In Vitro and In Vivo Activity of Zabofloxacin and Other Fluoroquinolones Against MRSA Isolates from A University Hospital in Egypt

Antimicrobial agent	MIC (μg/ml)			% Susceptible	% Intermediate	% Resistant
Antimicrobial agent	MIC range	MIC₅₀^*	MIC₉₀^*	% Susceptible	% Intermediate	% Resistant
Zabofloxacin	0.03 – 4	0.25	2	61.2	0.9	37.9
Moxifloxacin	0.06 – 16	0.5	8	50.9	8.6	40.5
Levofloxacin	0.125 – 64	4	16	46.5	0.9	52.6
Ciprofloxacin	0.125 – > 64	8	64	42.3	1.7	56

1* MIC₅₀ and MIC₉₀, MICs (μg/ml) for 50% and 90% of isolates tested, respectively.

Table II

MIC distribution of zabofloxacin, moxifloxacin, levofloxacin and ciprofloxacin determined by broth microdilution method for 116 MRSA isolates.

Antimicrobial agent	MIC (μg/ml)
Antimicrobial agent	0.03	0.06	0.125	0.25	0.5	1	2	4	8	16	32	64	> 64
Zabofloxacin	10	17	25	12	7	1	32	12	0	0	0	0	0
Moxifloxacin	0	2	7	35	15	10	11	21	13	2	0	0	0
Levofloxacin	0	0	10	33	11	0	1	8	22	29	0	2	0
Ciprofloxacin	0	0	4	18	19	8	2	4	11	19	14	14	3^a

1 Bold figures indicate CLSI breakpoints applied for resistant isolates; zabofloxacin and moxifloxacin: 2 µg/ml, levofloxacin and ciprofloxacin: 4 μg/ml.

2a MIC for these isolates was greater than or equal to the indicated value.

Bactericidal activities of (A) zabofloxacin, (B) moxifloxacin, (C) levofloxacin and (D) ciprofloxacin against fluoroquinolone-resistant MRSA clinical isolate S13. Blue line, 0.5 MIC; red line, 1 MIC; green line, 2 MIC; purple line, 4 MIC. Data points are geometric means with error bars being one standard deviation of replicate experiments (n = 3).

Bactericidal activities of (A) zabofloxacin, (B) moxifloxacin, (C) levofloxacin and (D) ciprofloxacin against fluoroquinolone-sensitive MRSA clinical isolate S15. Blue line, 0.5 MIC; red line, 1 MIC; green line, 2 MIC; purple line, 4 MIC. Data points are geometric means with error bars being one standard deviation of replicate experiments (n = 3).

Table III

MICs of zabofloxacin, moxifloxacin, levofloxacin and ciprofloxacin for selected 7 clinical MRSA isolates with detected mutations in QRDRs.

Strain No.	MIC (μg/ml)				Detected Mutation in QRDRs
Strain No.	ZAB^a	MOX	LEV	CIP	gyrA	parC	parE
S37	4	8	32	64	S84L^b	S80F^c	P451S^d
S30	2	8	16	64	S84L	S80F	P451S
S5	2	4	16	64	S84L	S80F	P451S
S3	2	8	32	64	S84L	S80F	P451S
S11	0.125	0.25	8	32	S84L	None	P451S
S38	0.25	0.25	8	16	None	S80F	None
S22	0.03	0.25	4	8	None	S80F	None

1a ZAB: zabofloxacin, MOX: moxifloxacin, LEV: levofloxacin and CIP: ciprofloxacin.

2b Serine → Leucine,

3c Serine → Phenylalanine,

4d Proline → Serine.

Table IV

In vivo activities of zabofloxacin, moxifloxacin, levofloxacin and ciprofloxacin against mice infected with MRSA S19 clinical isolate.

Microorganism inoculum (CFU/mouse)	Antimicrobial agent^a	MIC (μg/ml)	Count in dissected lungs log₁₀ (CFU/ml)^b	ED50^c (mg/kg)
Methicillin-resistant S. aureus clinical isolate S19	Zabofloxacin	0.06	3.66	29.05
	Moxifloxacin	0.06	4.31	38.69
	Levofloxacin	8	4.01	> 40.00
	Ciprofloxacin	16	4.24	> 40.00

1a Each antimicrobial agent was administrated twice orally at 1 and 4 h post infection.

2b Count in control group receiving saline was log₁₀ 5.5 CFU/ml.

3c ED50: median effective dose needed to protect 50% of the mice.

Lung tissue sections dissected from mice infected with MRSA clinical isolate and treated with (A) zabofloxacin showing very mild congestion (arrow) and inflammation with scarce inflammatory cells in the interstitial spaces; (B) moxifloxacin showing moderate congestion with ectatic vessels (arrow) and moderate interstitial inflammation; (C) levofloxacin showing moderate inflammation, congestion and oedema, with a dilated lymphatic vessel (arrow); and (D) ciprofloxacin showing bronchopneumonic changes with marked congestion, oedema, inflammatory infiltration and necrosis, with accumulation of necro-inflammatory exudate within the lumen of bronchioles (arrow) (H&E x400).

(A, × 100) cross section of lung tissue dissected from mice treated with zabofloxacin showing patent alveoli, (B, × 400) clear alveolar spaces and normal vessels, the bronchioles are lined by a layer of pneumocytes (arrow).

Table V

Scoring of detected congestion, inflammation, oedema and necrosis in lung tissues of mice groups infected with MRSA clinical isolate S19 and treated with zabofloxacin, moxifloxacin, levofloxacin and ciprofloxacin at a dose of 20 mg/kg of body weight/day.

Histological observation^a	(Score 0–3)
Histological observation^a	ZAB^b	MOX	LEV	CIP
Congestion	0 (40%)
	+1 (20%)	+1 (60%)	+2 (80%)	+3 (60%)
	+2 (40%)	+2 (40%)	+1 (20%)	+1 (40%)
Inflammation	0 (40%)
	+1 (20%)	+1 (60%)	+2 (80%)	+3 (60%)
	+2 (40%)	+2 (40%)	+1 (20%)	+1 (40%)
Edema	0 (40%)
	+1 (20%)	+1 (60%)	+2 (80%)	+3 (60%)
	+2 (40%)	+2 (40%)	+1 (20%)	+1 (40%)
Necrosis	0 (40%)
	+1 (20%)	+1 (60%)	+2 (80%)	+3 (60%)
	+2 (40%)	+2 (40%)	+1 (20%)	+1 (40%)

1a Randomly selected sections blindly scored with a score applied to review of a whole lung section, scored at X10 magnification.

2b ZAB: Zabofloxacin, MOX: moxifloxacin, LEV: levofloxacin and CIP: ciprofloxacin.

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DOI: https://doi.org/10.21307/pjm-2019-007 | Journal eISSN: 2544-4646 | Journal ISSN: 1733-1331

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Language: English

Page range: 59 - 69

Published on: Mar 27, 2019

Published by: Polish Society of Microbiologists

In partnership with: Paradigm Publishing Services

Publication frequency: 4 issues per year

Keywords:

MRSA,

ED50,

fluoroquinolones,

quinolone resistance-determining regions,

zabofloxacin

Related subjects:

Life sciences,

Microbiology and virology

© 2019 NELLY M. MOHAMED, AZZA S. ZAKARIA, EVA A. EDWARD, AMANY ABDEL-BARY, published by Polish Society of Microbiologists
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

Volume 68 (2019): Issue 1 (March 2019)

In Vitro and In Vivo Activity of Zabofloxacin and Other Fluoroquinolones Against MRSA Isolates from A University Hospital in Egypt

Figures & Tables

Table I

Table II

Fig. 1.

Fig. 2.

Table III

Table IV

Fig. 3.

Fig. 4.

Table V

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