Arbekacin: another novel agent for treating infections due to methicillin-resistant Staphylococcus aureus and multidrug-resistant Gram-negative pathogens

Figures & data

Figure 1 Structural formula of arbekacin sulfate.

Abbreviations: APH, aminogly coside-phosphotransferase; AAD, aminoglycoside-adenyltransferase; AAC, aminoglycoside-acetyltransferase.

Table 1 In vitro antibacterial activity against aerobic bacteria

Bacterial strain	(μg/mL)	Antibacterial agent
		Gentamicin	Tobramycin	Amikacin	Arbekacin	Vancomycin	Teicoplanin	Linezolid
Methicillin-resistant Staphylococcus aureus (n=76)	MIC50	16	≥256	16	0.5	1	0.5	2
	MIC90	128	≥256	32	1	2	2	2
	Range	0.125 to ≥256	0.25 to ≥256	1 to ≥256	0.125 to 4	0.5 to 2	0.125 to 4	1 to 4
Methicillin-susceptible S. aureus (n=54)	MIC50	0.25	0.5	2	0.5	1	0.5	2
	MIC90	16	8	4	1	2	1	2
	Range	0.125 to 64	0.125 to 32	0.5 to 8	0.125 to 1	0.5 to 2	0.25 to 2	1 to 4
Streptococcus pneumonia (n=127)	MIC50	4	16	32	16	0.25	≤0.06	1
	MIC90	8	16	64	32	0.5	0.125	1
	Range	2 to 16	4 to 32	16 to 128	8 to 64	0.125 to 0.5	≤0.06 to 0.125	0.125 to 2
Haemophilus influenzae (n=123)	MIC50	1	2	4	2	nt	nt	nt
	MIC90	1	2	8	4	nt	nt	nt
	Range	0.125 to 4	0.5 to 8	0.5 to 8	0.5 to 8	nt	nt	nt
Moraxella catarrhalis (n=70)	MIC50	0.125	0.25	0.5	0.125	64	16	8
	MIC90	0.125	0.25	1	0.25	128	32	8
	Range	≤0.06 to 0.25	≤0.06 to 0.5	≤0.06 to 2	≤0.06 to 0.5	32 to 128	8 to 32	2 to 16
Klebsiella pneumonia (n=78)	MIC50	0.25	0.5	1	0.5	nt	nt	nt
	MIC90	0.25	0.5	1	0.5	nt	nt	nt
	Range	≤0.06 to 0.5	≤0.06 to 8	0.125 to 2	≤0.06 to 0.5	nt	nt	nt
Pseudomonas aeruginosa (n=103)	MIC50	1	0.5	2	1	nt	nt	nt
	MIC90	8	2	8	8	nt	nt	nt
	Range	≤0.06 to ≥256	≤0.06 to ≥256	0.125 to 64	0.125 to 32	nt	nt	nt

Note: Inoculum size: 10⁶ CFU/mL.

Abbreviations: nt, not tested; CFU, colony forming units; MIC, minimal inhibitory concentration; MIC₉₀, minimal inhibitory concentration for 90% of the organisms; MIC₅₀, minimal inhibitory concentration for 50% of the organisms.

Figure 2 Antibacterial activity against MRSA.

Notes: The surveillance was jointly conducted by the Surveillance Committee of Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Clinical Microbiology. VCM, TEIC, ABK, and LZD: n=557; ST, RFP, and DAP: n=103.
Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus; VCM, vancomycin; TEIC, teicoplanin; ABK, arbekacin; LZD, linezolid; ST, sulfamethoxazole-trimethoprim; RFP, rifampicin; DAP, daptomycin.

Figure 3 Bactericidal activity of anti-MRSA agents against five MRSA strains.

Notes: Boxes and bars indicate mean and SD of viable cell counts. Mean ± SD of viable cell count (log of CFU/mL) before exposure to antibiotics was 6.40±0.06.
Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus; TEIC, teicoplanin; LZD, linezolid; VCM, vancomycin; QPR/DPR, quinupristin/dalfopristin; ABK, arbekacin; SD, standard deviation; CFU, colony forming units.

Figure 4 Effect of TSST-1 producing ability of MRSA.

Notes: (A) Effect on TSST-1 production in logarithmic growth phase; (B) effect on TSST-1 production of blood-containing medium. 1 MIC values of test drugs against S. aureus Sak-1 were all 1.56 μg/mL. The 1/2, 1/4, and 1/8 MIC values were 0.78, 0.39, and 0.195 μg/mL, respectively. C_max is the maximum concentration of serum after the administration of each drug in humans using the usual dose, and these values were 9.6 μg/mL for ABK, 49.5 μg/mL for VCM and 71.68 μg/mL for TEIC, respectively. Then, 1/16, 1/64, 1/256 and 1/1024 C_max were calculated using the C_max of each drug.
Abbreviations: MRSA, methicillin-resistant Staphylococcus aureus; ABK, arbekacin; VCM, vancomycin; TEIC, teicoplanin; TSST-1, toxic shock syndrome toxin-1; CFU, colony forming units; MIC, minimal inhibitory concentration; C_max, maximum concentration.

Figure 5 Scoring of combination effect for each drug combination against multidrug-resistant (MDR) Pseudomonas aeruginosa strains.

Notes: (A) All 47 MDRPs. (B) N=41 metallo-beta-lactamase (MBL)-positive MDRP strains.
Abbreviations: MDRP, multidrug-resistant Pseudomonas aeruginosa; AZT, aztreonam; AMK, amikacin; GM, gentamicin; ABK, arbekacin.

Figure 6 Results of Break-point Checkerboard Plate for (A) colistin plus rifampicin, (B) arbekacin plus aztreonam and (C) amikacin plus aztreonam.

Notes: The gray area indicates the drug concentration using the Break-point Checkerboard Plate. The open circles indicate the strains judged as “effective” and the closed circles indicate the strains judged as “non-effective”.

Figure 7 Plasma (serum) concentration after administration of ABK.

Notes: (A) Plasma concentration after administration of ABK 200 mg for MRSA infected adult patients; (B) serum concentrations of ABK in healthy adults after multiple administrations of ABK 400 mg (closed circles) or 600 mg (open circles). Mean ± SD (n=8).
Abbreviations: ABK, arbekacin; MRSA, methicillin-resistant Staphylococcus aureus; SD, standard deviation; Ccr, creatinine clearance (mL/min).

Table 2 Pharmacokinetic parameters after administration of ABK

Group		Cmax (μg/mL)	Ctrough (μg/mL)	T1/2 (hr)	AUC0–24 (μg · hr/mL)	CLtot (L/hr)	Vss (L)	Reference
All patients	n	17	17	12	12	12	12	^Citation24
	Mean ± SD	16.2±5.1	1.1±1.7	8.06±7.44	103.1 ±66.4	2.61 ±1.69	15.3±3.6
	Min–max	7.2–23.1	0.0–5.3	1.96–23.73	36.5–222.4	0.56–5.47	10.4–20.2
Normal renal function 80≦ Ccr	n	10	10	5	5	5	5
	Mean ± SD	15.2±5.7	0.3±0.4	3.51 ±2.67	58.6±22.5	3.71±1.31	14.6±4.3
	Min–max	7.2–23.1	0.0–1.2	1.96–8.3	36.5–96.3	1.81–5.47	10.4–20.2
Mild renal dysfunction 50≦ Ccr <80	n	3	3	3	3	3	3
	Mean ± SD	14.8±2.4	0.2±0.3	3.95±2.32	62.9± 18.0	3.30± 1.06	15.9±3.9
	Min–max	12.4–17.3	0.0–0.6	2.51–6.63	45.6–81.5	2.27–4.38	11.6–19.3
Moderate to severe renal dysfunction Ccr <50	n	4	4	4	4	4	4
	Mean ± SD	19.8±3.7	3.9± 1.1	16.82±6.02	188.8±24.0	0.7±0.14	15.7±3.5
	Min–max	14.6–23.1	2.7–5.3	10.27–23.73	165.3–222.4	0.56–0.87	10.6–18.5
Dose	n=8	Cmax (μg/mL)	Cpeak (μg/mL)	T1/2 (hr)	AUC0-infnity (μg · hr/mL)	CLtot (L/hr)	Vss (L)	Reference
400 mg Day 7	Mean ± SD	44.4±5.3	25.6±2.1	6.4± 1.7	107.5± 17.1	3.8±0.6	18.6±3.4	25
600 mg Day 7	Mean ± SD	68.9±5.4	38.0±2.8	4.1 ±1.6	149.9±12.9	4.0±0.3	14.5±2.8

Abbreviations: ABK, arbekacin; Ccr, creatinine clearance (mL/min); SD, standard deviation; C_max, maximum concentration; C_trough, trough concentration; T_1/2, half-life; AUC, area under the curve; CL_tot, total clearance; min, minimum; max, maximum; Vss, distribution volume at steady state.

Table 3 Relationship between final daily dosage and efficacy/adverse drug reaction (ADR) rates

Final daily dosage (mg/kg)	Type of infection	n/29	Efficacy rate (%)** 89.7 (26/29)		Incidence of ADRs (%)*		Type of ADR
					17.2	(5/29)
<5	Sepsis	1	0.0	(0/1)	100	(1/1)	Renal disorder, platelet count decreased
	Pneumonia	8	87.5	(7/8)	25.0	(2/8)	Renal disorder, constipation
	Total	9	77.8	(7/9)	33.3	(3/9)
≥5 to >6	Sepsis	3	100	(3/3)	0.0	(0/3)	Liver disorder
	Pneumonia	5	80.0	(4/5)	20.0	(1/5)
	Total	8	87.5	(7/8)	12.5	(1/8)
≥6	Sepsis	4	100	(4/4)	0.0	(0/4)	Elevated AST and ALT
	Pneumonia	8	100	(8/8)	12.5	(1/8)
	Total	12	100	(12/12)	8.3	(1/12)

Notes: Eighty-nine patients from eleven clinical sites in Japan were enrolled in this clinical investigation, who in total were diagnosed with pneumonia or sepsis with MRSA infection or suspected MRSA infection. Among the patients, 29 adult patients who showed positive for MRSA detection following serum concentration analysis at the dose levels specified in the protocol were regarded as subjects for efficacy/safety analysis. Efficacy rate (%): (effective)/(effective + not effective) ×100. Incidence of ADRs (%): (number of patients with ADRs)/(total patients) ×100.

* ADRs were observed in 5 patients. Incidence of ADRs was calculated by “5 patients/29 patients”.

** The efficacy of ABK were observed in 26 patients. The efficacy rate was calculated by “26 patients/29 patients”.

Abbreviations: ABK, arbekacin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; MRSA, methicillin-resistant Staphylococcus aureus.

AikawaNKohnoSKakuMWatanabeAYamaguchiKTanigawaraYAn open clinical study of arbekacin 200 mg qd in patients infected with methicillin-resistant Staphylococcus aureus (MRSA) – A clinical pharmacology studyJpn J Chemother2008563299312

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