Levonadifloxacin, a Novel Broad-Spectrum Anti-MRSA Benzoquinolizine Quinolone Agent: Review of Current Evidence

Figures & data

Figure 1 Chemical structures of (A) WCK 771 and (B) WCK 2349. Data from De Souza NJ, Gupte SV, Deshpande PK, et al. A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant staphylococcus aureus. J Med Chem. 2005;48(16):5232–5242.⁹

Table 1 In Vitro Activity of WCK 771 Against Staphylococcus aureus (QSSA, QRSA, VISA) Isolates

Quinolone	S. aureus (MICs in mg/L)
	All Isolates (N=116)		QSSA (N=44)		QRSA (N=53)		VISA (N=3)
	MIC50	MIC90	MIC50	MIC90	MIC50	MIC90	MIC50	MIC90
WCK 771	0.5	1	≤0.008	0.015	0.5	1	1	1
Levofloxacin	4	32	0.12	0.25	8	32	8	16
Ciprofloxacin	16	>32	0.25	0.5	>32	>32	32	32
Moxifloxacin	2	>4	0.03	0.06	4	>4	4	4
Clinafloxacin	0.25	2	0.015	0.03	1	2	1	1

Note: Data From: Jacobs MR, Bajaksouzian S, Windau A, et al. In vitro activity of the new quinolone WCK 771 against staphylococci. Antimicrob Agents Chemother. 2004;48(9):3338–3342.¹⁶

Abbreviations: QSSA, quinolone-susceptible S. aureus; QRSA, quinolone-resistant S. aureus; VISA, vancomycin-intermediate S. aureus.

Table 2 MIC₅₀ and MIC₉₀ of WCK 771 in Comparison to Metronidazole and Clindamycin in Different Anaerobes

Bacteria	Anaerobes MIC (mg/L)
	WCK 771		Metronidazole		Clindamycin
	MIC50	MIC90	MIC50	MIC90	MIC50	MIC90
Bacteroides fragilis	1	16	1	1	2	2
B. fragilis group	1	8	1	1	2	>32
Fusobacteria	0.5	8	≤0.125	0.25	0.06	32
Prevotella, Porphyromonas	0.25	1	1	4	≤0.016	0.06
Peptostreptococci	0.5	1	0.5	2	0.125	1
Propionibacteria	0.125	0.125	>16	>16	0.06	0.125
Clostridium perfringens	0.06	0.25	1	1	0.5	2
Clostridium difficile	0.5	1	0.25	0.25	8	>32

Note: Data From: Peric M, Jacobs MR, Appelbaum PC. Anti-anaerobic activity of a novel fluoroquinolone, WCK 771, compared to those of nine other agents. Antimicrob Agents Chemother. 2004;48(8):3188–3192.²³

Table 3 WCK 771 CLSI QC Ranges for Disk Diffusion and Broth Microdilution Testing

Recommended CLSI QC Ranges
ATCC Strain	10 µg Disk (Zone Size in mm)	Broth Microdilution MIC in mg/L
Staphylococcus aureus ATCC 25923	32–39	NA
Staphylococcus aureus ATCC 29213	NA	0.008–0.03
Escherichia coli ATCC 25922	27–33	0.03–0.25
Pseudomonas aeruginosa ATCC 27853	17–23	0.5–4
Haemophilus influenzae ATCC 49247	33–41	0.008–0.06
Streptococcus pneumoniae ATCC 49619	24–31	0.12−0.5

Note: Data From: Performance CLSI. Standards for Antimicrobial Susceptibility Testing, 26th Ed. CLSI Supplement M100S. Wayne, PA: Clinical and Laboratory Standards Institute; 2016.³⁴

Table 4 In Vivo Efficacy of WCK 771 in a Mouse Systemic Infection Model

Infecting Strain	SC Route		Oral Route
	ED50 (mg/kg)	ED90 (mg/kg)	ED50 (mg/kg)	ED90 (mg/kg)
S. aureus ATCC 25923	0.59	1.08	2.8	4.37
S. aureus Smith (ATCC 13709)	0.86	2.4	1.7	5.0
S. aureus 1199 NorA^−	2.2	3.1	2.2	3.1
S. aureus 1199B NorA^+	3.04	6.6	3.04	6.6
S. aureus 5023 (MRSA)	33.9	48.6	Not Studied
S. aureus 33 (MRSA)	38.3	70.4
S. aureus 34 (MRSA)	44.6	62.3
S. aureus 5002 (MRSA)	46.8	56.8
S. aureus 32 (MRSA)	27.8	62.1
S. aureus 97 (MRSA)	46.8	56.8

Note: Data From: Patel MV, De Souza NJ, Gupte SV, et al.Antistaphylococcal activity of WCK 771, a tricyclic fluoroquinolone, in animal infection models. Antimicrob Agents Chemother. 2004;48(12):4754–4761.³⁹

Table 5 Mean Levonadifloxacin C_max and AUC on Day 5 Following Intravenous WCK 771 and Oral WCK 2349 Administered Twice Daily to Healthy Indian Subjects

Dose	WCK 771		WCK 2349
	Cmax (µg/mL)	AUC(0–12) µg·h/mL	Cmax (µg/mL)	AUC(0–12) µg·h/mL
600 mg, q12h	26.3	142.97	14.81	91.11
800 mg, q12h	32.04	195.96	20.56	120.10
1000 mg, q12h	38.54	213.3	29.68	186.36
1200 mg, q12h	41.26	263.15	33.78	225.21

Note: Data From: Niu J, Ivaturi V, Gobburu J, Chugh R, Bhatia A. Pharmacokinetics of levonadifloxacin administered as intravenous WCK 771 and oral WCK 2349 in healthy Indian male adults. Abstract A-032, 55th ICAAC; 2015.⁴⁴

Table 6 Mean Levonadifloxacin C_max and AUC on Day 5 Following Intravenous WCK 771 and Oral WCK 2349 Administered Twice Daily to Healthy US Subjects

Dose	WCK 771		WCK 2349
	Cmax (µg/mL)	AUC0–24 µg·h/mL	Cmax (µg/mL)	AUC0–24 µg·h/mL
600 mg, q12h	15.84	183.68	–	–
800 mg, q12h	18.00	208.97	18.34	211.45
1000 mg, q12h	21.61	254.22	24.42	284.68
1200 mg, q12h	–	–	23.36	287.90

Note: Data From: Chugh R, Lakdavala F, Bhatia A. Safety and pharmacokinetics of multiple ascending doses of WCK 771 and WCK 2349. Abstract P1268. 26th Eur congr clin microbial infect dis, Amsterdam, Netherlands. European Society of Clinical Microbiology and Infectious Diseases; 2016; Basel, Switzerland.⁴⁵

De Souza NJ, Gupte SV, Deshpande PK, et al. A chiral benzoquinolizine-2-carboxylic acid arginine salt active against vancomycin-resistant staphylococcus aureus. J Med Chem. 2005;48(16):5232–5242. doi:10.1021/jm050035f16078842

 PubMed Web of Science ®Google Scholar

Jacobs MR, Bajaksouzian S, Windau A, et al. In vitro activity of the new quinolone WCK 771 against staphylococci. Antimicrob Agents Chemother. 2004;48(9):3338–3342. doi:10.1128/AAC.48.9.3338-3342.200415328094

 PubMed Web of Science ®Google Scholar

Peric M, Jacobs MR, Appelbaum PC. Anti-anaerobic activity of a novel fluoroquinolone, WCK 771, compared to those of nine other agents. Antimicrob Agents Chemother. 2004;48(8):3188–3192. doi:10.1128/AAC.48.8.3188-3192.200415273148

 PubMed Web of Science ®Google Scholar

Performance CLSI. Standards for Antimicrobial Susceptibility Testing, 26th Ed. CLSI Supplement M100S. Wayne, PA: Clinical and Laboratory Standards Institute; 2016.

 Google Scholar

Patel MV, De Souza NJ, Gupte SV, et al. Antistaphylococcal activity of WCK 771, a tricyclic fluoroquinolone, in animal infection models. Antimicrob Agents Chemother. 2004;48(12):4754–4761. doi:10.1128/AAC.48.12.4754-4761.200415561853

 PubMed Web of Science ®Google Scholar

Niu J, Ivaturi V, Gobburu J, Chugh R, Bhatia A. Pharmacokinetics of levonadifloxacin administered as intravenous WCK 771 and oral WCK 2349 in healthy Indian male adults. Abstract A-032, 55th ICAAC; 2015.

 Google Scholar

Chugh R, Lakdavala F, Bhatia A. Safety and pharmacokinetics of multiple ascending doses of WCK 771 and WCK 2349. Abstract P1268. 26th Eur congr clin microbial infect dis, Amsterdam, Netherlands. European Society of Clinical Microbiology and Infectious Diseases; 2016; Basel, Switzerland.

 Google Scholar