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Trovafloxacin is a quinolone antibiotic drug with broad‐spectrum activity, which was withdrawn from a global market relatively soon after approval because of serious liver injury. The characteristics of trovafloxacin‐induced liver injury are consistent with an idiosyncratic reaction; however, the details of the mechanism have not been elucidated. We examined whether trovafloxacin induces the release of damage‐associated molecular patterns (DAMPs) that activate inflammasomes. We also tested ciprofloxacin, levofloxacin, gatifloxacin, and grepafloxacin for their ability to activate inflammasomes. Drug bioactivation was performed with human hepatocarcinoma functional liver cell‐4 (FLC‐4) cells, and THP‐1 cells (human monocyte cell line) were used for the detection of inflammasome activation. The supernatant from the incubation of trovafloxacin with FLC‐4 cells for 7 days increased caspase‐1 activity and production of IL‐1ß by THP‐1 cells. In the supernatant of FLC‐4 cells that had been incubated with trovafloxacin, heat shock protein (HSP) 40 was significantly increased. Addition of a cytochrome P450 inhibitor to the FLC‐4 cells prevented the release of HSP40 from the FLC‐4 cells and inflammasome activation in THP‐1 cells by the FLC‐4 supernatant. These results suggest that reactive metabolites of trovafloxacin can cause the release of DAMPs from hepatocytes that can activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by trovafloxacin, which, in some patients, can cause immune‐related liver injury. Trovafloxacin is a quinolone antibiotic drug, which was withdrawn from a global market because of serious liver injury. We investigated whether trovafloxacin or its reactive metabolites induces the release of damage‐associated molecular patterns (DAMPs) that activate inflammasomes. This study suggested that the reactive metabolites of trovafloxacin can cause the release of DAMPs from hepatocytes and activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by trovafloxacin. [ABSTRACT FROM AUTHOR]

TBI is a leading cause of death and disability in young people and older adults worldwide. There is no gold standard treatment for TBI besides surgical interventions and symptomatic relief. Post-injury infections, such as lower respiratory tract and surgical site infections or meningitis are frequent complications following TBI. Whether the use of preventive and/or symptomatic antibiotic therapy improves patient mortality and outcome is an ongoing matter of debate. In contrast, results from animal models of TBI suggest translational perspectives and support the hypothesis that antibiotics, independent of their anti-microbial activity, alleviate secondary injury and improve neurological outcomes. These beneficial effects were largely attributed to the inhibition of neuroinflammation and neuronal cell death. In this review, we briefly outline current treatment options, including antibiotic therapy, for patients with TBI. We then summarize the therapeutic effects of the most commonly tested antibiotics in TBI animal models, highlight studies identifying molecular targets of antibiotics, and discuss similarities and differences in their mechanistic modes of action. [ABSTRACT FROM AUTHOR]

• TVX induces autophagy through protein expression inhibition of mTOR signaling pathway. • The increased autophagy by TVX plays roles in protective function on TVX-induced cytotoxicity. • TNFα co-treatment with TVX enhances the cytotoxicity by inhibiting the autophagy through activating p70S6K. Trovafloxacin (TVX) is associated with idiosyncratic drug-induced liver injury (iDILI) and inflammation-mediated hepatotoxicity. However, the inflammatory stress-regulated mechanisms in iDILI remain unclear. Herein, we elucidated the novel role of tumor-necrosis factor alpha (TNFα), an inflammatory stress factor, in TVX-induced in vitro hepatotoxicity and synergistic toxicity. TVX specifically induced synergistic toxicity in HepG2 cells with TNFα, which inhibits autophagy. TVX-treated HepG2 cells induced protective autophagy by inhibiting the expression of mTOR signaling proteins, while ATG5 knockdown in HepG2 cells, responsible for the impairment of autophagy, enhanced TVX-induced toxicity due to the increase in cytochrome C release and JNK pathway activation. Interestingly, the expression of mTOR signal proteins, which were suppressed by TVX, disrupted the negative feedback of the PI3K/AKT pathway and TNFα rebounded p70S6K phosphorylation. Co-treatment with TVX and TNFα inhibited protective autophagy by maintaining p70S6K activity, which enhanced TVX-induced cytotoxicity. Phosphorylation of p70S6K was inhibited by siRNA knockdown and rapamycin to restore TNFα-inhibited autophagy, which prevented the synergistic effect on TVX-induced cytotoxicity. These results indicate that TVX activates protective autophagy in HepG2 cells exposed to toxicity and an imbalance in negative feedback regulation of autophagy by TNFα synergistically enhanced the toxicity. The finding from this study may contribute to a better understanding of the mechanisms underlying iDILI associated with inflammatory stress. [ABSTRACT FROM AUTHOR]

The fluoroquinolone trovafloxacin (TVX) is associated with a high risk of drug-induced liver injury (DILI). Although part of the liver damage by TVX+TNF relies on neutrophils, we have recently demonstrated that liver recruitment of monocytes and neutrophils is delayed by TVX. Here we show that the delayed leukocyte recruitment is caused by a combination of effects which are linked to the capacity of TVX to block the hemichannel pannexin 1. TVX inhibited find-me signal release in apoptotic HepG2 hepatocytes, decelerated freshly isolated human neutrophils toward IL-8 and f-MLF, and decreased the liver expression of ICAM-1. In blood of TVX+TNF-treated mice, we observed an accumulation of activated neutrophils despite an increased MIP-2 release by the liver. Depletion of monocytes and neutrophils caused increased serum concentrations of TNF, IL-6, and MIP-2 in TVX-treated mice as well as in mice treated with the fluoroquinolone levofloxacin, known to have a lower DILI-inducing profile. This supports the idea that early leukocyte recruitment regulates inflammation. In conclusion, disrupted regulation by leukocytes appears to constitute a fundamental step in the onset of TVX-induced liver injury, acting in concert with the capability of TVX to induce hepatocyte cell death. Interference of leukocyte-mediated regulation of inflammation represents a novel mechanism to explain the onset of DILI. [ABSTRACT FROM AUTHOR]

Abstract: Idiosyncratic drug‐induced liver injury (iDILI) has a poorly understood pathogenesis. However, iDILI is often associated with inflammatory stress signals in human patients as well as animal models. Tumor necrosis factor (TNF) and neutrophils play a key role in onset of trovafloxacin (TVX)‐induced iDILI, but the exact role of neutrophils and other leukocytes remains to be defined. We therefore set out to study the kinetics of immunological changes during the development of TVX‐induced iDILI in the established murine model of acute liver injury induced by administration of TVX and TNF. Initially, TNF stimulated the appearance of leukocytes, in particular neutrophils, into the liver of TVX‐treated mice, but even more so in control mice treated with the non‐DILI inducing analogue levofloxacin (LVX) or saline as vehicle (Veh). This difference was apparent at 2 hours after TNF administration, but at 4 hours, the relative neutrophil amounts were reduced again in Veh‐ and LVX‐treated mice whereas the amounts in TVX‐treated mice remained at the same increased level as at 2 hours. The influx of monocytes/macrophages, which was unaffected in Veh‐ and LVX‐treated mice was markedly reduced or even absent in TVX‐treated mice. Unlike controls, mice receiving TVX + TNF display severe hepatotoxicity with clear pathology and apoptosis, coagulated hepatic vessels and increased alanine aminotransferase levels and interleukin 6/10 ratios. Findings indicate that TVX delays the acute influx of neutrophils and monocytes/macrophages. Considering their known anti‐inflammatory functions, the disruption of influx of these innate immune cells may hamper the resolution of initial cytotoxic effects of TVX and thus contribute to liver injury development. [ABSTRACT FROM AUTHOR]

Immunoassay is an emerging technique that has been used in the fields of food and environmental analysis to monitor and control hazardous residues. Multianalyte immunoassays (MAIAs) are favored because they can simultaneously determine several targets in a single test. In this review, an overview of various formats for the MAIA is given. New trends on how to produce antibodies, how to improve antibody specificity and how to manipulate assay formats to obtain the desired multi-analysis schemes are summarized. Finally, the limitations and prospects of MAIAs are discussed. [ABSTRACT FROM AUTHOR]

Owing to the growing need for novel antibacterial agents, we synthesized a novel series of fluoroquinolones including 7-substituted-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid derivatives, which were tested against clinically relevant Gram positive and Gram negative bacteria. Chemical structures of the synthesized compounds were identified using spectroscopic methods. In vitro antimicrobial effects of the compounds were determined via microdilution assay. Microbiological examination revealed that compounds 13 and 14 possess a good antibacterial profile. Compound 14 was the most active and showed an antibacterial profile comparable to that of the reference drugs trovafloxacin, moxifloxacin, and ciprofloxacin. A significant MIC 90 value (1.95 μg/mL) against S. aureus ATCC 25923, E. coli ATCC 35218, and E. coli ATCC 25922 was recorded for compound 14 . We observed reduced metabolic activity associated with compounds 13 and 14 in the relevant bacteria via a luminescence ATP assay. Results of this assay supported the antibacterial potency of compounds 13 and 14 . An E. coli DNA gyrase inhibitory assay indicated that compound 14 is a potent inhibitor of E. coli DNA gyrase. Docking studies revealed that there is a strong interaction between compound 14 and the E. coli DNA gyrase enzyme. Genotoxicity and cytotoxicity evaluations of compounds 13 and 14 showed that compound 14 is non-genotoxic and less cytotoxic compared to the reference drugs (trovafloxacin, moxifloxacin, and ciprofloxacin), which increases its biological importance. [ABSTRACT FROM AUTHOR]

Trovafloxacin develops severe hepatotoxicity; however, the underlying mechanism of the trovafloxacin-induced liver injury has not been cleared. It has been shown that microRNAs (miRNAs) can be involved in the development of drug-induced liver injuries. We performed a miRNA microarray analysis to identify hepatic miRNAs that were induced or reduced by trovafloxacin in mice. It was demonstrated that miR-877-5p was the most increased miRNA in the mouse liver 24 h after the trovafloxacin administration. To investigate the role of miR-877-5p in the liver, we established miR-877-5p-overexpressed HepG2 cells. Microarray analysis detected altered expressions in 2077 (>2-fold) and 1547 (<0.5-fold) genes in the miR-877-5p overexpressing cells compared to the mock cells. Especially, SLCO4C1, PEPCK, MT1M, HIST1H2BM, LGI1, and PLA2G2A were markedly increased or decreased in the miR-877-5p overexpressing cells. We conducted a correlation analysis between the expression levels of miR-877-5p and the six genes in eight miR-877-5p stably-expressed clones. It was shown that the PEPCK expression levels were correlated with miR-877-5p expression levels. PEPCK is associated with development of apoptotic cell death; therefore, the increased miR- 877-5p-induced PEPCK can be a trigger that is involved in the development of trovafloxacin-induced liver injury. [ABSTRACT FROM AUTHOR]

Trovafloxacin, a fluroquinolone antibiotic, was recently found to be an inhibitor of pannexin-1 channels through which ATP is released as “find-me” signals in apoptotic Jurkat cells. Our interest in the role of pannexin-1 channels in α 1 -adrenoceptor-mediated vasoconstriction led us to the novel finding reported here. Concentration-response curves to methoxamine and phenylephrine were competitively antagonised by trovafloxacin (1–30 µM) with a p K B of 5.54 and 5.32, respectively, in rat mesenteric small arteries isolated for myography. In comparison, prazosin (1–10 nM) antagonised methoxamine concentration-response curves with a p K B of 9.76. Trovafloxacin (1–30 µM) had no effect on either the thromboxane mimetic (U46619) or endothelin-1 concentration-contraction curves. Interestingly, the concentration range is similar for trovafloxacin antagonising the 3 distinct pharmacological targets: (i) fourth generation fluroquinolone antibiotic, (ii) pannexin-1 channel inhibitor in apoptotic cells, and now (iii) as an α 1 -adrenoceptor antagonist. When trovafloxacin was in use clinically, CNS side effects of dizziness, flushing and headache consistent with α 1 -adrenoceptor antagonism were common. We conclude that trovafloxacin with its quinolone moiety is a weak α 1 -adrenoceptor competitive antagonist in comparison with prazosin. [ABSTRACT FROM AUTHOR]

1. Interspecies allometry scaling for prediction of human excretory amounts in urine or feces was performed for numerous antibacterials. Antibacterials used for urinary scaling were: rifapentine, pefloxacin, trovafloxacin (Gr1/low; <10%); miloxacin, linezolid, PNU-142300 (Gr2/medium; 10–40%); aztreonam, carumonam, cefozopran, doripenem, imipenem, and ceftazidime (Gr3/high; >50%). Rifapentine, cabotegravir, and dolutegravir was used for fecal scaling (high; >50%). 2. The employment of allometry equation: Y = aWbenabled scaling of urine/fecal amounts from animal species. Corresponding predicted amounts were converted into % recovery by considering the respective human dose. Comparison of predicted/observed values enabled fold difference and error calculations (mean absolute error [MAE] and root mean square error [RMSE]). Comparisons were made for urinary/fecal data; and qualitative assessment was made amongst Gr1/Gr2/Gr3 for urine. 3. Average correlation coefficient for the allometry scaling was >0.995. Excretory amount predictions were largely within 0.75- to 1.5-fold differences. Average MAE and RMSE were within ±22% and 23%, respectively. Although robust predictions were achieved for higher urinary/fecal excretion (>50%), interspecies scaling was applicable for low/medium excretory drugs. 4. Based on the data, interspecies scaling of urine or fecal excretory amounts may be potentially used as a tool to understand the significance of either urinary or fecal routes of elimination in humans in early development. [ABSTRACT FROM AUTHOR]

To identify effective compounds that are active against Staphylococcus aureus (S. aureus) persisters, we screened a clinical drug library consisting of 1524 compounds and identified six drug candidates that had anti-persister activity: tosufloxacin, clinafloxacin, sarafloxacin, doxycycline, thiostrepton, and chlorosalicylanilide. Among them, tosufloxacin had the highest anti-persister activity, which could completely eradicate S. aureus persisters within 2 days in vitro. Clinafloxacin ranked the second with very few persisters surviving the drug exposure. Interestingly, we found that both tosufloxacin and trovafloxacin that had high activity against persisters contained at the N-1 position the 2,4-difluorophenyl group, which is absent in other less active quinolones and may be associated with the high anti-persister activity. Further studies are needed to evaluate tosufloxacin in animal models and to explain its unique activity against bacterial persisters. Our findings may have implications for improved treatment of persistent bacterial infections. [ABSTRACT FROM AUTHOR]

Use of the fluoroquinolone antibiotic trovafloxacin (TVX) was restricted due to idiosyncratic, drug-induced liver injury (IDILI). Previous studies demonstrated that tumor necrosis factor-alpha (TNF) and TVX interact to cause death of hepatocytes in vitro that was associated with prolonged activation of c-Jun N-terminal kinase (JNK), activation of caspases 9 and 3, and DNA damage. The purpose of this study was to explore further the mechanism by which TVX interacts with TNF to cause cytotoxicity. Treatment with TVX caused cell cycle arrest, enhanced expression of p21 and impaired proliferation, but cell death only occurred after cotreatment with TVX and TNF. Cell death involved activation of extracellular signal-related kinase (ERK), which in turn activated caspase 3 and ataxia telangiectasia and Rad3-related (ATR), both of which contributed to cytotoxicity. Cotreatment of HepG2 cells with TVX and TNF caused double-strand breaks in DNA, and ERK contributed to this effect. Inhibition of caspase activity abolished the DNA strand breaks. The data suggest a complex interaction of TVX and TNF in which TVX causes replication stress, and the downstream effects are exacerbated by TNF, leading to hepatocellular death. These results raise the possibility that IDILI from TVX results from MAPK and ATR activation in hepatocytes initiated by interaction of cytokine signaling with drug-induced replication stress. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is an infectious disease that occurs globally. Treatment of TB has been hindered by problems with multidrug-resistant strains (MDR-TB). Fluoroquinolones are one of the main drugs used for the treatment of MDR-TB. The success of therapy can be influenced by genetic factors and their impact on pharmacokinetic parameters. This review was conducted by searching the PubMed database with keywords polymorphism and fluoroquinolones. The presence of gene polymorphisms, including UGT1A1 , UGT1A9 , SLCO1B1 , and ABCB1 , can affect fluoroquinolones pharmacokinetic parameters such as area under the curve (AUC), creatinine clearance (C Cr ), maximum plasma concentration (C max ), half-life (t 1/2 ) and peak time (t max ) of fluoroquinolones., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Annisa, Barliana, Santoso and Ruslami.)

This year the world commemorates the beginning of the tragic USPHS syphilis experiments that occurred in Tuskegee, Alabama from 1932 to 1972. In light of this sobering anniversary, this article will briefly examine four studies: the already mentioned USPHS syphilis studies in Tuskegee, the Nazi Holocaust Experiments and the resulting Doctors' Trial at Nuremberg, the USPHS study on sexually transmitted diseases in Guatemala, and the Pfizer Trovan study in Nigeria. By reflecting critically upon these four tragic events in the history of research, the research community is reminded of its non-negotiable, ethical responsibility to protect human subjects, particularly those who are most vulnerable. Keywords: human research, USPHS syphilis experiments, Tuskegee, Guatemala, Trovan, Pfizer, Nigeria, Doctors' Trial at Nuremberg, Holocaust, Nazi Experiments, Introduction Much of the modern economy is impacted by today's increasing globalization, and clinical research is at the forefront. Cost is a significant factor that may propel clinical research beyond [...]

Drug-induced liver injury (DILI) is an adverse hepatic reaction and a serious concern for public healthcare systems and pharmaceutical companies. DILI is frequently caused by a combination of direct toxic stresses and subsequent immune damage to hepatocytes. However, little is known about the mechanism by which drugs facilitate the activation of the innate immune system. Here, we aimed to decipher the inflammatory events in trovafloxacin (TVX)-induced reactions using liver macrophages. We showed that proinflammatory M1-like macrophages mainly contributed to hepatotoxicity mediated by TVX, a DILI drug. Additionally, transcriptome results showed that the interferon type I pathway, cytokines, and apoptosis pathway were involved in the initiation of synergistic effects resulting in TVX-induced liver injury. We hypothesized that DILI drugs could drive liver injury by altering the activation and phenotype of hepatic macrophages. Furthermore, drug treatment-induced transcriptional changes such as Traf1 and 2 , Socs3 , and Hbegf in macrophage polarization could be used to assess drug-specific immune-mediated reactions. Therefore, we proposed that transcriptional change in the genes related to macrophage polarization index could be an indicator to reflect the severity of DILI in a preclinical setting during drug development. • Drug-induced liver injury (DILI) is an adverse drug reaction and its prediction remains extremely challenging. Further, drug-induced innate immune response such as inflammation can amplify liver tissue damage. • In this study, we found that the proinflammatory M1 macrophage is mainly activated, promoting trovafloxacin (TVX)-induced liver injury by the release of high levels of proinflammatory cytokines (TNF-α). • Further, the transcriptome in liver macrophages exposed to TVX suggests candidate biomarker genes to improve the early detection of immunological DILI in the absence of diagnostic DILI biomarkers. [ABSTRACT FROM AUTHOR]

Plasma membrane pannexin 1 channels (PANX1) release nucleotide find-me signals from apoptotic cells to attract phagocytes. Here we show that the quinolone antibiotic trovafloxacin is a novel PANX1 inhibitor, by using a small-molecule screen. Although quinolones are widely used to treat bacterial infections, some quinolones have unexplained side effects, including deaths among children. PANX1 is a direct target of trovafloxacin at drug concentrations seen in human plasma, and its inhibition led to dysregulated fragmentation of apoptotic cells. Genetic loss of PANX1 phenocopied trovafloxacin effects, revealing a non-redundant role for pannexin channels in regulating cellular disassembly during apoptosis. Increase in drug-resistant bacteria worldwide and the dearth of new antibiotics is a major human health challenge. Comparing different quinolone antibiotics suggests that certain structural features may contribute to PANX1 blockade. These data identify a novel linkage between an antibiotic, pannexin channels and cellular integrity, and suggest that re-engineering certain quinolones might help develop newer antibacterials. [ABSTRACT FROM AUTHOR]

Idiosyncratic drug-induced liver injury (IDILI) continues to be a significant human health problem. IDILI is characterized as occurring in a minority of individuals exposed to a drug, yet it accounts for as much as 17% of all cases of acute liver failure. Despite these concerns, the mechanisms underlying IDILI remain unknown. Trovafloxacin (TVX), which causes IDILI in humans, also causes hepatocellular death in vitro when combined with tumor necrosis factor-alpha (TNF) treatment. However, the molecular mechanisms involved in this toxicity are not fully characterized. The purpose of this study was to identify mechanisms by which TVX and TNF interact to cause hepatocellular death, with a focus on a human hepatocyte cell line. TVX and TNF interacted to cause cytotoxicity in HepG2 cells at drug concentrations similar to those in people undergoing TVX therapy. TVX/TNF treatment caused apoptosis and DNA damage in HepG2 cells that depended on caspase activation. Prolonged activation of JNK occurred in TVX/TNF-induced cytotoxicity, and treatment with the JNK selective inhibitor SP600125 attenuated cytotoxicity. TVX/TNF cotreatment also caused cytotoxicity in isolated primary murine hepatocytes that was dependent on caspase activation. These results increase understanding of molecular signaling pathways involved in hepatocellular death caused by a drug with idiosyncratic liability in the presence of TNF. [ABSTRACT FROM AUTHOR]

Antibiotic levels in livestock are usually evaluated through destructive analysis. Taking advantage of the fluorescent properties of marbofloxacin (MBX) and trovafloxacin (TVX), multiphoton microscopy (MPM) was evaluated as a minimally invasive and nondestructive method to determine the penetration of TVX and MBX into sheep neutrophils. Standard curves were measured with drug-only solutions and suggested that MBX was more suited for this type of analysis. The intracellular concentration of both TVX and MBX was higher than the extra- cellular concentration after incubating neutrophils for 30 min at concentrations ranging from 0.1 to 100 µg/ml for both the drugs. The intracellular concentration of TVX increased with the extracellular concentration but was always greater than the extracellular concentration, suggesting active internalization. On the other hand, intra-cellular/extracellular ratio (I/E) peaked at 1.6-fold I/E for 1 µg/ml and then gradually decreased with increased concentration to 1.2-fold I/E at 100 µg/ml. For the first time, this study showed the use ofMPMto quantify antibiotic uptake by sheep neutrophils and observed that both antibiotics were taken up by sheep neutrophils beyond extracellular levels. [ABSTRACT FROM AUTHOR]

Abstract: A simple and rapid high performance liquid chromatographic method was developed, validated and applied for the simultaneous determination of marbofloxacin (MBX) and trovafloxacin (TVX) in sheep plasma. Samples were extracted with 20% perchloric acid and MBX and TVX were separated on a C18 column using a gradient mobile phase system consisting of 17.5mM of NaH2PO4 and 1.5mM of tetrabutylammonium hydroxide aqueous solution, pH 3 (A) and 50% acetonitrile and 50% methanol (B), with UV detection at 293 and 270nm. The retention times of MBX and TVX were 4.9 and 6.6min respectively. The detection and quantification limits for MBX and TVX were 2ng/mL and 10ng/mL respectively for both compounds. The calibration curves were linear over a concentration range of 10–50,000ng/mL for both antibiotics. The linearity, precision, accuracy, recovery and stability of the assay were evaluated from spiked sheep plasma. The method was successfully applied to sheep plasma samples obtained from MBX and TVX pharmacokinetic studies. [Copyright &y& Elsevier]

Abstract: The carbon–hydrogen bond dissociation enthalpy (BDE) concept is evaluated as a potential computed indicator of stability of pharmaceutical drug substance candidates – specifically for oxidative stability of these molecules. Computational methods are discussed. Accuracy and validity of the methods are evaluated. BDEs are computed for several well-known molecules, for which stability and degradant identification information is known. Anecdotal correlations are noted between the lowest BDE energies of familiar molecules (sertraline, ezlopitant and related structures, ziprasidone, trovafloxacin, and varenicline), the sites of oxidative lability on these molecules and the identities of oxidative degradants. A low BDE may correlate in general with a reactive site on a molecule, not just an oxidatively susceptible one. [Copyright &y& Elsevier]

Synthesis of the Tc(CO)-trovafloxacin dithiocarbamate (Tc(CO)-TVND) complex and biological characterization in artificially Staphylococcus aureus ( S. aureus) infected rats model was assessed. The suitability of the complex was evaluated and compared with TcN-TVND, in terms of radiochemical immovability in saline, in vitro permanence in serum, in vitro binding with S. aureus and biodistribution in Male Sprague-Dawley rats (MSDR). After 30 min of the reconstitution both the complexes showed maximum radiochemical stabilities in saline and remain more than 90% stable up to 120 min. However the Tc(CO)-TVND showed to some extent higher stability than TcN-TVND complex. In serum 1.75% less de-tagging was observed than TcN-TVND complex. Both the complexes showed saturated in vitro binding with S. aureus and no significant difference were observed between the uptakes. Six fold uptakes were noted in the infected muscle as compared to the inflamed and normal muscles of the MDSR. The uptake of the Tc(CO)-TVND in infected muscle of the MSDR was 2.25% high as compared to the TcN-TVND complex. Based on radiochemical stabilities in saline, serum, in vitro binding with MRSA and significantly higher uptake in the infected muscle, we recommend both the complexes for in vivo investigation of the MRSA infection in human. [ABSTRACT FROM AUTHOR]

The radiolabeling of trovafloxacin dithiocarbamate (TVND) with technetium-99m using [Tc-N] core was investigated and biologically assessed as prospective infection imaging agent. The achievability of the TcN-TVND complex as a future MRSA infection radiotracer was investigated in artificially methicillin-resistant Staphylococcus aureus (MRSA) infected male Sprague-Dawley rats (MSDR). Radiochemically the TcN-TVND complex was characterized in terms of radiochemical purity (RCP) in saline, in vitro permanence in serum, in vitro binding with MRSA and biodistribution in living and heat killed MRSA infected MSDR. Radiochemically the complex showed stability in saline with a 97.90 ± 0.22% yield and serum at 37 °C up to 4 h. The TcN-TVND complex showed saturated in vitro binding with MRSA. Normal in vivo uptake in the MRSA infected MDRS was observed with a five fold uptake in the infected muscle as compared to inflamed and normal muscles. The high RCP values, in vitro permanence in serum, better in vitro binding with MRSA, biodistribution behavior and the target to non-target (infected to inflamed muscle) ratios posed the TcN-TVND complex as a promising MRSA infection radiotracer. [ABSTRACT FROM AUTHOR]

Idiosyncratic adverse drug reactions (IADRs) occur in a minority of patients yet account for the majority of postmarketing use restrictions by the Food and Drug Administration. Despite the impact of these toxicities, the underlying mechanisms are still poorly understood. Animal models of IADRs would be beneficial in understanding mechanisms and in developing assays with predictive potential. Recent work exploring the interactions between inflammatory stress and drugs associated with human idiosyncratic drug-induced liver injury (IDILI) has led to the development of the first animal models that apply to a range of drugs. Here, we discuss hypotheses for the mechanisms of IDILI and focus on a murine model of trovafloxacin-induced hepatotoxicity as an example related to the inflammatory stress hypothesis. [ABSTRACT FROM AUTHOR]

Abstract: Trovafloxacin (TVX) is a fluoroquinolone antibiotic whose therapeutic use was severely restricted due to an unacceptable risk of idiosyncratic liver injury. Oxidative stress and mitochondrial injury have been implicated in fluoroquinolone toxicity, but the mechanisms underlying liver injury are poorly understood. Because TVX-induced hepatotoxicity cannot be modeled in normal healthy rodents, we asked whether an underlying genetic defect (heterozygous deficiency in mitochondrial superoxide dismutase, Sod2) might aggravate TVX-induced mitochondrial adverse effects. Wild-type and Sod2 +/− mice were treated with vehicle or alatrofloxacin (the prodrug of TVX, 33mg/kg/day, ip) for 28 days. We found that hepatic protein carbonyls were increased by 2.5-fold and hepatic mitochondrial aconitase activity was decreased by 20% in mutant, but not wild-type mice. Because aconitase is a major target of peroxynitrite, we determined the extent of nitrotyrosine residues in hepatic mitochondrial proteins. Trovafloxacin significantly increased nitrotyrosine in Sod2 +/− mice only. Using the NO-selective probe DAF-2, we found that TVX increased the production of mitochondrial NO in immortalized human hepatocytes. Similarly, mitochondrial Ca2+ was increased by TVX, suggesting Ca2+-dependent activation of mitochondrial NOS activity. Furthermore, the transcript levels of the mtDNA-encoded gene Cox2/mtCo2 were decreased in Sod2 +/− mice only, while the expression of nDNA-encoded mitochondrial genes was not significantly altered in both genotypes, suggesting selective effects on mtDNA expression. The amount of mtDNA (copy number) was, however, unchanged. These data indicate that TVX enhances hepatic mitochondrial peroxynitrite stress in mice with underlying increased basal levels of superoxide, leading to the disruption of critical mitochondrial enzymes and gene regulation. [ABSTRACT FROM AUTHOR]

The article focuses on the legal case between Abdullahi versus American pharmaceutical company Pfizer Inc. concerning to judiciary law, the Alien Torts Statute (ATS), in Kano, Nigeria. It states that company has failed to treat child patients with meningitis isolated at Infectious Disease Hospital (IDH) using experimental drug Trovafloxacin. It prevailed that the case was dismissed, according to the court's decision because of customary international law prohibiting nonconsensual medical care.

Therapy employing the fluoroquinolone antibiotic, trovafloxacin (TVX) was curtailed due to idiosyncratic hepatotoxicity. Previous studies in mice showed that a nonhepatotoxic inflammatory stress induced by tumor necrosis factor α (TNF) synergized with a nonhepatotoxic dose of TVX to cause liver injury. The purpose of this study was to explore mechanisms by which TVX interacts with TNF to cause liver injury. TVX pretreatment prolonged the peak of plasma TNF after its administration. This prolongation of TNF by TVX was critical to the development of hepatotoxicity. The prolongation of TNF concentration in plasma was primarily due to reduced clearance when compared with secondary biosynthesis. TNF is cleared from plasma by binding to soluble TNF receptors (TNFRs) which are eliminated by the kidney; however, the plasma concentrations of soluble TNFRs were not reduced, and biomarkers of renal dysfunction were not elevated in TVX/TNF-treated mice. Two injections of TNF mimicked the prolongation of the TNF peak by TVX and caused liver injury, but injury was less severe than after TVX/TNF coexposure. TVX enhanced the induction of proinflammatory cytokines by TNF. Additionally, TVX sensitized Hepa1c1c7 cells to TNF-induced killing in a concentration-dependent manner and increased both potency and efficacy of TNF to activate effector caspases that were critically involved in cell death from TVX/TNF coexposure. In summary, TVX reduced the clearance of TNF independent of either receptor shedding or kidney dysfunction. Additionally, TVX interacted with TNF to enhance inflammation and sensitize hepatocytes to TNF-induced cell death. [ABSTRACT FROM PUBLISHER]

Abstract: The use of the fluoroquinolone antibiotic trovafloxacin (TVX) was severely restricted in 1999 due to its association with idiosyncratic hepatotoxicity. Previously, we reported that a nontoxic dose of TVX interacts with a nontoxic dose of lipopolysaccharide (LPS) to cause robust hepatocellular injury in mice. This interaction with LPS was not seen in mice treated with levofloxacin (LVX), a fluoroquinolone not associated with hepatotoxicity in people. TVX/LPS-coexposure caused an increase in plasma alanine aminotransferase (ALT) activity as early as 4.5 h after LPS administration which progressed through 15 h. We examined the role of the hemostatic system in TVX/LPS-induced liver injury. At the onset of liver injury, coexposure to TVX/LPS, but not exposure to TVX, LVX, LPS or LVX/LPS, caused increased plasma concentration of thrombin–antithrombin dimers and decreased plasma circulating fibrinogen. LPS treatment induced a small increase in plasma plasminogen activator inhibitor-1 (PAI-1) concentration, and TVX pretreatment enhanced this effect. TVX/LPS coexposure also resulted in hepatic fibrin deposition. Anticoagulant heparin administration reduced TVX/LPS-induced hepatic fibrin deposition and liver injury. PAI-1−/− mice treated with TVX/LPS exhibited similar fibrin deposition to wild-type mice but had significantly reduced hepatocellular injury. PAI-1−/− mice, but not heparin-treated mice, had reduced plasma concentrations of several cytokines compared to TVX/LPS-treated controls. In summary, TVX/LPS-coexposure caused an imbalance in the hemostatic system, resulting in thrombin activation increased, plasma concentration of PAI-1 and hepatic fibrin deposition. Both thrombin activation and PAI-1 play critical roles in the progression of TVX/LPS-induced liver injury, but through different modes of action. [Copyright &y& Elsevier]

The article discusses a court case on the prohibited drug experimentation on human subjects in Nigeria. The doctors from Pfizer Inc. and Nigerian doctors were complained after its clinical drug trial during the bacterial meningitis outbreak in Kano, Nigeria. The doctors were accused of being unable to secure permission in using Trovafloxacin, a drug, and its failure to reveal the clinical trial. The case was analyzed by the Court of Appeals under the Alien Tort Statute (ATS) in the U.S.

Trovafloxacin (Trovan) is a fluoroquinolone antibiotic drug with a long half-life and broad-spectrum activity. Since its entry into the market in 1998, trovafloxacin has been associated with numerous cases of hepatotoxicity, which has limited its clinical usefulness. Trovafloxacin possesses two substructural elements that have the potential to generate reactive intermediates: a cyclopropylamine moiety and a difluoroanilino system. The results presented here describe the in vitro metabolic activation of a synthetic drug model (DM) of trovafloxacin that contains the cyclopropylamine moiety. Cyclopropylamine can be oxidized to reactive ring-opened productsa carbon-centered radical and a subsequently oxidized α,β-unsaturated aldehyde. Experiments with monoamine oxygenases, horseradish peroxidase, flavin monooxygenase 3, and cDNA-expressed P450 isoenzymes revealed that P450 1A2 oxidizes DM to a reactive α,β-unsaturated aldehyde, M 1. Furthermore, myeloperoxidase (MPO) was also demonstrated to oxidize DM in the presence of chloride ion to produce M 1. DM proved to be a suicide inhibitor of MPO while showing no inhibition of P450 1A2. The structure of the reactive metabolite was confirmed by LC-MS/MS analysis by comparison with a synthetic standard. M 1was further shown to react with glutathione and the related thiol nucleophile, 4-bromobenzyl mercaptan, suggesting the potential of this intermediate to react with protein nucleophiles. In summary, these data provide evidence that trovafloxacin-induced hepatotoxicity may be mediated through the oxidation of the cyclopropylamine substructure to reactive intermediates that may form covalent adducts to hepatic proteins, resulting in damage to liver tissue. [ABSTRACT FROM AUTHOR]

Abstract: The mechanism for the hepatotoxicity of trovafloxacin remains unresolved. Trovafloxacin contains a cyclopropylamine moiety which has a potential to be oxidized to reactive intermediate(s) although other putative elements may exist. In this study, a drug model of trovafloxacin containing the cyclopropylamine substructure was synthesized. Chemical oxidation of the drug model by K3Fe(CN)6 and NaClO revealed that both oxidants oxidize this drug model to a reactive α,β-unsaturated aldehyde, 11. The structure of 11 was fully elucidated by LC/MS/MS and NMR analysis. These results suggested that P450s with heme-iron center and myeloperoxidase generating hypochlorous acid in the presence of chloride ion are capable of bioactivating the cyclopropylamine moiety of trovafloxacin. This deleterious metabolism may lead to eventual hepatotoxicity. [Copyright &y& Elsevier]

The objective of the present study was to determine the antimicrobial susceptibility of 136 canine isolates of Staphylococcus intermedius and 10 canine isolates of S. schleiferi subspecies coagulans to 16 fluoroquinolones (FQs), and to investigate the mechanisms of resistance in the nonsusceptible isolates. Of the 136 of S. intermedius tested 98.5% were susceptible to all 16 FQs whereas only 40% of the 10 isolates of S. schleiferi subspecies coagulans were susceptible. Two isolates of S. intermedius and six isolates of S. schleiferi, were found to be resistant to 13 out of 16 FQs, while they retained their susceptibility to fourth generation FQs such as gatifloxacin, moxifloxacin and trovafloxacin. Sequencing of the quinolone-resistance determining regions of gyrA and grlA genes showed that in S. intermedius, dichotomous resistance to FQs was associated with the occurrence of one alteration in GyrA-84 and one in GrlA-80, while in S. schleiferi the same pattern of resistance was observed in isolates showing these changes only in gyrA. This study is the first to screen FQs of the second, third and fourth generation for antimicrobial resistance in clinical isolates of S. intermedius and S. schleiferi of canine origin, and to describe mutations in gyrA and grlA associated with FQ resistance in these bacterial species. [ABSTRACT FROM AUTHOR]

Reports of low-level subtherapeutic concentrations of pharmaceuticals in surface and ground waters have raised questions as to whether such compounds would survive typical drinking water treatment (i. E, coagulation, settling, filtration, and disinfection) and ultimately result in inadvertent human exposure. To examine the impact of these processes, a bench-scale drinking water treatment plant (DWTP) was constructed and used to examine the potential removal of caffeine, trovafloxacin mesylate, estradiol and salicylic acid relative to a conservative bromide (Br-) tracer at pH 8, Radio-labeled compounds were used to provide good sensitivity within the small sample volume constraints of the system and to enable a more rigorous mass balance analysis The bench-scale system was comprised of several unit operations including: coagulation, flocculation, sedimentation, dual-media gravity filtration, granular activated carbon treatment (GAC), and chlorination, without GAC treatment, steady state analyses indicate removals of 3. 4 to 13%, 21 to 31%, 6. 9 to 12%, and 31 to 39% (95% confidence interval) for caffeine, trovafloxacin mesylate, estradiol, and salicylic acid, respectively, with most removal associated with flocculation/sedimentation and filtration, Biological degradation was likely the main process Contributing to the removal of salicylic acid. The addition of GAC treatment was found to significantly enhance the overall removal of caffeine (> 94%), trovafloxacin mesylate (> 95%), and estradiol (93-95%), but had limited effectiveness for salicylic acid (39-56%). [ABSTRACT FROM AUTHOR]

Aim: To investigate the susceptibility of Pediococcus species to antimicrobial agents. Methods and Results: The susceptibility to 14 antimicrobial agents of 31 genotypically distinct strains of six Pediococcus species was assessed by using Etests on ISO-sensitest agar supplemented with horse blood. The species included were Pediococcus acidilactici, Pediococcus damnosus, Pediococcus dextrinicus, Pediococcus inopinatus, Pediococcus parvulus and Pediococcus pentosaceus. For several antimicrobial agents, some species were more susceptible than others. The two industrially important species, P. acidilactici and P. pentosaceus, differed with respect to erythromycin and trovafloxacin susceptibility, and in general both species had higher minimum inhibitory concentrations than the other species. In an erythromycin-resistant P. acidilactici, an erythromycin resistance methylase B [ erm(B)] gene was identified by PCR. Using a plasmid preparation from strain P. acidilactici 6990, a previously erythromycin-sensitive Lactococcus lactis strain was made resistant. Transformants harboured a single plasmid, sized at 11·6 kb through sequence analysis. In addition, the erm(B) gene was identified within the plasmid sequence. Conclusions: The phenotypic test indicated the absence of acquired antimicrobial resistance genes in 30 of the strains. Significance and Impact of the Study: These results will help in selection of the best Pediococcus strains for use as starter cultures. [ABSTRACT FROM AUTHOR]

The article looks at the regulation of biomedical research in Africa. According to the author, regulations that guide biomedical research on the role of local research ethics committees, procedures of informed consent, and compensation for injuries would be beneficial. The article also discusses international ethical codes such as the Declaration of Helsinki and the medical trials of trovafloxacin mesylate in Nigeria.

Abstract: New series of 1-aryl-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic acid has been synthesized and the structures of the new compounds were established on the basis of 1H-NMR, mass (ES/MS), elemental analysis and IR spectral data. In vitro antibacterial activity (MIC activity) was evaluated and compared with standard drugs ciprofloxacin, sparfloxacin and trovafloxacin. Most of the compounds in the series have shown very interesting antibacterial activity against both Gram-positive and Gram-negative organisms. In this paper, we describe studies leading to identification of antibacterial agents incorporating novel pyridazine ring surrogate. In a gratifying result, the initial pyridazine-3-carboxylic acid analogues prepared were found to exhibit in vitro antibacterial activity approaching that of corresponding fluoroquinolone progenitor. [Copyright &y& Elsevier]

A spectrofluorimetric method for the determination of trace amounts of the antibacterial trovafloxacin has been developed based on its native fluorescence in a micellar solution of sodium dodecyl sulfate (SDS). The wavelengths of excitation and emission were 270 nm and 410 nm, respectively. The optimised method allows the determination of 3.0–40.0 ng mL−1 of trovafloxacin in 8 mM SDS solution and 0.1 M acetic acid-sodium acetate buffer solution (pH 5.5), with a relative standard deviation of 1.5% (for a level of 12.0 ng mL−1) and a detection limit of 0.8 ng mL−1. The method was applied to the determination of trovafloxacin in human urine and serum samples. It was validated using HPLC as a reference method. Recovery levels of the method reached 100% in all cases. [ABSTRACT FROM AUTHOR]

Objectives: To assess the impact of stable overproduction of efflux system MexAB-OprM on the bacteriostatic and bactericidal activities of fluoroquinolones against clinical Pseudomonas aeruginosa strains.Methods: The minimal inhibitory concentrations (MICs) and the minimal bactericidal concentrations (MBCs) of eight fluoroquinolones (pefloxacin, norfloxacin, ofloxacin, moxifloxacin, levofloxacin, ciprofloxacin, trovafloxacin and grepafloxacin) were determined for nine post-therapy resistant isolates of P. aeruginosa overexpressing MexAB-OprM. Clinical significance of low-level resistance conferred by the efflux mechanism was evaluated with a Monte Carlo simulation.Results: Compared with their pre-therapy susceptible counterparts, seven out of the nine post-therapy efflux mutants exhibited a modest two- to eight-fold increase in resistance to all the fluoroquinolones tested. Interestingly, stronger variations in resistance (up to 64-fold) were observed in two other mutants, one of which had acquired a GyrB target mutation in addition to efflux under chemotherapy. Timekill experiments showed that MexAB-OprM up-regulation did not confer tolerance to fluoroquinolones as the ratio of MBC to MIC was less than 4 for most of the strains. To gain an insight into the clinical significance of resistance conferred by MexAB-OprM, a Monte Carlo simulation was conducted with various fluoroquinolone regimens. With this model, low levels of resistance to ciprofloxacin (MIC?=?0.25?mg/L) or levofloxacin (MIC?=?1?mg/L), such as those due to overproduced MexAB-OprM, were predicted to result in poor clinical outcomes.Conclusions: Altogether, these data strongly suggest that when derepressed, MexAB-OprM provides P. aeruginosa with a resistance that may be sufficient to impair the efficacy of single therapy with highly potent fluoroquinolones, such as ciprofloxacin and ofloxacin. [ABSTRACT FROM AUTHOR]

Gene expression analysis applied to toxicology studies, also referred to as toxicogenomics, is rapidly being embraced by the pharmaceutical industry as a useful tool to identify safer drugs in a quicker, more cost-effective manner. Studies have already demonstrated the benefits of applying gene expression profiling towards drug safety evaluation, both for identifying mechanisms underlying toxicity, as well as for providing a means to identify safety liabilities early in the drug discovery process. Furthermore, toxicogenomics has the potential to better identify and assess adverse drug reactions of new drug candidates or marketed products in humans. While much still remains to be learned about the relevance and the application of gene expression changes in human toxicology, the next few years should see gene expression technologies applied to more stages and more programs of the drug discovery and development process. This review will focus on how toxicogenomics can or has been applied in drug discovery and development, and will discuss some of the challenges that still remain. [Copyright &y& Elsevier]

A flow injection method including chemiluminescence detection has been developed and applied to the determination of fluoroquinolones levofloxacin, moxifloxacin and trovafloxacin in tablets. The proposed method is based on the luminescent properties of the system Ce(IV)–sulphite–fluoroquinolone and the addition of a trivalent lanthanide ion as emission-sensitizer. The optimum conditions for chemiluminescence emission were investigated for each fluoroquinolone. The best results were achieved when employing Eu(III) as lanthanide cation for levofloxacin and moxifloxacin, and Tb(III) for trovafloxacin. These fluoroquinolones were determined over the concentration range of 0.5–3.5 µg mL-1, 0.2–3.0 µg mL-1 and 0.008–0.400 µg mL-1, with detection limits of 0.100, 0.035 and 0.008 µg mL-1, respectively. The relative standard deviations were in the range of 1.0–2.5% for all three cases. The method was applied to the determination of three fluoroquinolones in their respective pharmaceutical preparations and compared with an independent UV-spectrophotometric method. The results were satisfactory. [ABSTRACT FROM AUTHOR]

Objective: To investigate the therapeutic role of trovafloxacin mesylate, a newer-generation fluoroquinolone with an expanded spectrum of activity, in the treatment of experimental bacterial keratitis. Methods: Susceptibility studies were performed on various strains of ocular isolates to determine the minimum inhibitory concentration (MIC) of trovafloxacin compared with ciprofloxacin and ofloxacin, using the E-test method. Pharmacokinetic studies were performed by a single topical administration of trovafloxacin to rabbit eyes with either an intact or denuded corneal epithelium. Aqueous humor, vitreous, and corneal concentrations of trovafloxacin were determined at different time points. Experimental bacterial keratitis studies were performed in rabbit eyes. Three identical studies were conducted using Staphylococcus aureus, Streptococcus pneumoniae, or Pseudomonas aeruginosa. Therapy groups included 0.5% trovafloxacin, 0.3% ciprofloxacin, 0.3% ofloxacin, and isotonic sodium chloride solution. After 12 hours of drops administration, corneas were excised, homogenized, and serially plated. The main outcome measure was quantitative bacteriologic analysis for residual colony-forming units. Results: In vitro susceptibility study findings indicated that the MIC of trovafloxacin was significantly lower than the MIC of ciprofloxacin and ofloxacin for S aureus, S pneumoniae, and Haemophilus influenzae, lower than the MIC of ciprofloxacin and ofloxacin for Staphylococcus epidermidis, and intermediate between ciprofloxacin and ofloxacin for P aeruginosa. Pharmacokinetic studies showed a significant concentration of trovafloxacin in the treated corneas, especially in eyes with a denuded epithelium. All serum samples had undetectable trovafloxacin concentrations. Experimental keratitis studies showed a statistically significant decrease of colony-forming units in trovafloxacin-treated eyes in the S aureus model and a similar decrease in the S pneumoniae and P aeruginosa models. Conclusions: Topical 0.5% trovafloxacin proved to be an effective ocular medication for the therapy of gram-positive and gram-negative keratitis. Clinical Relevance: Trovafloxacin may provide an excellent therapeutic alternative in bacterial keratitis. [ABSTRACT FROM AUTHOR]

Purpose. Trovafloxacin is an expanded spectrum, newer-generation fluoroquinolone antibiotic with improved Gram-positive and anaerobic activity compared with existing quinolones, while maintaining Gram-negative activity comparable to ciprofloxaein. Given its broad spectrum of activity, trovaftoxacin may have potential use for treatment of acute bacteria] endophthalmitis. This study examined the toxicity of intravitreally administered trovafloxacin in the pigmented rabbit eye. Methods. Doses of trovafloxacin ranging from 12.5μg to l000μg were injected into the mid-vitreous of Dutch Belted rabbit eyes. Clinical examination was performed at 1, 3, and 14 days following injection. Animals were sacrificed and eyes were enucleated 14 days following injection. Light microscopy (LM) and transmission electron microscopy (TEM) studies of the optic nerve head medullary ray. and inferior retina were performed to determine toxicity. Results. At intravitreal doses of 500μg and less, no toxicity was observed at the ophthalmoscopic or light microscopic level. By TEM. a dose-dependent increase in injury to retinal pigment epithelium, photoreceptors, and nerve fibers in the optic nerve head and medullary ray was observed from 50μg to 500μg. No toxicity was noted at doses of 12.5μg and 25μg. At doses of 750μg and above, edema of the medullary ray was noted on ophthalmoscopy. Swelling of the peripapillary medullary ray and necrosis of the inferior retina were evident on LM. Conclusion. Intravitreal trovafloxacin doses of 50μg and higher in the pigmented rabbit eye cause retinal and nerve fiber injury. Intravitreal doses 25μg and lower appear to be safe, with no evidence of ocular toxicity. [ABSTRACT FROM AUTHOR]

Current estimates of the mortality associated with brain abscesses range from 0–24%, with neurological sequellae in 30–55% of survivors. Although the incidence of brain abscess appears to be increasing, likely due to an increase in the population of immunosuppressed patients, the condition is still sufficiently uncommon to make human clinical trials of therapy problematic. An animal model to study the efficacy of new treatment regimens, specifically, new antimicrobial agents is therefore necessary. This study uses a well-defined experimental paradigm as an inexpensive method of inducing and studying the efficacy of antibiotics in brain abscess. The rat model of brain abscess/cerebritis developed at this institution was used to determine the relative efficacy of trovafloxacin as compared to ceftriaxone in animals infected with Staphylococcus aureus. S. aureus (&ap;105 CFU in 1 microliter) was injected with a Hamilton syringe, very slowly, over the course of 70 minutes after a two mm burr hole was created with a spherical carbide drill just posterior to the coronal suture and four mm lateral to the midline. Eighteen hours later treatment was begun; every 8 hours the rats were dosed with subcutaneous ceftriaxone (n = 10), trovafloxacin (n = 11) or 0.9% sterile pyogen-free saline (n = 10). After four days of treatment the brains were removed and sectioned with a scalpel. The entire injected hemisphere was homogenized and quantitative cultures performed. The mean ± SEM log10 colony forming units/ml S. aureus recovered from homogenized brain were as follows: controls 6.10 ± 0.28; ceftriaxone 3.43 ± 0.33; trovafloxacin 3.65 ± 0.3. There was no significant difference in bacterial clearance between ceftriaxone versus trovafloxacin (p = 0.39). Trovafloxacin or other quinolones may provide a viable alternative to intravenous antibiotics in patients with brain abscess/cerebritis. [Copyright &y& Elsevier]