Ceftobiprole: An Extended-Spectrum Anti–Methicillin-Resistant Staphylococcus aureus Cephalosporin

Shawn D Anderson, PharmD; John G Gums, PharmD, FCCP

The Annals of Pharmacotherapy. 2008;42(6):806-816.

Pharmacology and Mechanism of Action

Transpeptidases, or penicillin-binding proteins (PBPs), cross-link polypeptide chains in bacterial cell walls and are the target for β-lactam antibiotics. β-Lactam antibiotics mimic the substrate for PBPs, bind irreversibly by covalent acylation, and incapacitate PBPs, all of which result in cell death.^[5] In MRSA, the mecA gene located on the staphylococcal chromosome cassette mec encodes PBP2a.^[6] The extended-spectrum cephalosporin, ceftobiprole, was developed specifically to bind to PBP2a of MRSA.^[3,5] Crystallography revealed that PBP2a is located in a narrow groove on the bacterial cell surface.^[7] Currently available β-lactams are not equipped to acylate PBP2a within this groove.^[8] Ceftobiprole possesses a vinylpyrrolidinone moiety at position 3, which aids in the interaction with PBP2a.^[5] As such, ceftobiprole is active against resistant S. aureus isolates due to mecA production of PBP2a.

Davies et al.^[9] determined the PBP affinity of ceftobiprole in S. aureus, Streptococcus pneumoniae, Escherichia coli, and Pseudomonas aeruginosa. Ceftobiprole had good affinity (50% inhibitory concentration [IC ₅₀ ] 1 µg/mL) for PBP1, PBP2, PBP3, and PBP4 in a methicillin-susceptible S. aureus (MSSA) isolate and for PBP2a in an MRSA isolate. In S. pneumoniae, ceftobiprole had an IC ₅₀ of 0.06 µg/mL or less for PBP1a, PBP2b, and PBP2x in a penicillin-susceptible isolate and an IC ₅₀ of 1 µg/mL or less for PBP1a and PBP2x in a penicillin-resistant S. pneumoniae isolate. Ceftobiprole exhibited high affinity for PBP1a, PBP2, PBP3, and PBP4 in E. coli. An IC ₅₀ of 0.5 µg/mL or less was shown for PBP1a, PBP1b, PBP3, and PBP4, and no affinity was observed for PBP5/6 in P. aeruginosa. Potent inhibition of multiple PBPs, specifically PBP2a in MRSA, PBP2x in penicillin-resistant S. pneumoniae, and PBP3 in E. coli and P. aeruginosa, explains ceftobiprole's broad activity spectrum.^[8,10]

1 2 3 4 5 6 7 8 9 10 11 12

Next Section

Cite this: Ceftobiprole: An Extended-Spectrum Anti–Methicillin-Resistant Staphylococcus aureus Cephalosporin - Medscape - Jun 01, 2008.

Table 1. In Vitro Activity of Ceftobiprole ^{[11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31]}
Aerobic and facultative gram-positive	BPR	CTX	CIP	VAN	LIN
Organism			MIC₉₀ (µg/mL)
MS Staphylococcus aureus	0.5	4	1	1	2
MR S. aureus	2	>32	>2	2	2
MS coagulase-negative staphylococci	0.25	8	≤0.25	2	2
MR coagulase-negative staphylococci	2	>32	>2	2	2
group A streptococci	0.06	≤0.25	>2	1
β-hemolytic streptococci	≤0.015	≤0.25	1	0.5
	BPR	CTX	ERY	AMOX	MOX
PS Streptococcus pneumoniae	≤0.015	0.06	2	≤0.06	0.25
PI S. pneumoniae	0.12	1	>32	1	0.12
PR S. pneumoniae	0.25	4	>32	8	0.25
	BPR	CTX	AMP	VAN	LIN
Enterococcus faecalis^a	4	>32	4	>16	2
Enterococcus faecium^b	>32	>32	>16	>16	2
Aerobic and facultative gram-negative	BPR	CPM	CIP	IMI	MER
ESBL-negative Escherichia coli	0.06	≤0.12	0.12	0.25	≤0.06
ESBL-positive E. coli	>32	>16	>2	0.12	≤0.06
ESBL-negative Klebsiella pneumoniae	0.06	≤0.12	≤0.25	0.5	≤0.06
ESBL-positive K. pneumoniae	>32	>16	>2	0.5	0.25
Citrobacter freundii	0.5	0.5	≤0.25	0.5	≤0.06
Enterobacter cloacae	0.12	0.25	≤0.25	0.5	≤0.06
Enterobacter aerogenes	>32	4	>2	1	0.12
Proteus mirabilis	≤0.015	≤0.12	≤0.25	1	≤0.06
Proteus vulgaris	>32	0.25	0.12	2	0.5
Morganella morganii	0.12	0.12	>2	2	0.5
Providencia spp.	0.12	0.5	>2	2	1
Serratia marcescens	8	0.5	2	1	≤0.06
Acinetobacter spp.	>32	>16	>2	>8	8
ceftazidime-susceptible Pseudomonas aeruginosa	8	8	1	2	2
ceftazidime-resistant P. aeruginosa	>32	32	>2	2	4
	BPR	CTX	AZM	CO-AMOX	MOX
Haemophilus influenzae	0.06	0.03	2	2	≤0.03
Moraxella catarrhalis	0.5	0.5	≤0.12	≤0.25	0.06
	BPR	CXM
Neisseria gonorrhoeae	0.06	0.12
Anaerobes	BPR	CTX	CFX	PIP/TAZ	MER
Bacteroides fragilis	>128	64	16	4	0.5
Prevotella spp.	>128	32	8	1	0.25
Clostridium difficile	8	64	32	2	2
Clostridium perfringens	≤0.016	4	2	1	≤0.016

AMOX = amoxicillin; AMP = ampicillin; AZM = azithromycin; BPR = ceftobiprole; CFX = cefoxitin; CIP = ciprofloxacin; CO-AMOX = amoxicillin/clavulanate; CPM = cefepime; CTX = ceftriaxone; CXM = cefotaxime; ERY = erythromycin; ESBL = extended-spectrum β-lactamase; IMI = imipenem; LIN = linezolid; MER = meropenem; MOX = moxifloxacin; MR = methicillin-resistant; MS = methicillin-susceptible; PI = penicillin-intermediate; PIP/TAZ = piperacillin/tazobactam; PR = penicillin-resistant; PS = penicillin-susceptible; VAN = vancomycin
^a Twenty of 62 isolates were vancomycin-resistant
^b Twenty-four of 50 isolates were vancomycin-resistant

Table 2. Pharmacokinetic and Pharmacodynamic Characteristics of Ceftobiprole ^{[33,34,35,36]}
Variable	500 mg	750 mg	1000 mg	Day 1	Day 8	Day 1	Day 8
				Multiple Dose, n = 16, Mean ± SD
	Single Dose, n = 39, Mean ± SD			500 mg		750 mg
C _max (µg/mL)^a	35.5 ± 6.8	59.6 ± 11	72.2 ± 8.8	40.6 ± 7.4	44.2 ± 11	60.7 ± 4.6	60.6 ± 10
AUC (µg·h/mL)	76.6 ± 3.9	135 ± 28	151 ± 9.0	101 ± 9.0	108 ± 22	156 ± 19	165 ± 13
t _1/2 (h)	3.4 ± 0.3	3.5 ± 0.4	3.2 ± 0.2	3.6 ± 0.5	4.0 ± 0.3	3.6 ± 0.3	4.1 ± 0.4
Cl _ren (L/h)	5.07 ± 0.2	4.08 ± 0.8	4.16 ± 0.6	4.1 ± 0.75	4.5 ± 1.1	4.0 ± 0.5	4.1 ± 0.6
V _ss (L)	19.8 ± 2.0	18.4 ± 2.6	18.9 ± 2.3	16.4 ± 2.1	16.7 ± 3.6	16.3 ± 1.8	16.1 ± 2.2
T > MIC(%)^b	42	58	58	40–58		58–75
	PAE (h)
Organism	MIC₉₀ (µg/mL)	Mean	Range
Streptococcus pneumoniae	0.016–1.0 (n = 3)	1.8	1.4–3.1
MSSA	0.25 (n = 2)	0.4	0–0.8
MRSA	0.25 – 2.0 (n = 4)	1.0	0–1.8
Enterococcus faecalis	0.125 – 0.5 (n = 3)	0.4	0–0.9

Organism	MIC₉₀ (µg/mL)	Mean	Range
	PAE (h)
Streptococcus pneumoniae	0.016–1.0 (n = 3)	1.8	1.4–3.1
MSSA	0.25 (n = 2)	0.4	0–0.8
MRSA	0.25 – 2.0 (n = 4)	1.0	0–1.8
Enterococcus faecalis	0.125 – 0.5 (n = 3)	0.4	0–0.9

AUC = area under the concentration–time curve; C _max = maximum serum concentration; Cl _ren = total renal clearance; MIC ₉₀ = 90% minimum inhibitory concentration; MRSA = methicillin-resistant Staphylococcus aureus, MSSA = methicillin-susceptible Staphylococcus aureus, PAE = postantibiotic effect; t _1/2 = elimination half-life; T > MIC ₉₀ = time above the 90% minimum inhibitory concentration; V _ss = volume of distribution at steady-state
^a After a 30-minute infusion
^b Of a 12-hour dosing interval with MIC 4 µg/mL

Table 3. TARs for Multiple Ceftobiprole Dosing Schemes
Mouton(2004)⁴⁰	MIC₉₀ (µg/mL)	500 mg q12h (30 min) TAR (%)			750 mg q12h (30 min) TAR (%)			500 mg q8h (30 min) TAR (%)
		40	50	60	40	50	60	40	50	60
	2	100	100	72		100	99		100	100
	4	59	1	0	100	78	15	100	99	79
Lodise(2007)³⁹	MIC₉₀ (µg/mL)	Cl_cr (mL/min)	500 mg q12h (1 h) TAR (%)			500 mg q8h (30 min) TAR (%)			500 mg q8h (1 h) TAR (%)			500 mg q8h (2 h) TAR (%)
			40	50	60	40	50	60	40	50	60	40	50	60
	2	120	83	74		93	88	83	95	90	85	97	94	89
		100	87	79		95	92	87	96	93	88	98	95	92
		80	91	84		97	94	90	97	95	92	99	97	94
	4	120	59	47		80	71	63	83	74	66	89	80	71
		100	67	55		85	78	70	87	80	73	92	85	77
		80	74	63		89	83	77	91	85	79	94	89	83

MIC₉₀ (µg/mL)	Cl_cr (mL/min)	500 mg q12h (1 h) TAR (%)			500 mg q8h (30 min) TAR (%)			500 mg q8h (1 h) TAR (%)			500 mg q8h (2 h) TAR (%)
		40	50	60	40	50	60	40	50	60	40	50	60
2	120	83	74		93	88	83	95	90	85	97	94	89
	100	87	79		95	92	87	96	93	88	98	95	92
	80	91	84		97	94	90	97	95	92	99	97	94
4	120	59	47		80	71	63	83	74	66	89	80	71
	100	67	55		85	78	70	87	80	73	92	85	77
	80	74	63		89	83	77	91	85	79	94	89	83

Table 4. Results from Phase 3 Clinical Trials in cSSSIs
Analysis Population^a	BPR Cure Rate (%)	VAN Cure Rate (%)	Difference (%)	95% CI of Difference	BPR Cure Rate (%)	VAN/CTZ Cure Rate (%)	Difference (%)	95% CI of Difference
	Noel(2008)⁴²				Noel(2008)⁴³
ITT	309/397 (77.8)	300/387 (77.5)	0.3	–5.5 to 6.1	448/547 (81.9)	227/281 (80.8)	1.1	–4.5 to 6.7
MITT (+)	225/276 (81.5)	219/267 (82.0)	–0.5	–7.0 to 6.0
MITT (–)	27/36 (75)	17/34^b (50)	25	3.0 to 47.0
CE	263/282 (93.3)	259/277 (93.5)	–0.2	–4.4 to 3.9	439/485 (90.5)	220/244 (90.2)	0.3	–4.2 to 4.9
ME	213/226 (94.2)	203/217 (93.5)	0.7	–3.8 to 5.2
ME (+)					292/318 (91.8)	149/165 (90.3)	1.5	–3.6 to 7.6
ME (–)					109/124 (87.9)	61/68 (89.7)	–1.8	–11.0 to 9.1
	Pts., n (%)		Pts., n (%)
	BPR (n = 389)	VAN (n = 382)	BPR (n = 543)	VAN/CTZ (n = 279)
Any AE	203 (52)	193 (51)	304 (56)	159 (57)
Serious AE	24 (6)	23 (6)	39 (7)	24 (9)
Discontinuation due to AE	17 (4)	22 (6)	22 (4)	10 (4)

	BPR (n = 389)	VAN (n = 382)	BPR (n = 543)	VAN/CTZ (n = 279)
	Pts., n (%)		Pts., n (%)
Any AE	203 (52)	193 (51)	304 (56)	159 (57)
Serious AE	24 (6)	23 (6)	39 (7)	24 (9)
Discontinuation due to AE	17 (4)	22 (6)	22 (4)	10 (4)

AE = adverse event; BPR = ceftobiprole; CE = clinically evaluable; cSSSI = complicated skin and skin-structure infection; CTZ = ceftazidime; ITT = intent-to-treat; ME = microbiologically evaluable; MITT = modified intent-to-treat; VAN = vancomycin; (+) = gram-positive organisms; (–) = gram-negative organisms
^a Noninferiority conditions met in both trials and no significant difference in the number of total AEs
^b Cure occurred in 3 of 4 patients who received aztreonam and in 14 of 30 who received only vancomycin

Table 4. Results from Phase 3 Clinical Trials in cSSSIs
Analysis Population^a	BPR Cure Rate (%)	VAN Cure Rate (%)	Difference (%)	95% CI of Difference	BPR Cure Rate (%)	VAN/CTZ Cure Rate (%)	Difference (%)	95% CI of Difference
	Noel(2008)⁴²				Noel(2008)⁴³
ITT	309/397 (77.8)	300/387 (77.5)	0.3	–5.5 to 6.1	448/547 (81.9)	227/281 (80.8)	1.1	–4.5 to 6.7
MITT (+)	225/276 (81.5)	219/267 (82.0)	–0.5	–7.0 to 6.0
MITT (–)	27/36 (75)	17/34^b (50)	25	3.0 to 47.0
CE	263/282 (93.3)	259/277 (93.5)	–0.2	–4.4 to 3.9	439/485 (90.5)	220/244 (90.2)	0.3	–4.2 to 4.9
ME	213/226 (94.2)	203/217 (93.5)	0.7	–3.8 to 5.2
ME (+)					292/318 (91.8)	149/165 (90.3)	1.5	–3.6 to 7.6
ME (–)					109/124 (87.9)	61/68 (89.7)	–1.8	–11.0 to 9.1
	Pts., n (%)		Pts., n (%)
	BPR (n = 389)	VAN (n = 382)	BPR (n = 543)	VAN/CTZ (n = 279)
Any AE	203 (52)	193 (51)	304 (56)	159 (57)
Serious AE	24 (6)	23 (6)	39 (7)	24 (9)
Discontinuation due to AE	17 (4)	22 (6)	22 (4)	10 (4)

	BPR (n = 389)	VAN (n = 382)	BPR (n = 543)	VAN/CTZ (n = 279)
	Pts., n (%)		Pts., n (%)
Any AE	203 (52)	193 (51)	304 (56)	159 (57)
Serious AE	24 (6)	23 (6)	39 (7)	24 (9)
Discontinuation due to AE	17 (4)	22 (6)	22 (4)	10 (4)

Table 4. Results from Phase 3 Clinical Trials in cSSSIs
Analysis Population^a	BPR Cure Rate (%)	VAN Cure Rate (%)	Difference (%)	95% CI of Difference	BPR Cure Rate (%)	VAN/CTZ Cure Rate (%)	Difference (%)	95% CI of Difference
	Noel(2008)⁴²				Noel(2008)⁴³
ITT	309/397 (77.8)	300/387 (77.5)	0.3	–5.5 to 6.1	448/547 (81.9)	227/281 (80.8)	1.1	–4.5 to 6.7
MITT (+)	225/276 (81.5)	219/267 (82.0)	–0.5	–7.0 to 6.0
MITT (–)	27/36 (75)	17/34^b (50)	25	3.0 to 47.0
CE	263/282 (93.3)	259/277 (93.5)	–0.2	–4.4 to 3.9	439/485 (90.5)	220/244 (90.2)	0.3	–4.2 to 4.9
ME	213/226 (94.2)	203/217 (93.5)	0.7	–3.8 to 5.2
ME (+)					292/318 (91.8)	149/165 (90.3)	1.5	–3.6 to 7.6
ME (–)					109/124 (87.9)	61/68 (89.7)	–1.8	–11.0 to 9.1
	Pts., n (%)		Pts., n (%)
	BPR (n = 389)	VAN (n = 382)	BPR (n = 543)	VAN/CTZ (n = 279)
Any AE	203 (52)	193 (51)	304 (56)	159 (57)
Serious AE	24 (6)	23 (6)	39 (7)	24 (9)
Discontinuation due to AE	17 (4)	22 (6)	22 (4)	10 (4)

	BPR (n = 389)	VAN (n = 382)	BPR (n = 543)	VAN/CTZ (n = 279)
	Pts., n (%)		Pts., n (%)
Any AE	203 (52)	193 (51)	304 (56)	159 (57)
Serious AE	24 (6)	23 (6)	39 (7)	24 (9)
Discontinuation due to AE	17 (4)	22 (6)	22 (4)	10 (4)

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....

Ceftobiprole: An Extended-Spectrum Anti–Methicillin-Resistant Staphylococcus aureus Cephalosporin

Pharmacology and Mechanism of Action

Tables

Tables

Tables

Tables

Tables

Tables

Authors and Disclosures

Authors and Disclosures

Comments

Most Popular Articles

Email This

Feedback