Activities of bay Y 3118, levofloxacin, and ofloxacin alone or in combination with ethambutol against Mycobacterium avium complex in vitro, in human macrophages, and in beige mice

Abstract

Levofloxacin, ofloxacin, and Bay Y 3118 are new fluoroquinolones with variable in vitro bacteriostatic and bactericidal activities against the Mycobacterium avium complex (MAC). The potential therapeutic activities of these agents both alone and combined with ethambutol were evaluated in a human macrophage test system and in the beige mouse animal test system with MAC strain 101. Bay Y 3118 at a human-equivalent dose of 30 mg/kg/day for 4 weeks caused a significant reduction in mortality compared with that in untreated controls (P = 0.02). Bay Y 3118 also caused significant reductions in the number of MAC organisms in the blood, liver tissue, and spleen tissue compared with those in untreated controls. Levofloxacin at a human-equivalent dose of 200 mg/kg/day was associated with a significant reduction in mortality (10 versus 39%); however, treatment with either levofloxacin or ofloxacin (200 mg/kg/day) did not result in significant reductions in the numbers of MAC organisms in blood, liver, and spleen compared with those in untreated controls. When Bay Y 3118 was combined with ethambutol, there was no enhancement in therapeutic activity except in the spleen in terms of CFU per gram (reductions of 89% compared with the untreated control, 63% compared with Bay Y 3118 alone, and 72.5% compared with ethambutol alone). Levofloxacin in combination with ethambutol was more active than either drug alone in the reduction of organisms in blood, liver, and spleen. Bay Y 3118 was the most active fluoroquinolone for monotherapy of MAC infection in beige mice, and the combination of ethambutol plus either levofloxacin or ofloxacin was at least additive. In summary, this study demonstrates that quinolones, although active, are inhibitory against MAC in vivo and that there is little correlation between the activity of quinolones in vitro and the activity in mice.

Comparative in vitro and in vivo antimicrobial activities of sitafloxacin, gatifloxacin and moxifloxacin against Mycobacterium avium

“…10 mg/kg per adult). The present dose is the same as or less than those used in previous studies by other researchers [5][6][7][16][17][18] and, in a murine experimental mycobacterial infection model, the chemotherapeutic outcome is generally smaller than that available in chemotherapy of humans with mycobacteriosis. However, to make a precise comparison of the therapeutic activities of the four quinolones, it is necessary to perform animal experiments to examine exact dose-responses of test quinolones, since comparing drugs at a fixed dose is a perilous exercise as that dose may magnify differences that would appear trivial if examining whole dose-response curve.…”

“…However, at present the general consensus is that fluoroquinolones are only weakly efficacious against M. avium infections, although they are effective as second-line therapeutics against tuberculosis (TB) [1,4]. Bermudez et al [5][6][7] reported that moxifloxacin was effective in treating M. avium-infected mice and exhibited combined effects in some multidrug regimens, such as moxifloxacin plus ethambutol and moxifloxacin plus mefloquine. It has been reported that another 8-methoxy quinolone, gatifloxacin, as well as sitafloxacin with a chloro substituent at the C-8 position exhibited good antimicrobial activity against extracellular and intramacrophage M. avium [8][9][10].…”

Perspective on Animal Models: Chronic Intracellular Infections

“…Furthermore, ethambutol has been advocated by our group and others as the companion therapeutic agent to macrolides. Ethambutol has also been shown to have a rather reproducible, but primarily bacteriostatic, effect in the beige mouse test system [12]. Aminoglycosides, such as amikacin, have also been shown to be effective in treating tissue infection [9].…”

Prospects for development of new antimycobacterial drugs

“…16,18,[20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Fluoroquinolones exhibit fairly potent anti-MTB, anti-M. kansasii, and anti-M. fortuitum activities, 16,20,26,27 and the in-vitro anti-MTB activities of new quinolones, as determined by their MICs, are in the order STFX Լ GFLX Լ MXFX Լ SPFX Ͼ LVFX м CPFX Ͼ OFLX. 16,[20][21][22][23]27,29,32,39 Newly synthesized quinolones, such as WQ-3034 and HSR-903, had activity against MTB comparable to that of LVFX, 23,39 and newly Alangaden (1995), Kawahara (1994), , Skinner (1995) Ji ( , 1998, , Herbert (1996), , Sbarbaro (1996), Yajko (1996), Tomioka (1996 Tomioka (1990, Saito (1990, Ji ( , 1998, 33,35 Although fluoroquinolones also exhibit efficacy against MAC in combination with EB, CFZ, AMK, RFP, and rifabutin (RBT), their anti-MAC activities are relatively weak.…”

“…33,34 As indicated in Table 1, fluoroquinolones exhibited fairly good in-vivo activity against experimental mouse infections caused by MTB, M. kansasii, and M. fortuitum. 21,22,28,30,41,42 Their therapeutic efficacies against MTB infection were in the order MXFX Լ SPFX Լ LVFX Ͼ OFLX Ͼ pefloxacin (PFLX). In addition, as shown in Table 2, appreciable efficacy of fluoroquinolones, including CPFX, OFLX, and SPFX, was demonstrated in clinical studies of the treatment of MDR-TB and disseminated MAC infection in AIDS patients, particularly when the fluoroquinolones were included in multidrug regimens.…”