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Discontinued Fluoroquinolones
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Clinical trials demonstrating the efficacy of trovafloxacin have been performed in patients with community-acquired pneumonia, nosocomial pneumonia, acute exacerbations of chronic bronchitis, complicated intraabdominal infections, urinary tract infections, Chlamydia trachomatis genital infection, and skin/skin structure infection. The oral dosages of trovafloxacin in these studies ranged from 50–200 mg daily for chlamydial infection to 100–300 mg daily for lower respiratory tract infections (Brighty and Gootz, 1997; Leophonte et al., 1998; O’Doherty and Daniel, 1998; Tremolieres et al., 1998; Roerig, 2000). An international, multicenter, randomized clinical trial involving 311 children (aged 3 months to 12 years) with bacterial meningitis was performed comparing the intravenous prodrug alatrofloxacin against the conventional therapy of ceftriaxone ± vancomycin. S. pneumoniae made up 27% of cerebrospinal fluid (CSF) isolates, of which close to one-third demonstrated some degree of penicillin and/or ceftriaxone resistance. There was no statistical difference in the incidences of clinical endpoints between the intervention and comparator arms, including clinical success at 5–7 weeks (79% versus 81%), death (2% versus 3%) and severe sequelae (14% versus 14%) (Saez-Llorens et al., 2002).
Safety of treating acute liver injury and failure
Published in Expert Opinion on Drug Safety, 2022
Miren García-Cortés, Aida Ortega-Alonso, Raúl J. Andrade
Although an increased risk of DILI in patients with ALI or ALF has not been proved, the development of such complication could be fatal in patients with impaired liver function. The incidence and risk of antibiotic-related DILI is variable. Among currently available antimicrobials, amoxicillin/clavulanic acid, co-trimoxazole, and flucloxacillin appear as the most frequently involved drugs [58]. Amoxicillin/clavulanic acid is the drug most frequently implicated in the hepatic reactions reported to the Spanish DILI Registry and in the DILI network in the United States [59,60]. Thus, caution is recommended when this antibiotic is used in patients with liver disease. Apparently, macrolides, tetracyclines, or fluoroquinolones have a lower rate of liver toxicity. Exceptions to the latter are trovafloxacin, a quinolone withdrawn from the market, and telithromycin, a macrolide with restrictions due to liver toxicity [58].
The relationship between UGT1A1 gene & various diseases and prevention strategies
Published in Drug Metabolism Reviews, 2022
Dan Liu, Qi Yu, Qing Ning, Zhongqiu Liu, Jie Song
Trovafloxacin is reported to be an antibiotic and its main metabolic pathway is glucuronidation (Mitsugi et al. 2016). However, it was withdrawn due to severe liver toxicity. Fujiwara et al. have shown UGT1A1 is mainly responsible for metabolizing trovafloxacin in the human body. In human liver microsomes prepared by poor metabolizers (UGT1A1*28), trovafloxacin acyl-glucuronide was significantly reduced, which indicates that UGT1A1 low-activity patients are likely to be protected against toxicity when using trovafloxacin (Fujiwara et al. 2015). Tamoxifen is the main drug used for adjuvant therapy of hormone receptor-positive breast cancer in pre- and post-menopausal women (Bezerra et al. 2018). Hammad et al. found that tamoxifen improved liver damage induced by CCl4 in mice, and that the level of UGT1A1 in mice with improved liver damage was higher (Hammad et al. 2018). Carlinoside is an active ingredient extracted from fresh ripe leaves of C. cajan. Carlinoside significantly enhanced the binding of Nrf2 and UGT1A1 promoter, up-regulated the expression of Nrf2 gene, increased its nuclear transport, and stimulated the activity of UGT1A1 promoter in the experiment of resisting CCl4-induced liver injury, which improved the abnormal liver function caused by Hyperbilirubinemia (Kundu et al. 2011).
A Review of Immunomodulatory Effects of Fluoroquinolones
Published in Immunological Investigations, 2021
Shokrollah Assar, Reza Nosratabadi, Hossein Khorramdel Azad, Javad Masoumi, Mahshad Mohamadi, Gholamhossein Hassanshahi
During mixed lymphocyte reaction (MLR), ciprofloxacin inhibits the expression of stimulatory factors including, ICAM-1, B7.1, B7.2, and CD40 in monocytes. In addition, it suppresses IFN-γ production at the presence of IL-18 (Katsuno et al. 2006). In Langerhans cells treated with norfloxacin, IFN-γ production is diminished in mice due to CD40 suppression in Langerhans cells (Matsui et al. 2019) (Figure 1). In tumor-bearing rats under treatment with either ciprofloxacin alone or ciprofloxacin in combination with chemotherapy, IFN-γ production decreased in splenocytes at the presence of various mitogens (Xue et al. 2009). It has been well evidenced that ciprofloxacin and moxifloxacin, in a dose-dependent fashion, decrease IFN expression in healthy individuals’ lymphocytes (Williams et al. 2005). In a mouse model with the PR8 (H1N1) influenza virus-induced lung injury, levofloxacin treatment reduced oxidative stress markers in the lungs and IFN-γ in BALF; it also improved the survival rate in the infected mice (Enoki et al. 2015). It is also reported that consumption of levofloxacin by healthy individuals inhibits BCG-induced increase in IFN-γ (Serebryakova et al. 2018). In mice stimulated with a peptidoglycan-lipoteichoic acid (PGN-LTA) mixture isolated from Staphylococcus aureus (the gram-positive stimulus), pre-treatment with trovafloxacin inhibited TNF-α and IFN-γ production (Shaw et al. 2009). In primary human peripheral blood lymphocytes activated with PHA, ciprofloxacin has elevated IL-2 and IFN-γ production (Riesbeck et al. 1998). In general, these results indicate that FQs exert their immunomodulatory effects through attenuation of IFN-γ production (Figure 1); however, findings of study indicated that ciprofloxacin has elevated IFN-γ production by lymphocytes activated with PHA. The result of the last study could possibly be due to the presence of a co-stimulant (Dalhoff 2005).