic acid and teicoplanin from cancellous bone allografts

The characteristics of cancellous bone allografts as carriers of fusidic acid and teicoplanin, are described. Particles of cancellous bone were compressed into a wire-mesh cylinder; five replicas were impregnated for one hour into fusidic acid; and another five for one hour into teicoplanin. Elution, was estimated daily. Concentrations of fusidic acid and teicoplanin were determined by a microbiological assay. Both antibiotics were eluted at very high concentrations within the first days. Allografts impregnated in fusidic acid provided concentrations above 20 μg/ml for 20 days. Eluted teicoplanin after day 4 was below 10 μg/ml. It is concluded that cancellous bone allografts may allow adequate in vitro elution of fusidic acid but not of teicoplanin. The latter results support their application in experimental models of osteomyelitis. © E.S.I.F.T. srl - Firenze

Kinetics of Angiopoietin-2 in serum of multi-trauma patients: Correlation with patient severity

Background: Angiopoietin-2 (Ang-2) is considered a proinflammatory mediator promoting vascular leakage. Its participation in the inflammatory process following multiple injuries was investigated. Methods: Blood was sampled on consecutive days from 54 patients with multiple injuries and six healthy volunteers. Ang-2 was estimated in serum by an enzyme immunoassay. Results: From the enrolled patients, 10 did not develop any complication; 17 developed systemic inflammatory response syndrome (SIRS); 16 developed sepsis and 11 severe sepsis. Among those who did not develop any complication, all survived. Ang-2 was increased on days 4 and 7 of follow-up in patients with SIRS. Ang-2 was highly increased upon advent of sepsis and of severe sepsis. Patients with serum levels below 15,200 pg/ml survived longer compared to those with levels above 15,200 pg/ml (p = 0.015). OR for death with serum Ang-2 above 15,200 pg/ml was 4.00 (p = 0.037). Conclusions: Serum levels of Ang-2 in multi-trauma patients are increased upon advent of septic complications and they are connected with bad prognosis. Its exact role in the process of multiple trauma remains to be defined. © 2008 Elsevier Ltd. All rights reserved

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. (c) 2005 Elsevier Inc. All rights reserved

Eicosapentanoic acid prolongs survival and attenuates inflammatory response in an experimental model of lethal trauma

In an attempt to define the efficacy of intravenously administered n-3 polyunsaturated fatty acids (PUFAs) in an animal model of lethal trauma following femur fracture, an intravenous solution of eicosapentanoic acid (EPA) - one n-3 PUFA - was administered in 25 rabbits; 13 were controls and 12 were treated with EPA 30. min after fracture. Vital signs were recorded and serum concentrations of tumor necrosis factor-alpha (TNFα) and respiratory burst of neutrophils were assessed. Survival of controls was 7.7% and of animals treated with EPA 50% (log-rank: 5.162; p: 0.023). Vital signs of both groups did not differ. Oxidative burst of neutrophils was greater among EPA-treated animals compared with controls at 48. h (p: 0.010). Serum levels of TNFα of the former group were decreased compared with the latter at 48. h (p: 0.019). Bacterial growth of enterobacteriaceae from liver and spleen after death or euthanasia was lower among EPA-treated rabbits than controls. These results suggest that EPA possesses considerable immunomodulatory activities improving survival in a model of lethal trauma. Restoration of oxidative burst conferring efficient phagocytosis of evading bacteria seems the most probable mechanism of action. © 2010 Elsevier Ltd

Thalidomide prolongs survival after experimental musculoskeletal injury, through an effect on mononuclear apoptosis

Background This study was conducted to investigate the effects of intravenous thalidomide administration in an experimental model of musculoskeletal trauma. We hypothesized that because thalidomide inhibits secretion of tumor necrosis factor alpha (TNF-α), survival of animals that received thalidomide would be significantly prolonged. Material and methods After an open fracture of the right femur, 24 rabbits were randomly assigned to control and thalidomide groups. Intravenous therapy with thalidomide was started 30 min after fracture. Hemodynamic monitoring of all animals was performed for 4 h. Survival was recorded and bacterial growth in blood and organs was measured after animal death or sacrifice. Blood was sampled for TNF-α measurement and for isolation of peripheral blood mononuclear cells (PBMCs). Apoptosis of PBMCs was measured by flow cytometry. Results Survival was significantly prolonged in the thalidomide group. Apoptosis of PBMCs was increased in the control group compared with the thalidomide group at 24 h. There were no differences in vital signs, blood and tissue cultures, and serum TNF-α concentration between the two groups. Conclusions Intravenous thalidomide prolonged survival in an experimental model of severe musculoskeletal injury in rabbits. Its mechanism of action did not involve TNF-α suppression but prevention of mononuclear apoptosis. In view of these promising results, further research is needed to clarify the immunomodulatory mechanism of action of thalidomide and its potential use for the management of severe trauma. © 2014 Elsevier Inc. All rights reserved

Efficacy of tigecycline alone and in combination with gentamicin in the treatment of experimental endocarditis due to linezolid-resistant Enterococcus faecium

We evaluated the efficacy of tigecycline in a rabbit model of experimental endocarditis caused by a linezolid-resistant clinical strain of Enterococcus faecium. Tigecycline-treated animals had a 2.8-log10-CFU/g reduction in microbial counts in excised vegetations compared with controls. Addition of gentamicin caused a further arithmetical reduction in colony counts. The therapeutic effect was sustained 5 days after completion of treatment, as shown by relapse studies performed in treatment groups. Copyright © 2013, American Society for Microbiology