Levofloxacin Treatment Research Articles

The effects of levofloxacin on rabbit anterior cruciate ligament cells in vitro

Articular cartilage, epiphyseal growth plate and tendons have been recognized as targets of fluoroquinolone-induced connective tissue toxicity. The effects of fluoroquinolones on ligament tissues are still unknown. The aim of this study was to investigate the effects of levofloxacin, a typical fluoroquinolone antibiotic drug, on rabbit anterior cruciate ligament (ACL) cells in vitro. Rabbit ACL cells were treated with levofloxacin at different concentrations (0, 14, 28, 56, 112 and 224 μM) and were assessed to determine the possible cytotoxic effects of levofloxacin on ACL cells. Levofloxacin, with concentrations ranging from 28 to 224 μM, induced dose-dependent ACL cell apoptosis. Characteristic markers of programmed cell death and degenerative changes were identified by electron microscopy in the ACL cells treated with 28 μM of levofloxacin. Moreover, levofloxacin significantly increased the mRNA expression of matrix metalloproteinase 3 (MMP-3) and MMP-13 and decreased the expression of tissue inhibitors of metalloproteinase 1 (TIMP-1) in a concentration-dependent manner; TIMP-3 and collagen type I alpha 1 (Col1A1) mRNA expression was not affected. Immunocytochemical analysis indicated that levofloxacin markedly increased the expression of active caspase-3 within a concentration range of 28 to 224 μM, whereas a clear-cut decrease in Col1A1 expression was found with levofloxacin treatment concentrations of 112 and 224 μM, compared to controls. Our data suggest that levofloxacin has cytotoxic effects on ACL cells characterized by enhanced apoptosis and decreased extracellular matrix, which suggest a potential adverse effect of fluoroquinolones.

Can oral levofloxacin cause of flexor digitorum profundus rupture?

Fluoroquinolones are broad-spectrum antibacterial agents. Reports of Achilles tendon rupture as a possible side effect of the quinolones have been previously presented but mechanism of the side effect of the medication is still unknown. Tendon rupture in the forearm associated with fluoroquinolone use has not been reported. We present a patient who underwent levofloxacin treatment for skin infections and subsequently developed left small finger flexor digitorum profundus rupture. We propose that this rupture may be related to the side effect of the medication. If it is, clinicians have to be aware of possible tendon ruptures in the upper extremity due to side effects of quinolones and patients have to be informed about it.

Tsukamurella tyrosinosolvens and Rhizobium radiobacter sepsis presenting with septic pulmonary emboli

Septic pulmonary embolism (SPE) is an uncommon, but life-threatening event that is usually associated with extrapulmonary infections. We report the first case of bilateral SPE secondary to a central venous catheter-related bloodstream infection involving pathogens commonly considered environmental contaminants: Tsukamurella tyrosinosolvens and Rhizobium radiobacter. Empirical levofloxacin treatment was confirmed by in vitro susceptibility data and produced prompt clinical improvement, but removal of the infected line proved indispensable for eradication of the infection. Laboratory personnel should be aware of the pathogenic potential of these environmental organisms, particularly in immunocompromised hosts with indwelling catheters.

Levofloxacin reduces inflammatory cytokine levels in human bronchial epithelia cells: implications for aerosol MP-376 (levofloxacin solutionfor inhalation) treatment of chronic pulmonary infections

Inflammation resulting from chronic bacterial infection in the lung contributes to long-term pulmonary complications in chronic pulmonary infections such as cystic fibrosis. Aerosol administration of levofloxacin as in the form of the investigational formulation MP-376 results in higher concentrations in lung tissues that are higher than those that can be attained with oral or intravenous dosing of levofloxacin. The objective of this study was to evaluate the effect of high concentrations of levofloxacin achieved with aerosol administration of MP-376 on proinflammatory cytokine secretion by immortalized human bronchial epithelia cells in vitro. Additionally, we investigated the potential mechanisms of the immunomodulatory effect of levofloxacin. In vitro studies in human lung epithelial cell lines showed that levofloxacin led to a dose-related reduction in IL-6 and IL-8 concentrations, with 300 μg mL(-1) resulting in the reduction of levels of IL-6 by fourfold and IL-8 by twofold (P<0.05); in contrast, tobramycin increased IL-6 levels by 50%, but had no effect on IL-8. Levofloxacin treatment did not affect the cytokine mRNA level and nuclear factor-κB-dependent promoter activity. These findings suggest that high concentrations of levofloxacin obtained in pulmonary tissues following the administration of aerosol MP-376 may provide additional benefits in patients with chronic pulmonary infections that are independent of its antibacterial properties.

Levofloxacin cures experimental pneumonic plague in African green monkeys.

Background Yersinia pestis, the agent of plague, is considered a potential bioweapon due to rapid lethality when delivered as an aerosol. Levofloxacin was tested for primary pneumonic plague treatment in a nonhuman primate model mimicking human disease.Methods and ResultsTwenty-four African Green monkeys (AGMs, Chlorocebus aethiops) were challenged via head-only aerosol inhalation with 3–145 (mean = 65) 50% lethal (LD50) doses of Y. pestis strain CO92. Telemetered body temperature >39°C initiated intravenous infusions to seven 5% dextrose controls or 17 levofloxacin treated animals. Levofloxacin was administered as a “humanized” dose regimen of alternating 8 mg/kg and 2 mg/kg 30-min infusions every 24-h, continuing until animal death or 20 total infusions, followed by 14 days of observation. Fever appeared at 53–165 h and radiographs found multilobar pneumonia in all exposed animals. All control animals died of severe pneumonic plague within five days of aerosol exposure. All 16 animals infused with levofloxacin for 10 days survived. Levofloxacin treatment abolished bacteremia within 24 h in animals with confirmed pre-infusion bacteremia, and reduced tachypnea and leukocytosis but not fever during the first 2 days of infusions.ConclusionLevofloxacin cures established pneumonic plague when treatment is initiated after the onset of fever in the lethal aerosol-challenged AGM nonhuman primate model, and can be considered for treatment of other forms of plague. Levofloxacin may also be considered for primary presumptive-use, multi-agent antibiotic in bioterrorism events prior to identification of the pathogen.

Acute hepatitis associated with the use of levofloxacin

Background: Levofloxacin is a fluoroquinolone used globally to treat respiratory, skin, and genitourinary tract infections. It is generally well tolerated and there is a very low risk for liver injury in patients taking this antibiotic. Objective: We report an acute case of hepatitis following treatment with levofloxacin for pneumonia. Case summary: A 77-year-old white male (height, 162 cm; weight, 58 kg) with chronic bronchitis presented to the emergency department of the Hospital Curry Cabral, Lisbon, Portugal, with respiratory difficulty and productive cough. The patient had a history of chronic bronchitis, arterial hypertension, hypercholesterolemia, and benign prostatic hyperplasia, and was being treated with salmeterol 50 μg plus fluticasone 250 μg BID, and amlodipine 5 mg, simvastatin 20 mg, alfuzosin 10 mg, and finasteride 5 mg once daily. Initially, the patient refused admission and was sent home, medicated with levofloxacin 500 mg once daily (single dose) for pneumonia and acetaminophen 1 g (as needed, maximum TID) if axillary temperature exceeded 38.0°C (100.4°F). Three days later, the patient returned for a follow-up visit, and despite clinical and radiologic improvement, blood tests revealed a slight aggravation of anemia. On the seventh day of treatment with levofloxacin, the patient showed an elevation of transaminases. The temporal relation between the use of levofloxacin and the liver injury, the exclusion of other causes of hepatitis, and a compatible liver biopsy (conducted 14 days after identification of hepatitis) was consistent with the diagnosis of levofloxacin-associated hepatotoxicity. Levofloxacin treatment was stopped and the patient made a full recovery. The Naranjo Adverse Drug Reaction Probability Scale score for this association was “probable” (score 7) and the Roussel Uclaf Causality Assessment Method Scale score was “highly probable” (score 9). Unlike the 5 reported cases in the literature, this is the only case in which both a liver biopsy was performed in the course of the disease and the patient survived. Conclusion: The acute hepatitis observed in this elderly patient was probably associated with the administration of levofloxacin.

Effects of reduced glutathione on plasma level of cytokines and pulmonary ultrastructure in rats with sepsis

To investigate the protection mechanism of reduced glutathione (GSH) in acute lung injury in rats with sepsis. Sepsis in Sprague-Dawley (SD) rats were reproduced by cecal ligation and puncture (CLP). They were randomly divided into four groups, sham-operated group, model group, GSH treatment group and levofloxacin (LEV) treatment group. Heart blood of 7 rats in all groups was collected at 3, 6, 12, 24 hours after operation. The plasma levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured. The lung ultrastructure changes were observed with electron microscope at 24 hours in all groups. Compared with the sham-operated group, the plasma level of TNF-alpha increased more obviously at 6 hours of the model group [(227+/-28) microg/L vs. (132+/-9) microg/L, P<0.01]. Compared with the model group, the plasma level of TNF-alpha in the GSH treatment group decreased obviously [(144+/-28) microg/L], and it was obviously lower than that of LEV treatment group [(214+/-48) microg/L , both P<0.01] . No obvious difference of plasma level of TNF-alpha was found at 3, 12, 24 hours among all the groups. Compared with the sham-operated group, the plasma level of IL-6 of the model group raised obviously at 3 hours [(267.65+/-72.87) microg/L vs. (135.43+/-40.08) microg/L, P<0.01]. In the GSH treatment group, the plasma level of IL-6 [(191.97+/-62.98) microg/L] was lower than that of the model group and the LEV treatment group [(268.75+/-74.67) microg/L, both P<0.05]. The plasma level of IL-6 was not obviously different among all groups at 6, 12, 24 hours. In the model group, the injury of pulmonary ultrastructure was obvious, especially in the mitochondria of the pulmonary cells. In the GSH treatment group, the change in ultrastructure of the lung was slight. TNF-alpha and IL-6 play significant role in the development of pulmonary ultrastructure injury in acute lung injury of septic rats. Treatment with GSH was effective in preventing such injury.

W1850 Inhibition of Postoperative Adhesion Formation by Daikenchuto, a Releaser of Endogenous Adrenomedullin in Intestinal Tract

Background: Intestinal scarring is a major cause of morbidity in Crohn's disease. Current therapies treat inflammation, but do not alter the progression of fibrosis and bowel obstruction. Given the observation that late use of potent anti-inflammatory therapies does not reduce stenosis or obstruction, we hypothesized that intestinal fibrosis becomes self-propagating, despite removal of inflammatory stimuli. Methods: The Salmonella typhimurium murine model of inflammation and fibrosis in which clearance of commensal microbiota by streptomycin, followed by infection with S. typhimurium, produces chronic inflammation, culminating with fibrosis by day 21 post infection was used. The inflammatory stimulus (S. typhimurium) was removed with the oral antibiotic levofloxacin at day 2, 4, or 8 post-infection. Eradication of S.typhimurium was confirmed by stool plating and T-RFLP analysis. Results: By day 2 post-infection, the mouse cecae infected with S.typhimurium developed an inflammatory phenotype, characterized by a shrunken yet heavier cecum, expansion of the cecal submucosa, and induction of inflammatory genes (IL-1b, TNFa, IL-6, IL-17, IL12p40). However, fibrotic gene expression (CTGF, IGF-1, TGFb) was indistinguishable from uninfected controls. In addition, aSMA protein expression was not induced until day 8 postinfection. Early intervention (day 2 & 4) repressed inflammation as determined by gross pathology, histopathology, and repression of inflammatory genes. Fibrotic gene expression was partially repressed by day 2 levofloxacin treatment. However, day 8 levofloxacin treatment did not prevent induction of aSMA protein or pro-fibrotic genes (CTGF, IGF-1, TGFb) by day 8 and which continued to increase after levofloxacin treatment to day 21, remaining significantly higher than uninfected controls or matched S.typhimurium infected mice harvested at day 4 and 8 post-infection (p < 0.03) Conclusions: Early removal of the inflammatory stimulus reduces fibrosis, but fibrosis after initiation continues to propagate in the absence of an inflammatory stimulus. Since many Crohn's patients develop complications of fibrosis, understanding the mechanisms of auto-propagation of fibrosis and developing anti-fibrotic therapies is critical to improving outcomes in Crohn's disease.

W1851 BPC 157 Reduced Postoperative Adhesion Formation in Rats

Background: Intestinal scarring is a major cause of morbidity in Crohn's disease. Current therapies treat inflammation, but do not alter the progression of fibrosis and bowel obstruction. Given the observation that late use of potent anti-inflammatory therapies does not reduce stenosis or obstruction, we hypothesized that intestinal fibrosis becomes self-propagating, despite removal of inflammatory stimuli. Methods: The Salmonella typhimurium murine model of inflammation and fibrosis in which clearance of commensal microbiota by streptomycin, followed by infection with S. typhimurium, produces chronic inflammation, culminating with fibrosis by day 21 post infection was used. The inflammatory stimulus (S. typhimurium) was removed with the oral antibiotic levofloxacin at day 2, 4, or 8 post-infection. Eradication of S.typhimurium was confirmed by stool plating and T-RFLP analysis. Results: By day 2 post-infection, the mouse cecae infected with S.typhimurium developed an inflammatory phenotype, characterized by a shrunken yet heavier cecum, expansion of the cecal submucosa, and induction of inflammatory genes (IL-1b, TNFa, IL-6, IL-17, IL12p40). However, fibrotic gene expression (CTGF, IGF-1, TGFb) was indistinguishable from uninfected controls. In addition, aSMA protein expression was not induced until day 8 postinfection. Early intervention (day 2 & 4) repressed inflammation as determined by gross pathology, histopathology, and repression of inflammatory genes. Fibrotic gene expression was partially repressed by day 2 levofloxacin treatment. However, day 8 levofloxacin treatment did not prevent induction of aSMA protein or pro-fibrotic genes (CTGF, IGF-1, TGFb) by day 8 and which continued to increase after levofloxacin treatment to day 21, remaining significantly higher than uninfected controls or matched S.typhimurium infected mice harvested at day 4 and 8 post-infection (p < 0.03) Conclusions: Early removal of the inflammatory stimulus reduces fibrosis, but fibrosis after initiation continues to propagate in the absence of an inflammatory stimulus. Since many Crohn's patients develop complications of fibrosis, understanding the mechanisms of auto-propagation of fibrosis and developing anti-fibrotic therapies is critical to improving outcomes in Crohn's disease.

W1849 Late Removal of Inflammatory Stimulus Does Not Abrogate Fibrosis Development In Vivo in a Mouse Model of Inflammation and Fibrosis

Background: Intestinal scarring is a major cause of morbidity in Crohn's disease. Current therapies treat inflammation, but do not alter the progression of fibrosis and bowel obstruction. Given the observation that late use of potent anti-inflammatory therapies does not reduce stenosis or obstruction, we hypothesized that intestinal fibrosis becomes self-propagating, despite removal of inflammatory stimuli. Methods: The Salmonella typhimurium murine model of inflammation and fibrosis in which clearance of commensal microbiota by streptomycin, followed by infection with S. typhimurium, produces chronic inflammation, culminating with fibrosis by day 21 post infection was used. The inflammatory stimulus (S. typhimurium) was removed with the oral antibiotic levofloxacin at day 2, 4, or 8 post-infection. Eradication of S.typhimurium was confirmed by stool plating and T-RFLP analysis. Results: By day 2 post-infection, the mouse cecae infected with S.typhimurium developed an inflammatory phenotype, characterized by a shrunken yet heavier cecum, expansion of the cecal submucosa, and induction of inflammatory genes (IL-1b, TNFa, IL-6, IL-17, IL12p40). However, fibrotic gene expression (CTGF, IGF-1, TGFb) was indistinguishable from uninfected controls. In addition, aSMA protein expression was not induced until day 8 postinfection. Early intervention (day 2 & 4) repressed inflammation as determined by gross pathology, histopathology, and repression of inflammatory genes. Fibrotic gene expression was partially repressed by day 2 levofloxacin treatment. However, day 8 levofloxacin treatment did not prevent induction of aSMA protein or pro-fibrotic genes (CTGF, IGF-1, TGFb) by day 8 and which continued to increase after levofloxacin treatment to day 21, remaining significantly higher than uninfected controls or matched S.typhimurium infected mice harvested at day 4 and 8 post-infection (p < 0.03) Conclusions: Early removal of the inflammatory stimulus reduces fibrosis, but fibrosis after initiation continues to propagate in the absence of an inflammatory stimulus. Since many Crohn's patients develop complications of fibrosis, understanding the mechanisms of auto-propagation of fibrosis and developing anti-fibrotic therapies is critical to improving outcomes in Crohn's disease.

Toll-Like Receptor 3 Agonist Protection against ExperimentalFrancisella tularensisRespiratory Tract Infection

We investigated whether Toll-like receptor 3 (TLR3) stimulation would protect the host from inhaled Francisella tularensis. TLR3 is expressed by respiratory epithelial cells and macrophages and can be activated by a synthetic double-stranded RNA ligand called polyinosine-polycytosine [poly(I:C)]. Thus, we evaluated poly(I:C) as a novel treatment against inhaled F. tularensis. In vivo, BALB/c mice intranasally (i.n.) treated with poly(I:C) (100 microg/mouse) 1 h before or after Schu 4 or LVS (100 CFU) i.n. challenge showed that poly(I:C) treatment significantly reduced bacterial load in the lungs (P < 0.05). Bronchoalveolar lavage from poly(I:C)-treated mice alone or combined with F. tularensis infection significantly increased cytokine secretion and enhanced neutrophil influx to lung tissues. Poly(I:C) responses were transient but significantly prolonged the survival of treated mice after i.n. F. tularensis challenge relative to mock treated animals. This prolonged survival providing a longer window for initiation of levofloxacin (LEVO) treatment (40 mg/kg). Animals treated with poly(I:C), challenged with F. tularensis, and then treated with LEVO 5 days later had 100% survival relative to 0% survival in animals receiving LEVO alone. Mechanistically, poly(I:C) given to human monocyte-derived macrophages before or after Schu 4 or LVS challenge (multiplicity of infection, 20:1) had significantly reduced intracellular bacterial replication (P < 0.05). These data suggest that poly(I:C) may represent a potential therapeutic agent against inhaled F. tularensis that prolongs survival and the opportunity to initiate standard antibiotic therapy (i.e., LEVO).

Levofloxacin-Induced Achilles Tendinitis in a Young Adult in the Absence of Predisposing Conditions

Fluoroquinolones (FQs) represent a major class of antimicrobials that have a high potential as therapeutic agents. Although FQs are generally safe for the use as antimicrobials, they may induce tendinopathic complications such as tendinitis and tendon rupture. A number of factors have been suggested to further predispose a patient to such injuries. Hitherto, a few published cases on tendon disorders have implicated levofloxacin, a more recently introduced FQ. Here, we report a patient with levofloxacin-induced Achilles tendinitis, who exhibited no known predisposing factors. A 20-year-old man without any history of disease or medication presented with community-acquired pneumonia. Levofloxacin was administered and 3 days later, he complained of pain in the left Achilles tendon and revealed redness and swelling in the area. On suspecting Achilles tendinitis, levofloxacin treatment was discontinued, and the tendinitis subsequently improved. To our knowledge, this is the first case report on FQ-induced Achilles tendinitis in Korea.

Hospital visits and costs following outpatient treatment of CAP with levofloxacin or moxifloxacin

Background:Hospital admissions (inpatient and emergency room) are a major source of medical costs for community-acquired pneumonia (CAP) initially treated in the outpatient setting. Current CAP treatment guidelines do not differentiate between outpatient treatment with levofloxacin and moxifloxacin.Objective:Compare health care resource use and medical costs to payers for CAP outpatients initiating treatment with levofloxacin or moxifloxacin.Research design and methods:CAP episodes were identified in the PharMetrics database between 2Q04 and 2Q07 based on: pneumonia diagnosis, chest X-ray and treatment with levofloxacin or moxifloxacin. Subsequent 30-day risk of pneumonia-related hospital visits and 30-day health care costs to payers for levofloxacin vs. moxifloxacin treatment were estimated after adjusting for pre-treatment demographics, health care resource use and pneumonia-specific risk factors using propensity score and exact factor matching.Results:A total of 15,472 levofloxacin- and 6474 moxifloxacin-initiated CAP patients were identified. Among 6352 matched pairs, levofloxacin treatment was associated with a 35% reduction in the odds of pneumonia-related hospital visits (odds ratio = 0.65, P = 0.004), lower per-patient costs for pneumonia-related hospital visits ($102 vs. $210, P = 0.001), lower pneumonia-related total costs (medical services and prescription drugs, $363 vs. $491, P < 0.001) and lower total costs ($1308 vs. $1446, P < 0.001) vs. moxifloxacin over the 30-day observation period.Limitations:Although observational analyses of claims data provide large sample sizes and reflect routine care, they do have several inherent limitations. Since randomization of subjects is not possible, adequate statistical techniques must be used to ensure that patient characteristics are well-balanced between treatment groups. In addition, data may be missing or miscoded.Conclusions:CAP outpatients initiated with levofloxacin generated substantially lower costs to payers compared to matched patients initiated with moxifloxacin. The cost savings for patients initiated with levofloxacin were largely attributable to reduced rates of pneumonia-related hospitalization or ER visits.

Doxycycline vs. levofloxacin in the treatment of community-acquired pneumonia

Community-acquired pneumonia (CAP) affects 5-10 million adults annually in the United States with approximately 1.1 million hospitalizations. Current guidelines recommend fluoroquinolones as monotherapy for treatment of CAP in general medical wards and doxycycline monotherapy for outpatient therapy only. Fluoroquinolones are expensive and development of bacterial resistance to them has become a concern. Therefore, we studied whether doxycycline is as efficacious as levofloxacin in treatment of CAP in general medical wards. In this prospective double-blinded trial, non-pregnant adults with clinical and radiological evidence of pneumonia requiring hospitalization were enrolled. Patients who were septic, hypoxic requiring intubations, nursing home residents, diagnosed with severe hepatic or renal dysfunction, recently hospitalized or immunocompromised were excluded from the study. Subjects were randomly assigned to either i.v. levofloxacin 500 mg daily or doxycycline 100 mg twice daily. After discharge, patients were followed for 2 months. There were 30 patients in the levofloxacin group and 35 patients in the doxycycline group. Groups were comparable in both clinical and laboratory profiles. Additionally, efficacy of treatment was not significantly different between the two groups (P = 0.844). Length of stay was 5.7 +/- 2.05 days in the levofloxacin group and 4.0 +/- 1.82 days in the doxycycline group (P < 0.0012). Failure rate was similar in both groups (P = 0.893). Total antibiotic cost was $122.07 +/- 15.84 for levofloxacin and $64.98 +/- 24.4 for doxycycline (P < 0.0001). Our study supports doxycycline as an effective and economical alternative therapy for levofloxacin in the empirical treatment of CAP in general medical wards.

Biofilm dispersal of community‐associated methicillin‐resistant Staphylococcus aureus on orthopedic implant material

Orthopedic implant-related bacterial infections are associated with high morbidity that may lead to limb amputation and exert significant financial burden on the healthcare system. Staphylococcus aureus is a dominant cause of these infections, and increased incidence of community-associated methicillin-resistant S. aureus (CA-MRSA) is being reported. The ability of S. aureus to attach to the foreign body surface and develop a biofilm is an important determinant of resistance to antibiotic prophylaxis. To gain insight on CA-MRSA biofilm properties, USA300 biofilm maturation and dispersal was examined, and these biofilms were found to exhibit pronounced, quorum-sensing mediated dispersal from a glass surface. For comparison of biofilm maturation on different surface chemistries, USA300 biofilm growth was examined on glass, polycarbonate, and titanium, and minimal differences were apparent in thickness, total biomass, and substratum coverage. Importantly, USA300 biofilms grown on titanium possessed a functional dispersal mechanism, and the dispersed cells regained susceptibility to rifampicin and levofloxacin treatment. The titanium biofilms were also sensitive to proteinase K and DNaseI, suggesting the matrix is composed of proteinaceous material and extracellular DNA. These studies provide new insights on the properties of CA-MRSA biofilms on implant materials, and indicate that quorum-sensing dispersion could be an effective therapeutic strategy.

Urinary Bactericidal Activity of Doripenem versus That of Levofloxacin in Patients with Complicated Urinary Tract Infections or Pyelonephritis

The aim of this study was to investigate the urinary bactericidal titers (UBTs) and 24-h area under the UBT-versus-time curve (AUBT) of intravenous doripenem (500 mg every 8 h [q8h]), a new carbapenem, versus those of intravenous levofloxacin (250 mg q24h) in patients with complicated urinary tract infections (cUTIs) or pyelonephritis. UBTs and AUBTs are pharmacokinetic/pharmacodynamic parameters able to reflect the activity of an antimicrobial substance in the urine. Doripenem and levofloxacin show comparable urinary excretion of approximately 80% and are therefore registered for the treatment of UTIs. In order to assess and compare the urinary antimicrobial activities of the two substances, UBTs were investigated for 24 patients (10 treated with doripenem and 14 with levofloxacin) for 31 uropathogens and one control strain. Eight strains were tested for all patients and 27 only in the urine of the corresponding patient. Median UBTs (AUBTs) of doripenem for the uropathogens tested ranged between 1.5 and 65,536 (224 and 909,312) and were significantly higher than median UBTs (AUBTs) of levofloxacin, ranging between 0 and 128 (0 and 2,208). Eight microbiological failures were observed, three after doripenem treatment and five after levofloxacin treatment. For levofloxacin, microbiological failures correlated well with low UBTs and AUBTs, whereas for doripenem there was no correlation. From this study, a calculated target attainment rate for levofloxacin predicting therapeutic success in patients with UTIs approximated mean UBTs of 100 over 24 h or AUBTs of 2,240. Doripenem demonstrated excellent urinary bactericidal activity with the dose administered and appears to be a good alternative in the empirical treatment of cUTI.

Levofloxacin rescues mice from lethal intra-nasal infections with virulent Francisella tularensis and induces immunity and production of protective antibody

The ability to protect mice against respiratory infections with virulent Francisella tularensis has been problematic and the role of antibody-versus-cell-mediated immunity controversial. In this study, we tested the hypothesis that protective immunity can develop in mice that were given antibiotic therapy following infection via the respiratory tract with F. tularensis SCHU S4. We show that mice infected with a lethal dose of SCHU S4, via an intra-nasal challenge, could be protected with levofloxacin treatment. This protection was evident even when levofloxacin treatment was delayed 72 h post-infection. At early time points after levofloxacin treatment, significant numbers of bacteria could be recovered from the lungs and spleens of mice, which was followed by a dramatic disappearance of bacteria from these tissues. Mice successfully treated with levofloxacin were later shown to be almost completely resistant to re-challenge with SCHU S4 by the intra-nasal route. Serum antibody appeared to play an important role in this immunity. Normal mice, when given sera from animals protected by levofloxacin treatment, were solidly protected from a lethal intra-nasal challenge with SCHU S4. The protective antiserum contained high titers of SCHU S4-specific IgG2a, indicating that a strong Th1 response was induced following levofloxacin treatment. Thus, this study describes a potentially valuable animal model for furthering our understanding of respiratory tularemia and provides suggestive evidence that antibody can protect against respiratory infections with virulent F. tularensis.

Levofloxacin plus rifampicin conservative treatment of 25 early staphylococcal infections of osteosynthetic devices for rigid internal fixation

Therapeutic conclusions for staphylococcal implant infections treated with debridement and implant retention can only be drawn from a small series. To this aim, data from patients with implant staphylococcal infections (1998–2006) treated with debridement and implant retention were retrospectively reviewed. Infections were defined by staphylococci isolation (two or more consecutive debridement or three sinus tract discharge samples) along with clinical criteria. Patients received oral levofloxacin plus rifampicin for ≥6 weeks after the resolution of signs/symptoms and C-reactive protein normalisation. Failure was defined as lack of response or recurrence of signs/symptoms and/or sinus tract bacterial isolation during therapy or follow-up and/or implant removal. Twenty-five patients (53.2 ± 20.8 years; 48% males) were included, 12 with spinal infections and 13 with limb implant infections. Diagnosis was performed from debridement material (72%) and sinus tract discharge (28%) (11 Staphylococcus aureus and 14 coagulase-negative staphylococci (CoNS)). Time from surgery to symptom onset was higher in CoNS infections compared with S. aureus infections (21.6 ± 9.3 days vs. 12.6 ± 5.2 days; P = 0.007). Seven patients (28%) were failures, with no differences between cured patients with respect to age, sex, infection site, time from surgery to symptom onset, sinus tract diagnosis and aetiology. Longer symptom duration prior to attendance was observed in failures (5.7 ± 6.2 months vs. 1.4 ± 0.6 months; P = 0.04). Levofloxacin plus rifampicin showed efficacy in implant infections, which was higher for short duration of symptoms.

A Randomized Comparative Study of Levofloxacin Versus Amoxicillin/Clavulanate for Treatment of Infants and Young Children With Recurrent or Persistent Acute Otitis Media

The need for alternative antimicrobial therapy for recurrent and persistent acute otitis media (AOM) in children has raised interest in assessing the efficacy and safety of fluoroquinolones for treatment of these infections. In an evaluator-blinded, active-comparator, noninferiority, multicenter study, children (6 months to <5 years) were randomized 1:1 to receive levofloxacin (10 mg/kg twice daily) or amoxicillin/clavulanate (14:1; amoxicillin 45 mg/kg twice daily) for 10 days, with evaluations 4-6 days of therapy (visit 2), 2-5 days after completing therapy (visit 3), and 10-17 days after last dose (visit 4). Primary outcome was clinical cure at visit 3 based on resolution of clinical signs and symptoms of AOM. A total of 1650 children were randomized and 1305 were clinically evaluable at visit 3 (630 levofloxacin, 675 comparator). Clinical cure rates were 72.4% (456 of 630) in levofloxacin-treated and 69.9% (472 of 675) in amoxicillin/clavulanate-treated children. Cure rates were also similar for levofloxacin and comparator for each age group (< or =24 months: 68.9% versus 66.2%; >24 months: 76.9% versus 75.1%; respectively). Cure rates at visit 4 were 74.9% and 73.8% in levofloxacin and amoxicillin/clavulanate groups, respectively. The upper limits of the confidence intervals were less than the noninferiority margin of 10% indicating that levofloxacin treatment is noninferior to comparator treatment overall and in both infants (6 months to 2 years) and children 2-5 years. No differences between treatment groups regarding the frequency or type of adverse events were apparent. Levofloxacin was not inferior to amoxicillin/clavulanate for the treatment of recurrent and/or persistent AOM in infants and children.

A High-Throughput In Vitro Model Illustrating Potential Microbiological Interactions During Treatment of Pseudomonas Aeruginosa Biofilm Associated Infections

Objective: Amend a real-time, high-throughput method of bacterial growth detection for use as a model of biofilm response to co-administered pharmaceuticals during the treatment of devise associated infections. Background: Biofilms are the root etiology for chronic infections, particularly in regard to infections in patients with implanted medical devices. Calcium channel blockers (CCBs) are used for control of hypertension and angina and are commonly prescribed to elderly patients. We address potential interference of commonly prescribed CCBs with levofloxacin for treatment of Pseudomonas aeruginosa biofilms. Methods: Inoculum of 1–3×106CFU∕mL in the log phase were seeded into each well of a polystyrene plate. Biofilms developed over 6h at 37°C, was washed and medium containing various CCBs plus levofloxacin was added to the biofilm. OD measurements were obtained at 1h intervals over 90h at 37°C. Changes in turbidity were kinetically measured with a vertical photometer with a wide-band filter. Results: Mibefradil and diltiazem appear to be strongly antagonistic toward levofloxacin where both of them decrease antibiofilm effect of levofloxacin and they encourage the selection of resistant mutants from biofilm. Discussion: Implanted medical devices are quite common and are subjected to biofilm infections. Increasing multi-drug resistance underscores the need to conserve current antibiotics by judicious use. This necessitates consideration of evidence regarding antagonistic or synergistic activity of commonly prescribed drugs of different classes toward commonly used antibiotics. The combinations described here show vital and previously unreported effects of some CCBs when co-prescribed with levofloxacin on Pseudomonas aeruginosa biofilm.