In Vitro Synergy of Pongamia pinnata Extract in Combination with Antibiotics for Inhibiting and Killing Methicillin-Resistant Staphylococcus aureus.

AIMS: Currently, we face the serious problem of multiple drug-resistant pathogens. The development of new antimicrobial agents is very costly and time-consuming. Therefore, the use of medicinal plants as a source of alternative antibiotics or for enhancing antibiotic effectiveness is important. METHODS: The antibacterial effects of aqueous extracts of the seed coat of Pongamia pinnata (Linn.) Pierre in combination with several antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) were tested by broth dilution, checkerboard, and time-kill methods. RESULTS: For the combinations of P. pinnata with ampicillin, meropenem, cefazolin, cefotaxime, cefpirome, and cefuroxime, 70% to 100% were synergistic, with a fractional inhibitory concentration (FIC) index of < 0.5. For the time-kill method with 0.5× minimum inhibitory concentration (MIC) of P. pinnata in combination with 8, 4, 2, and 1 µg mL-1 of the various antibiotics, almost all of the combinations showed synergistic effects, even with the lowest concentrations of P. pinnata, except for aztreonam. No antagonistic effect was observed for these combinations. CONCLUSIONS: Based on these findings, aqueous seed coat extracts of P. pinnata have good potential for the design of new antimicrobial agents.

Treatment outcome of non-carbapenemase-producing carbapenem-resistant Klebsiella pneumoniae infections: a multicenter study in Taiwan.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections are associated with high mortality, and experiences with its treatment are usually based on carbapenemase-producing strains. Non-carbapenemase-producing CRKP is of clinical significance, but relevant studies are lacking. This nationwide study aimed to evaluate the outcome of antimicrobial therapy in patients with non-carbapenemase-producing CRKP infections. Patients with non-carbapenemase-producing CRKP infections were enrolled from 16 hospitals during January 2013 to December 2014 in Taiwan. Carbapenem resistance was defined as reduced susceptibility with a minimum inhibitory concentration of ≥2 mg/L for imipenem or meropenem. The resistance mechanisms of CRKP isolates were analyzed, and the clinical data of these patients were collected retrospectively. Independent risk factors of 14-day morality were determined by Cox regression analysis. A total of 99 patients with non-carbapenemase-producing CRKP infections were enrolled, and 14-day mortality was 27.3%. Among 67 patients treated with appropriate antimicrobial therapy, most (n = 61) patients received monotherapy. The 14-day mortality was lower in patients treated with appropriate monotherapy (21.3%) than in those with inappropriate therapy (37.5%). The multivariate regression model identified monotherapy (hazard ratio [HR], 0.30; 95% confidence interval [CI], 0.13-0.71; P = 0.005) as protective factor, and APACHE II scores (HR, 1.09; 95% CI, 1.01-1.18; P = 0.022) as risk factor associated with 14-day mortality. Tigecycline, colistin, and carbapenem were the most commonly used drugs in monotherapy. This study provides evidence supporting the efficacy of monotherapy in the treatment of non-carbapenemase-producing CRKP infections, and provides a future target for antibiotics stewardship for CRKP infection.

In vitro and in vivo antibacterial activity of tigecycline against Vibrio vulnificus.

BACKGROUND/PURPOSE: The aim of this study is to investigate the role of tigecycline in Vibrio vulnificus infection. METHODS: Eight randomly selected clinical V. vulnificus isolates were studied to obtain the minimal inhibitory concentrations (MICs) of minocycline, cefotaxime, and tigecycline, and the time-kill curves of tigecycline alone or in combination with other drugs. A peritonitis mouse model was used for the evaluation of the therapeutic efficacy of tigecycline alone or cefotaxime in combination with minocycline or tigecycline. RESULTS: The MIC of minocycline, cefotaxime, and tigecycline for eight clinical V. vulnificus isolates was 0.06-0.12 µg/mL, 0.03-0.06 µg/mL, and 0.03-0.06 µg/mL, respectively. In time-killing studies, at the concentration of 1 × MIC, the inhibitory effect of tigecycline persisted for 24 hours in five of eight isolates. With 2 × MIC and trough level, the inhibitory effect was noted in all isolates for 24 hours. With the combination of minocycline plus cefotaxime and tigecycline plus cefotaxime at 1/2 × MIC, the bactericidal effect was noted in 25% and 62.5% of eight isolates and synergism in 50% and 75% of isolates. With a low (1.25 × 105 CFU/mL) inoculum, all infected mice survived with tigecycline alone, tigecycline plus cefotaxime, or minocycline plus cefotaxime on the 14th day. At the inoculum of 1.25 × 106 CFU, the survival rate was 33.3% on the 14th day in the tigecycline plus cefotaxime-treated group, but none of the mice treated by tigecycline alone or minocycline plus cefotaxime survived (33.3% vs. 0%, p = 0.01 by Fisher's exact test). CONCLUSION: Our in vitro combination and animal studies indicate that tigecycline could be an option for the treatment of invasive V. vulnificus infections.

Comparison of synergism between colistin, fosfomycin and tigecycline against extended-spectrum ß-lactamase-producing Klebsiella pneumoniae isolates or with carbapenem resistance.

PURPOSE: To investigate the synergistic and bactericidal effects of antimicrobial combinations of any two of colistin, fosfomycin and tigecycline against the nine extended-spectrum ß-lactamase (ESBL)-producing Klebsiella pneumoniae (KP) clinical isolates, including 4 carbapenem-susceptible strains and five imipenem and/or meropenem-resistant strains. METHODS: In vitro synergism and bactericidal activity of combination of colistin, fosfomycin and tigecycline were evaluated by time-kill studies in standard inoculum of bacterial densities of a suspension containing 5 × 105 CFU/mL by using 1/2× MIC for each alone, and both 1/2× and 1/4× MIC for any two drugs. The settings of low MIC dosing were allowed to rapidly survey the most active drug combination. RESULTS: The most active combination group was colistin plus tigecycline, showing synergy in 8 isolates and bactericidal activities in 6 isolates by using concentrations of 1/2× MIC and 1/4× MIC, respectively. The least active combination was tigecycline plus fosfomycin, which showed synergy in only 4 isolates and no bactericidal activities by using concentrations of 1/2× MIC and 1/4× MIC, respectively. CONCLUSIONS: The combination of tigecycline and colistin may be considered as a last-resort approach to the ESBL-producing KP infections, especially those isolates with carbapenem resistance.

Improved survival in patients with severe tuberculosis after exposure to fluoroquinolones.

BACKGROUND: The clinical impact of prior exposure to antibiotics on patients with tuberculosis (TB) is largely unknown. This study investigated the survival of patients with severe TB after exposure to a variety of antibiotics. METHODS: A retrospective cohort study was conducted in TB patients with prior exposure to fluoroquinolones (FQs) (FQ group), to third-generation cephalosporins (CEPH group), and to third-generation penicillins (PCN group). To understand the impact of monotherapy with antibiotics on survival, patients with prior exposure to only moxifloxacin, ceftriaxone, or piperacillin were investigated. RESULTS: Patients in the FQ group (N= 401) had a significantly higher survival rate (82.5%) than patients in the CEPH (N = 210) and PCN (N = 172) groups (67.6% and 62.8%, respectively; both p < 0.0001) at 180 d after TB diagnosis. Adjusted odds ratio (AOR) logistic regression analysis demonstrated that patients in the FQ group had significantly more favourable outcomes than those in the CEPH and PCN groups in terms of intensive care unit (ICU) admission rate (versus CEPH cohort: AOR, 1.70; 95% CI: 1.16-2.50; p = 0.0067, versus PCN cohort: AOR, 3.58; 95% CI: 2.42-5.29; both p < 0.0001), mechanical ventilation rate (versus CEPH cohort: AOR, 1.70; 95% CI: 1.09-2.66; p = 0.0205, versus PCN cohort: AOR, 3.92; 95% CI: 2.54-6.05; both p < 0.0001), and acute respiratory failure rate (versus CEPH cohort: AOR, 1.62; 95% CI: 1.07-2.45; p = 0.0223, versus PCN cohort: AOR, 4.29; 95% CI: 2.86-6.43; both p < 0.0001). TB patients with prior exposure to moxifloxacin (N = 198) had a significantly higher survival rate (85.9%) than that of patients with exposure to ceftriaxone (N = 119) and piperacillin (N = 172) monotherapy (survival rates: 69.8% and 62.8%, respectively; both p < 0.001). CONCLUSIONS: TB patients with prior exposure to FQs had more favourable outcomes compared with patients who had prior exposure to third-generation cephalosporins or third-generation penicillins. This study provides new insights into the impact of previous exposure to FQs on the survival of TB patients.

RNA polymerase B subunit gene mutations in biofilm-embedded methicillin-resistant Staphylococcus aureus following rifampin treatment.

BACKGROUND/PURPOSE: This study was conducted to compare the mutation rates of different rpoB sites and rifampin minimum inhibitory concentration (MIC) changes prior to and after rifampin therapy for biofilm-embedded methicillin-resistant Staphylococcus aureus (MRSA) isolates. METHODS: The screening of rifampin-resistant MRSA isolates, from the biofilm at Day 5 with or without exposure to the susceptible breakpoint concentration of rifampin recommended by the Clinical and Laboratory Standards Institute (1 mg/L), was conducted using agar plates containing rifampin. A partial fragment of RNA polymerase B subunit gene (rpoB), including clusters I and II, was amplified and sequenced. The rifampin MIC values and mutation frequencies at different sites of rpoB were measured and evaluated in rifampicin-resistant isolates. RESULTS: Rifampin-resistant mutants could be selected from all of 39 randomly selected rifampin-susceptible MRSA isolates in the biofilm model. The spontaneous mutation frequency ranged from 1.00 × 10(-4) to 3.85 × 10(-7). Mutation at codon 481 was most commonly found at 35 (89.7%) of 39 MRSA isolates. Without rifampin induction, the MIC ranged between 0.125 mg/L and1024 mg/L and mutation sites included cluster I 464, 466, 468, 471, 474, 477, 481, 484, 486 and cluster II 519, 527, 529 with the percentage of 471 (35.9%), 477 (33.3%), 481 (53.8%), and 484 (35.9%). Conversely, with the induction of rifampin, the MIC value ranged ∼256-1024 mg/L. The mutation sites that were more concentrated included 468 (17.9%), 477 (30.8%), 481 (89.7%), 484 (17.9%), and 486 (33.3%). CONCLUSION: We documented high rifampin resistance induction activity when MRSA was engaged in biofilm with rifampin exposure. Monotherapy seems to be inadequate for MRSA in biofilm. There is an urgent need for developing effective combination therapies with less rifampin resistance-inducing activities for treating MRSA in biofilms.

Efficacy of Appropriate Antimicrobial Therapy on the Survival of Patients With Carbapenem Nonsusceptible Klebsiella Pneumoniae Infection: A Multicenter Study in Taiwan.

The impact of antimicrobial treatment on the outcome of carbapenem nonsusceptible Klebsiella pneumoniae (CnsKP) infections needs to be elucidated. This nationwide, multicenter study was conducted to evaluate the impact of appropriate antimicrobial therapy on 14-day mortality among patients with CnsKP infection in Taiwan.Patients with CnsKP infections from 11 medical centers and 4 regional hospitals in Taiwan were enrolled in 2013. Carbapenem nonsusceptibility was defined as a minimum inhibitory concentration of ≥2 mg/L for imipenem or meropenem. Predictors of 14-day mortality were determined using the Cox proportional regression model. The influence of infection severity on the impact of appropriate use of antimicrobials on 14-day mortality was determined using the Acute Physiology and Chronic Health Evaluation (APACHE) II score.Overall 14-day mortality was 31.8% (49/154). Unadjusted mortality for appropriate antimicrobial therapy was 23.1% (18/78 patients). Appropriate therapy was independently associated with reduced mortality (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.24-0.80; P = 0.007). A subgroup analysis revealed that the benefit of appropriate therapy was limited to patients with higher APACHE II scores (HR for patients with scores >15 and ≤35, 0.46; 95% CI 0.23-0.92; and for those with scores >35, 0.14; 95% CI, 0.02-0.99).In conclusion, appropriate antimicrobial therapy significantly reduces 14-day mortality for CnsKP infections. Survival benefit is more notable among more severely ill patients.

Carbapenems and piperacillin/tazobactam for the treatment of bacteremia caused by extended-spectrum ß-lactamase-producing Proteus mirabilis.

This study was intended to delineate the role of carbapenems and piperacillin/tazobactam in treating bacteremia caused by extended-spectrum ß-lactamase (ESBL)-producing Proteus mirabilis. We performed a multicenter and retrospective study of the patients with ESBL-producing P. mirabilis bacteremia. The outcomes of the patients treated by piperacillin/tazobactam or a carbapenem for at least 48 hours and the MICs of the prescribed drugs for these isolates were analyzed. Forty-seven patients with available clinical data were included. The overall 30-day mortality rate was 29.8%. All available isolates (n = 44) were susceptible to ertapenem, meropenem, and doripenem, and 95.6% were susceptible to piperacillin/tazobactam; however, only 11.4% of the isolates were susceptible to imipenem. Among the 3 patients infected with isolates exhibiting non-susceptibility to imipenem (MIC ≥2 mg/L) who were treated with imipenem, none died within 28 days. The 30-day (14.3% versus 23.1%, P = 0.65) or in-hospital (19.1% versus 30.8%, P = 0.68) mortality rate of 21 patients treated by a carbapenem was lower than that of 13 treated by piperacillin/tazobactam. However, among those treated by piperacillin/tazobactam, the mortality rate of those infected by the isolates with lower piperacillin/tazobactam MICs (≤0.5/4 mg/L) was lower than that of the isolates with MICs of ≥1/4 mg/L (0%, 0/7 versus 60%, 3/5; P = 0.045). ESBL-producing P. mirabilis bacteremia is associated with significant mortality, and carbapenem therapy could be regarded as the drugs of choice. The role of piperacillin/tazobactam, especially for the infections due to the isolates with an MIC ≤0.5/4 mg/L, warrants more clinical studies.

Short-term glutamine supplementation decreases lung inflammation and the receptor for advanced glycation end-products expression in direct acute lung injury in mice.

BACKGROUND: Glutamine (GLN) has been reported to improve clinical and experimental sepsis outcomes. However, the mechanisms underlying the actions of GLN remain unclear, and may depend upon the route of GLN administration and the model of acute lung injury (ALI) used. The aim of this study was to investigate whether short-term GLN supplementation had an ameliorative effect on the inflammation induced by direct acid and lipopolysaccharide (LPS) challenge in mice. METHODS: Female BALB/c mice were divided into two groups, a control group and a GLN group (4.17% GLN supplementation). After a 10-day feeding period, ALI was induced by intratracheal administration of hydrochloric acid (pH 1.0; 2 mL/kg of body weight [BW]) and LPS (5 mg/kg BW). Mice were sacrificed 3 h after ALI challenge. In this early phase of ALI, serum, lungs, and bronchoalveolar lavage fluid (BALF) from the mice were collected for further analysis. RESULTS: The results of this study showed that ALI-challenged mice had a significant increase in myeloperoxidase activity and expression of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α in the lung compared with unchallenged mice. Compared with the control group, GLN pretreatment in ALI-challenged mice reduced the levels of receptor for advanced glycation end-products (RAGE) and IL-1ß production in BALF, with a corresponding decrease in their mRNA expression. The GLN group also had markedly lower in mRNA expression of cyclooxygenase-2 and NADPH oxidase-1. CONCLUSIONS: These results suggest that the benefit of dietary GLN may be partly contributed to an inhibitory effect on RAGE expression and pro-inflammatory cytokines production at an early stage in direct acid and LPS-induced ALI in mice.

Correlation between carbapenem consumption and resistance to carbapenems among Enterobacteriaceae isolates collected from patients with intra-abdominal infections at five medical centers in Taiwan, 2006-2010.

We investigated the trend in resistance to carbapenems among isolates of Enterobacteriaceae that had been collected from patients with intra-abdominal infections at five medical centers in Taiwan from 2006 to 2010 and evaluated the correlation between resistance to carbapenems and consumption of said agents as part of the Study for Monitoring Antimicrobial Resistance Trends (SMART). During the study period, the usage of ertapenem and that of total carbapenems (ertapenem, imipenem, and meropenem) increased significantly from 6.13 to 13.38 defined daily doses per 1000 patient-days for ertapenem and from 20.43 to 34.25 defined daily doses per 1000 patient-days for total carbapenems. The most common species were Escherichia coli (n = 1095), Klebsiella spp. (n = 663), and Enterobacter spp. (n = 202). The susceptibility of all isolates to ertapenem and to imipenem varied during the study period. For ertapenem, the rates of nonsusceptibility ranged from 3.5% to 10.3% and those for imipenem ranged from 3.5% to 10.7%. Although the use of carbapenems increased during the study period, there was no marked increase in resistance to carbapenems. Continuous monitoring of resistance trends is necessary so that antimicrobial prescription policies can be adjusted and infection control intervention programs can be implemented.

Use of Carbapenems against clinical, nontyphoid Salmonella isolates: results from in vitro and in vivo animal studies.

The emergence of multidrug-resistant Salmonella isolates has created the need for new therapeutic agents. We evaluated the intracellular activity of four carbapenem compounds against clinical nontyphoid Salmonella (NTS) isolates in vitro and ex vivo. Subsequently, the efficacy of carbapenem treatment against selected Salmonella isolates in vivo was assessed using a murine peritonitis model. The MIC(50) and MIC(90) for doripenem, ertapenem, imipenem, and meropenem against 126 NTS isolates were found to be 0.062 and 0.062, 0.015 and 0.015, 0.5 and 1, and 0.031 and 0.031 µg/ml, respectively. The intracellular killing effect of ertapenem was sustained for 24 h and was superior to that of imipenem, meropenem, and doripenem; its effect was comparable to that of ceftriaxone. Ertapenem demonstrated an excellent pharmacokinetic profile with a percent time above the MIC of 75.5% and an area under the concentration-time curve/MIC ratio of 20,733. When peritoneal exudate cells were examined directly ex vivo from mice with Salmonella-induced peritonitis, cells from mice treated with ertapenem and ceftriaxone had intracellular and extracellular bacterial counts reduced 10(2)- to 10(4)-fold and exhibited killing effects similar to each other. The survival rates of mice inoculated with 1 × 10(5) and 10(6) CFU of a ceftriaxone-susceptible Salmonella isolate that were subsequently treated with ertapenem or ceftriaxone were 100% and 90%, respectively. When mice were inoculated with 5 × 10(4) and 10(5) CFU of a ceftriaxone-resistant and ciprofloxacin-resistant Salmonella isolate, mice treated with ertapenem had a higher survival rate than mice treated with ceftriaxone (70% versus 0% and 50% versus 0%, respectively; P < 0.001). Our results suggest that ertapenem is at least as effective as ceftriaxone in treating murine Salmonella infections and show that further clinical investigations on the potential use of ertapenem in treatment of human Salmonella infections are warranted.

Efficacy and safety of tigecycline monotherapy compared with vancomycin-aztreonam in the treatment of complicated skin and skin structure infections in patients from India and Taiwan.

BACKGROUND: To compare the monotherapy of tigecycline with vancomycin-aztreonam in hospitalized patients from India and Taiwan with complicated skin and skin structure infections (cSSSIs). METHODS: Safety and efficacy data were analyzed for Indian (n = 86) and Taiwanese (n = 41) patients hospitalized with cSSSIs who participated in two international Phase 3, randomized, double-blind studies. RESULTS: Patients were treated for 5-14 days. Cure rates at the test-of-cure assessment (12-92 days post-therapy) were generally similar between tigecycline and vancomycin-aztreonam in the clinically evaluable populations (India, 83.3% vs. 75.8%; Taiwan, 78.6% vs. 90%) and in the clinical modified intent-to-treat populations (India, 78.6% vs. 66.7%; Taiwan, 73.3% vs. 75.0%). Nausea and vomiting occurred more frequently with tigecycline, but overall safety and tolerability were comparable between the two treatments. CONCLUSIONS: Tigecycline monotherapy is a safe and effective therapy for cSSSIs in geographically distinct populations in Asia.

Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia.

To compare efficacy and safety of a tigecycline regimen with an imipenem/cilastatin regimen in hospital-acquired pneumonia patients, a phase 3, multicenter, randomized, double-blind, study evaluated 945 patients. Coprimary end points were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure. Cure rates were 67.9% for tigecycline and 78.2% for imipenem (CE patients) and 62.7% and 67.6% (c-mITT patients), respectively. A statistical interaction occurred between ventilator-associated pneumonia (VAP) and non-VAP subgroups, with significantly lower cure rates in tigecycline VAP patients compared to imipenem; in non-VAP patients, tigecycline was noninferior to imipenem. Overall mortality did not differ between the tigecycline (14.1%) and imipenem regimens (12.2%), although more deaths occurred in VAP patients treated with tigecycline than imipenem. Overall, the tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT but not the CE population; this difference appears to have been driven by results in VAP patients.

Cefazolin plus minocycline against a clinical isolate of Vibrio vulnificus: in vitro and animal studies.

Cefotaxime plus minocycline has been shown to have synergistic activity against Vibrio vulnificus; however, the clinical role of cefazolin in combination with minocycline in immunocompromised hosts has not been established. Therefore, antimicrobial susceptibility of the V. vulnificus clinical isolate Vv05191 was studied by the agar dilution method. Antibacterial activity of cefazolin, minocycline, and a combination of the two drugs was investigated by time-kill studies in vitro and further examined for therapeutic efficacy in a murine model. When cefazolin at a combination of 4 mg/L (1/2 x MIC) was combined with minocycline at a concentration of 0.03 mg/L (1/2 x MIC), sustained inhibitory activity was noted until 24 h. In BALB/cByJ mice with cyclophosphamide-induced neutropenia, an inoculum of 1.5 x 10(8) CFU caused death within 96 h when the infected mice were treated by cefazolin (400 mg/kg every 3 h), while 6.3% of mice survived when treated by minocycline (4 mg/kg stat, then 2 mg/kg every 12 h). However, 62.5% of mice survived for 96 h when mice were treated by cefazolin (400 mg/kg every 3 h) plus minocycline (4 mg/kg stat, then 2 mg/kg every 12 h) (P = 0.002, log rank test). In conclusion, cefazolin in combination with minocycline exhibits in vitro synergistic antibacterial activity against V. vulnificus and provides a therapeutic advantage in neutropenic mice with V. vulnificus infection.

Sesame oil attenuates hepatic lipid peroxidation by inhibiting nitric oxide and superoxide anion generation in septic rats.

BACKGROUND: Sepsis is a major cause of mortality in the intensive care unit. Oxidative stress plays an important role in the pathogenesis of organ failure during sepsis. Sesame oil decreases circulating oxygen free radicals in septic rats; however, its effect on hepatic oxidative status is unknown. The authors examined the effect of sesame oil on hepatic lipid peroxidation in septic rats. METHODS: Hepatic injury was induced using cecal ligation and puncture (CLP). Rats were divided into 4 groups: sham, rats given a sham operation without CLP; SO, rats given sesame oil alone; CLP, rats given saline and then CLP; and CS, rats given sesame oil and then CLP. All rats were first given a 1-week daily oral supplement of sesame oil or saline (4 mL/kg/d) and then CLP or a sham operation. The authors assessed hepatic oxidative stress by determining hepatic lipid peroxidation, hydroxyl radical, superoxide anion, and nitric oxide levels 12 hours after CLP. They also assessed xanthine oxidase activity and nitric oxide synthase expression. RESULTS: Hepatic lipid peroxidation (P < .0001), hydroxyl radical (P < .05), superoxide anion (P < .05), and nitrite (P < .05) levels were significantly lower in sesame oil-treated septic rats. Furthermore, sesame oil significantly reduced xanthine oxidase activity (P < .01) and inducible nitric oxide synthase expression (P < .005) in septic rats. CONCLUSIONS: Sesame oil might attenuate hepatic lipid peroxidation by inhibiting superoxide anion and nitric oxide, at least partially, in experimental septic rats.

Comparing the protective effects of ciprofloxacin, moxifloxacin and levofloxacin in mice with lipopolysaccharide-induced acute lung injuries.

BACKGROUND AND OBJECTIVE: Ciprofloxacin, moxifloxacin and levofloxacin are recognized immunomodulators. Their effects in acute lung injuries have not been tested. This study compared the immunoprotective effects of these agents in mice with lung injuries induced by LPS by measuring the cytokine profiles in the injured lung and the associated mortality. METHODS: The development of lung injury and mortality was compared in mice pretreated with either ciprofloxacin, levofloxacin, moxifloxacin or saline (control group) after the intratracheal administration of LPS. BALF and serum were collected at 1, 3 and 6 h to measure the concentrations of tumour necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6, IL-10 and macrophage inflammatory protein-2 (MIP-2) using enzyme-linked immunoassay. RESULTS: Levels of TNF-alpha, IL-1beta and MIP-2 in the BAL of the ciprofloxacin group were significantly lower compared with those of controls (all P < 0.0083) at 3 and 6 h after LPS challenge. There were no significant differences in the levels of these cytokines in the moxifloxacin and levofloxacin groups compared with controls. Overall, the 96-h survival for the mice pretreated with ciprofloxacin, but not for those pretreated with moxifloxacin or levofloxacin, was significantly greater than that of the control animals (P = 0.019). CONCLUSIONS: In the setting of LPS-induced lung injuries, ciprofloxacin appears to provide better anti-inflammatory properties and survival benefits than the other fluoroquinolones tested.

Combination carbapenem-sulbactam therapy for critically ill patients with multidrug-resistant Acinetobacter baumannii bacteremia: four case reports and an in vitro combination synergy study.

Infections caused by multidrug-resistant Acinetobacter baumannii have become a therapeutic challenge for clinicians worldwide. Although colistin and tigecycline have been successful in treating patients with these infections, these agents are not available on a worldwide basis. We describe four critically ill patients in Taiwan who were diagnosed with multidrug-resistant Acinetobacter baumannii bacteremia. All bacterial isolates from these patients were resistant to commonly available antibiotics, including carbapenems and sulbactam; however, combination therapy with a carbapenem and sulbactam led to favorable clinical outcomes in all four patients. We also conducted an in vitro study using isolates from these patients that showed that this drug combination had a synergistic effect with enhanced antibacterial activity against the isolates. Thus, a carbapenem-sulbactam combination may be a therapeutic alternative for multidrug-resistant Acinetobacter baumannii bacteremia in countries where colistin and tigecycline are not available for clinical use.

Sesame oil attenuates acute iron-induced lipid peroxidation-associated hepatic damage in mice.

Acute iron intoxication from the accidental ingestion of iron-containing preparations is one important cause of death in children. The aim of this study was to investigate the protective effect of sesame oil on acute iron-induced lipid peroxidation (LPO) and hepatic injury in mice. Acute iron intoxication was induced by giving ferric nitrilotriacetate to mice. Hepatic function was assessed using blood biochemistry. Free radicals were determined using a high-performance chemiluminescence analyzer. Ferric nitrilotriacetate increased serum ferrous (Fe) and LPO levels, and induced acute hepatic injury. Sesame oil (a) dose-dependently decreased acute iron-induced LPO and hepatic injury, (b) reduced acute iron-associated hydroxyl radical and superoxide anion generation, and (c) inhibited the activity of xanthine oxidase in acute iron intoxication. Thus, sesame oil might ameliorate LPO and acute hepatic injury by inhibiting xanthine oxidase-initiated superoxide anion generation, thereby reducing hydroxyl radical production, at least partially, in acutely iron-intoxicated mice.

Prognostic factors and antibiotics in Vibrio vulnificus septicemia.

BACKGROUND: Immunocompromised patients with Vibrio vulnificus septicemia are at high risk for fatality. When a hemorrhagic bullous necrotic cutaneous lesion (HBNCL) and decreased blood pressure develop, approximately 50% of V vulnificus septicemic patients die within 48 hours. This study aimed to evaluate the risk factor(s) for fatality among patients with V vulnificus septicemia, emphasizing the role of prescribed antimicrobial agents in general and the therapeutic efficacy of the combination of a third-generation cephalosporin and tetracycline or its analogue in particular. METHODS: Patients with the diagnosis of V vulnificus infection admitted to 5 large medical centers in Taiwan between 1995 and 2003 were included in this retrospective study. Patients were divided into 2 groups: those without [corrected] HBNCLs (group 1) [corrected] and those with [corrected] HBNCLs (group 2) [corrected]Patients were further divided into subgoups with [corrected] fatalities (fatal subgroup) and those without fatalities (nonfatal subgroup). RESULTS: A total of 93 patients participated in the study. In group 1, the fatal subgroup had higher Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (P = .006) and a higher proportion of shock at arrival at the medical center (P = .015) than the nonfatal subgroup. In group 2, the effect of a first- or second-generation cephalosporin plus an aminoglycoside was negative (P = .01) and that of combined third-generation cephalosporin and tetracycline or its analogue was positive (P<.001); significant differences were found between the fatal and nonfatal subgroups in the APACHE II score (P<.001), number who were in shock at arrival at the medical center (P = .02), delayed surgical intervention (P = .03), and peripheral leukocytosis (P = .03). Shock at arrival at the medical center (odds ratio [OR], 19.25; 95% confidence interval [CI], 1.768-209.54; P = .02) was an independent risk factor for fatality in patients without HBNCLs. Use of a third-generation cephalosporin and tetracycline or its analogue significantly reduced fatality rates in patients with HBNCLs (OR, 0.037; 95% CI, 0.007-0.192; P<.001). CONCLUSION: Septic shock is a determinant of fatality in patients with V vulnificus septicemia without HBNCLs; our data suggest that the combination of a third-generation cephalosporin and tetracycline or its analogue may be a better choice in antimicrobial treatment of V vulnificus septicemic patients with HBNCLs.