Pharmacodynamic activity of ceftobiprole compared with vancomycin versus methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate Staphylococcus aureus (VISA) and vancomycin-resistant Staphylococcus aureus (VRSA) using an in vitro model

Abstract

Background

This study compared the pharmacodynamics of ceftobiprole and vancomycin against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) using an in vitro model.

Methods

Two methicillin-susceptible S. aureus (MSSA), two community-associated (CA)-MRSA, one healthcare-associated (HA)-MRSA, three VISA and two VRSA were studied. The pharmacodynamic model was inoculated with a concentration of 1 × 10⁶ cfu/mL and ceftobiprole dosed every 8 h (at 0, 8 and 16 h) to simulate the fC_max and t_1/2 obtained after 500 mg intravenous (iv) every 8 h dosing (fC_max, 30 mg/L; t_1/2, 3.5 h). Vancomycin was dosed every 12 h (at 0 and 12 h) to simulate fC_max and t_1/2 obtained after 1 g iv every 12 h dosing (fC_max, 20 mg/L; t_1/2, 8 h). Samples were collected over 24 h to assess viable growth.

Results

Ceftobiprole T > MIC of ≥100% (ceftobiprole MICs, ≤2 mg/L) was bactericidal (≥3 log₁₀ killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin fAUC₂₄/MIC of 340 (vancomycin MIC, 1 mg/L for MSSA and MRSA) resulted in a 1.8–2.6 log₁₀ reduction in colony count at 24 h. Vancomycin fAUC₂₄/MIC of 85–170 (vancomycin MIC, 2–4 mg/L for VISA) resulted in a 0.4–0.7 log₁₀ reduction at 24 h. Vancomycin fAUC₂₄/MIC of 5.3 (vancomycin MIC, 64 mg/L for VRSA) resulted in a limited effect.

Conclusions

Ceftobiprole T > MIC of ≥100% (ceftobiprole MICs, ≤2 mg/L) was bactericidal (≥3 log₁₀ killing) against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h. Vancomycin was bacteriostatic against MSSA, MRSA and VISA, while demonstrating no activity against VRSA.

bactericidal, bacterial killing, inhibition

Introduction

Treatment options for patients with serious invasive infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are limited.¹ These options include vancomycin and newer agents such as linezolid and daptomycin.¹ Ceftobiprole, a cephalosporin, is currently in Phase III clinical development in the USA and UK, but has recently been approved for use in patients in both Canada and Switzerland.^2–4 Ceftobiprole is a broad-spectrum cephalosporin with demonstrated in vitro activity against Gram-positive cocci, including MRSA and methicillin-resistant Staphylococcus epidermidis (MRSE), penicillin-resistant Streptococcus pneumoniae, Enterococcus faecalis, Gram-negative bacilli including AmpC-producing Escherichia coli and Pseudomonas aeruginosa but excluding extended-spectrum β-lactamase (ESBL)-producing strains. In single-step and serial passage in vitro resistance development studies, ceftobiprole demonstrated a low propensity to select for resistant subpopulations.² Ceftobiprole, like cefepime, is a weak inducer and a poor substrate for AmpC β-lactamases.

Ceftobiprole medocaril, the prodrug of ceftobiprole, is converted by plasma esterases into ceftobiprole in <30 min. Peak serum concentrations of ceftobiprole observed at the end of a single 30 min infusion were 35.5 mg/L for a 500 mg dose and 59.6 mg/L with a 750 mg dose.² The volume of distribution of ceftobiprole is 0.26 L/kg (∼18 L), protein binding is ∼16% and its serum half-life is ∼3.5 h. Ceftobiprole is renally excreted (∼70% in the active form) and systemic clearance correlates with creatinine clearance, meaning that dosage adjustment is required in patients with renal dysfunction.

Ceftobiprole medocaril is being jointly developed by Basilea Pharmaceutica AG and Johnson and Johnson Pharmaceutical Research and Development LLC.^2–4 Currently, ceftobiprole has completed Phase III trials for complicated skin and skin structure infections due to MRSA, nosocomial pneumonia due to suspected or proven MRSA, while Phase III trials are ongoing for community-acquired pneumonia. The purpose of this study was to assess the pharmacodynamic activity of ceftobiprole and vancomycin against MRSA, vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) using an in vitro model.

Materials and methods

Bacterial strains and culture conditions

Ten S. aureus strains including two methicillin-susceptible S. aureus (MSSA), two community-associated (CA)-MRSA, one healthcare-associated (HA)-MRSA, three VISA and two VRSA were studied. The MSSA, CA-MRSA and HA-MRSA are clinical strains obtained from the CAN-ICU study, a national surveillance study assessing antimicrobial resistance in Canadian intensive care units.⁵ The MRSA strains had the following genotypes: CA-MRSA 63307 [CMRSA7/USA400/MW2, Panton–Valentine leucocidin (PVL) + ], CA-MRSA 61592 (CMRSA10/USA300, PVL + ); and HA-MRSA 60392 (CMRSA2/USA100/800/New York, PVL − ).⁶ VISA and VRSA isolates were obtained through the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) programme, supported under NIAID, NIH Contract No. N01-AI-95359.

For the pharmacodynamic studies, logarithmic phase cultures were prepared by initially suspending several colonies in cation-supplemented Mueller–Hinton broth (Oxoid, Nepean, Ontario, Canada) at a density equivalent to that of a 0.5 McFarland standard (1 × 10⁸ cfu/mL). This suspension was then diluted 1:100 and 20 µL of the diluted suspension was further diluted in 60 mL of cation-supplemented Mueller–Hinton broth. Following overnight growth at 37°C, suspensions were diluted 1:10 and ∼60 mL of the diluted suspension was added to the in vitro pharmacodynamic model. Viable bacterial counts consistently yielded a starting inoculum of ∼1 × 10⁶ cfu/mL.^7,8

Antibiotic preparations and susceptibility testing

Ceftobiprole was obtained as laboratory-grade powder from the manufacturer (Ortho-McNeil, NJ, USA). Vancomycin was purchased commercially. Stock solutions of each agent were prepared and dilutions made according to the CLSI M7-A7 method.⁹ Following two subcultures from frozen stock, antimicrobial agent MICs for the strains were determined by the CLSI broth microdilution method.⁹ All MIC determinations were performed in triplicate on separate days.

Pharmacokinetics of antibiotics in the in vitro pharmacodynamic model

Experiments were performed simulating peak free drug serum concentrations (fC_max) and fAUC₂₄ of ceftobiprole and vancomycin achieved in human serum after standard intravenous doses in healthy volunteers [ceftobiprole dose 500 mg every 8 h (fC_max, 30 mg/L); vancomycin 1 g dose every 12 h (fC_max, 20 mg/L)].^2,10,11 Protein free (f), also known as unbound, serum concentrations were simulated using known protein binding fractions (ceftobiprole ∼16%; vancomycin ∼50%).^2,10,12 Ceftobiprole clearance was simulated using a reported serum half-life of 3.5 h, while for vancomycin a half-life of 8 h was simulated.^2,10,11 The pharmacokinetics of ceftobiprole and vancomycin were evaluated by dosing using standard doses in the central compartment and sampling from this compartment at 0, 1, 2, 4, 6, 8, 12, 16 and 24 h. Ceftobiprole concentrations were determined in quadruplicate using E. coli ATCC 25922 as the test organism with a lower limit of quantification of 0.25 mg/L and was linear from 0.25 to 128 mg/L.^7,8,13 Specifically, concentrations were determined by measuring the diameters of zones of inhibition and comparing those zone sizes with zones sizes produced by known concentrations from a standard series. The lower and upper detection limits were 0.15 and 256 mg/L, respectively. Both the inter-day and intra-day variation was <15%. Vancomycin concentrations were assessed using a fluorescence polarization immunoassay (Abbott Diagnostics TDx).¹¹ The fAUC₂₄ (mg·h/L) for ceftobiprole and vancomycin was calculated using the trapezoidal rule.^7,8 The fAUC₂₄/MIC was calculated for ceftobiprole and vancomycin for each of the S. aureus strains studied.

In vitro pharmacodynamic model/pharmacodynamic experiments

The in vitro pharmacodynamic model used in this study has been previously described.^7,8 Logarithmic phase cultures were diluted (1:10) into fresh cation-supplemented Mueller–Hinton broth to achieve a starting inoculum of ∼1 × 10⁶ cfu/mL. This initial inoculum was introduced into the central compartment (volume, 610 mL) of the in vitro pharmacodynamic model and exposed to ceftobiprole, simulating free (protein unbound) serum concentrations obtained after standard 500 mg every 8 h or vancomycin 1 g every 12 h dosing. Pharmacodynamic experiments were performed in ambient air at 37°C. At 0, 1, 2, 4, 6, 8, 12, 16 and 24 h, samples were removed from the central compartment and viable bacterial counts carried out by plating serial 10-fold dilutions onto cation-supplemented Mueller–Hinton agar. Plates were incubated overnight at 37°C in ambient air. The lowest dilution plated was 0.1 mL of undiluted sample and the lowest level of detection was 200 cfu/mL (20 colonies grown from 0.1 mL of undiluted sample). Antibiotic carryover was minimized by diluting samples withdrawn from the model.

Bacterial inhibition including bactericidal (≥3 log₁₀ killing) activity as well as complete eradication of organisms from the model (below the limit of detection) was assessed at 8, 16 and 24 h and compared for ceftobiprole and vancomycin. Changes in cfu/mL at 24 h were compared using analysis of variance with Tukey's post hoc test. P ≤ 0.05 was considered significant.

Results

The susceptibility profiles of the 10 strains of S. aureus studied are presented in Table 1. The two MSSA strains demonstrated ceftobiprole MICs of 0.25 mg/L, while the three strains of MRSA produced ceftobiprole MICs of 1 mg/L (Table 1). The VISA and VRSA strains demonstrated ceftobiprole MICs of 1 or 2 mg/L (Table 1). Vancomycin MICs for all MSSA and MRSA were 1 mg/L, while vancomycin MICs for strains of VISA and VRSA were 2–4 and 64 mg/L, respectively (Table 1).

Table 1

Susceptibility profiles of 10 Staphylococcus aureus strains to ceftobiprole, vancomycin and comparator agents

	MIC (mg/L)
Strain	ceftobiprole	vancomycin	ceftriaxone	clarithromycin	clindamycin	levofloxacin	SXT
MSSA 62819	0.25	1	2	0.12	0.12	0.25	0.12
MSSA 61222	0.25	1	2	0.12	0.12	0.25	0.12
CA-MRSA 63307	1	1	32	0.25	0.12	0.25	0.12
CA-MRSA 61592	1	1	128	32	0.12	8	0.12
HA-MRSA 60392	1	1	128	32	8	32	0.12
VISA NRS18	1	4	32	32	8	8	0.12
VISA NRS21	2	2	128	0.12	0.12	16	4
VISA NRS4	1	4	128	32	8	16	0.12
VRSA VRS1	2	64	128	32	8	32	0.25
VRSA VRS3	1	64	128	32	8	16	0.12

SXT, trimethoprim/sulfamethoxazole; MSSA, methicillin-susceptible S. aureus; CA-MRSA, community-associated methicillin-resistant S. aureus; HA-MRSA, healthcare-associated methicillin-resistant S. aureus; VISA, vancomycin-intermediate S. aureus; VRSA, vancomycin-resistant S. aureus.

VISA and VRSA isolates were obtained through the Network on Antimicrobial Resistance in Staphylococcus aureus (NARSA) programme, supported under NIAID, NIH Contract No. N01-AI-95359.

For both ceftobiprole and vancomycin, the pharmacokinetic values achieved were within 15% of the expected (simulated) pharmacokinetic values in the model. The achieved pharmacokinetic values of ceftobiprole and vancomycin in the central compartment of the pharmacodynamic model were: ceftobiprole fC_max 28.0 ± 2.0 mg/L, t_1/2 3.6 ± 0.5 h and fAUC₂₄ 86.0 ± 6.9 mg·h/L; vancomycin fC_max 19.2 ± 1.6 mg/L, t_1/2 7.6 ± 0.9 h and fAUC₂₄ 340 ± 21.1 mg·h/L. The achieved ceftobiprole pharmacodynamic parameters were: T > MIC, 100%, fC_max/MIC, 14–112; and fAUC₂₄/MIC, 43–344 (Table 2). The vancomycin pharmacodynamics achieved were: T > MIC, 100%; fC_max/MIC, 0.3–19.2; fAUC₂₄/MIC, 5.3–340 (Table 3).

Table 2

Ceftobiprole pharmacodynamic parameters achieved in pharmacodynamic model

Strain	Ceftobiprole MIC (mg/L)	T > MIC [h (%)]	fCmax/MIC	fAUC24/MIC
MSSA 62819	0.25	24 (100)	112	344
MSSA 61222	0.25	24 (100)	112	344
CA-MRSA 63307	1	24 (100)	28	86
CA-MRSA 61592	1	24 (100)	28	86
HA-MRSA 60392	1	24 (100)	28	86
VISA NRS18	1	24 (100)	28	86
VISA NRS21	2	24 (100)	14	43
VISA NRS4	1	24 (100)	28	86
VRSA VRS1	2	24 (100)	14	43
VRSA VRS3	1	24 (100)	28	86

MSSA, methicillin-susceptible S. aureus; CA-MRSA, community-associated methicillin-resistant S. aureus; HA-MRSA, healthcare-associated methicillin-resistant S. aureus; VISA, vancomycin-intermediate S. aureus; VRSA, vancomycin-resistant S. aureus.

Table 3

Vancomycin pharmacodynamic parameters achieved in pharmacodynamic model

Strain	Vancomycin MIC (mg/L)	T > MIC [h (%)]	fCmax/MIC	fAUC24/MIC
MSSA 62819	1	24 (100)	19.2	340
MSSA 61222	1	24 (100)	19.2	340
CA-MRSA 63307	1	24 (100)	19.2	340
CA-MRSA 61592	1	24 (100)	19.2	340
HA-MRSA 60392	1	24 (100)	19.2	340
VISA NRS18	4	24 (100)	4.8	85
VISA NRS21	2	24 (100)	9.6	170
VISA NRS4	4	24 (100)	4.8	85
VRSA VRS1	64	24 (100)	0.3	5.3
VRSA VRS3	64	24 (100)	0.3	5.3

MSSA, methicillin-susceptible S. aureus; CA-MRSA, community-associated methicillin-resistant S. aureus; HA-MRSA, healthcare-associated methicillin-resistant S. aureus; VISA, vancomycin-intermediate S. aureus; VRSA, vancomycin-resistant S. aureus.

The pharmacodynamic activity of ceftobiprole against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA is described in Table 4. For the two MSSA strains, ceftobiprole T > MIC ≥100% (ceftobiprole MICs, 0.25 mg/L) resulted in bactericidal (≥3 log₁₀ killing) activity within 8 h after administration and completely eradicated the organisms from the model (below the limit of detection) at 24 h (Table 4). With the MRSA strains, ceftobiprole T > MIC ≥100% (ceftobiprole MIC 1 mg/L) resulted in bactericidal (≥3 log₁₀ killing) activity at 16 and 24 h after administration. No difference in bacterial killing was noted between CA-MRSA and HA-MRSA strains (P > 0.05). With the VISA and VRSA strains, ceftobiprole T > MIC ≥100% (ceftobiprole MICs, 1–2 mg/L) resulted in bactericidal (≥3 log₁₀ killing) activity at 16 and 24 h after administration. No difference in bacterial killing for ceftobiprole was observed between VISA, VRSA and MRSA strains (P > 0.05).

Table 4

Ceftobiprole killing of 10 strains of S. aureus in a pharmacodynamic model simulating free serum concentrations

	Log10 killing at 8, 16 and 24 ha
Strain	8 h	16 h	24 h
MSSA 62819	3.0 ± 0.5	3.5 ± 0.5	≥4.0
MSSA 61222	3.0 ± 0.4	3.6 ± 0.5	≥4.0
CA-MRSA 63307	2.1 ± 0.4	3.2 ± 0.4	3.5 ± 0.7
CA-MRSA 61592	2.0 ± 0.4	3.0 ± 0.3	3.3 ± 0.4
HA-MRSA 60392	1.9 ± 0.3	3.1 ± 0.3	3.2 ± 0.4
VISA NRS18	2.1 ± 0.3	3.5 ± 0.4	3.8 ± 0.5
VISA NRS21	1.7 ± 0.2	3.0 ± 0.3	3.2 ± 0.5
VISA NRS4	1.5 ± 0.3	3.2 ± 1.0	3.2 ± 0.9
VRSA VRS1	1.0 ± 0.3	3.0 ± 0.5	3.7 ± 0.4
VRSA VRS3	2.4 ± 0.4	3.1 ± 0.5	3.1 ± 0.5

MSSA, methicillin-susceptible S. aureus; CA-MRSA, community-associated methicillin-resistant S. aureus; HA-MRSA, healthcare-associated methicillin-resistant S. aureus; VISA, vancomycin-intermediate S. aureus; VRSA, vancomycin-resistant S. aureus.

^aGrowth reduction relative to initial inoculum.

The pharmacodynamic activity of vancomycin against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA is described in Table 5. Against the two MSSA and three MRSA strains, vancomycin fAUC₂₄/MIC of 340 (vancomycin MIC, 1 mg/L) resulted in a 0.3–1.1 log₁₀ reduction at 8 h, 1.0–1.4 log₁₀ reduction at 16 h and 1.8–2.6 log₁₀ reduction at 24 h (Table 5). No difference in bacterial killing was noted between CA-MRSA and HA-MRSA strains (P > 0.05). Against the VISA strains, vancomycin fAUC₂₄/MIC 85–170 (vancomycin MIC, 2–4 mg/L) resulted in a 0.2–0.3 log₁₀ reduction at 8 h, 0.3–0.6 log₁₀ reduction at 16 h and 0.4–0.7 log₁₀ reduction at 24 h. With the VRSA strains, vancomycin fAUC₂₄/MIC 5.3 (vancomycin MIC 64 mg/L) resulted in a limited effect compared with growth control with re-growth at 16 and 24 h. In all pharmacodynamic comparisons, ceftobiprole displayed significantly greater (P < 0.05) reductions in cfu/mL compared with vancomycin (Tables 4 and 5).

Table 5

Vancomycin killing of 10 strains of S. aureus in a pharmacodynamic model simulating free serum concentrations

	Log10 killing at 8, 16 and 24 ha
Strain	8 h	16 h	24 h
MSSA 62819	1.1 ± 0.4	1.4 ± 0.4	2.1 ± 0.5
MSSA 61222	1.0 ± 0.3	1.3 ± 0.4	2.0 ± 0.5
CA-MRSA 63307	0.8 ± 0.6	1.0 ± 0.4	2.4 ± 0.6
CA-MRSA 61592	0.3 ± 0.5	1.1 ± 0.4	2.6 ± 0.6
HA-MRSA 60392	0.4 ± 0.4	1.0 ± 0.5	1.8 ± 0.7
VISA NRS18	0.3 ± 0.3	0.6 ± 0.4	0.7 ± 0.5
VISA NRS21	0.2 ± 0.3	0.3 ± 0.4	0.4 ± 0.5
VISA NRS4	0.2 ± 0.4	0.3 ± 0.4	0.5 ± 0.4
VRSA VRS1	0	0	0
VRSA VRS3	0	0	0

MSSA, methicillin-susceptible S. aureus; CA-MRSA, community-associated methicillin-resistant S. aureus; HA-MRSA, healthcare-associated methicillin-resistant S. aureus; VISA, vancomycin-intermediate S. aureus; VRSA, vancomycin-resistant S. aureus.

^aGrowth reduction relative to initial inoculum.

Discussion

The first major observation in this study was that ceftobiprole was bactericidal against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA. As CA-MRSA and VISA are emerging pathogens worldwide, new bactericidal therapies are needed.^3,4,11,14 Previous work has documented that the MIC₅₀ and MIC₉₀ of ceftobiprole for MRSA are 1 and 2 mg/L, respectively.^2,15,16 The activity of ceftobiprole versus both CA-MRSA and HA-MRSA is not surprising given that its affinity (IC₅₀, 0.9 mg/L) for PBP2a is very high compared with ceftriaxone and ceftazidime (both demonstrate an IC₅₀ of >50 mg/L).¹⁷ Ceftobiprole in time–kill studies has been reported to be bactericidal against MRSA at 4 × MIC with no differences in killing between strains of CA-MRSA and HA-MRSA.^16,18 An interesting finding by Leonard et al.,¹⁶ was that ceftobiprole was bactericidal against MRSA at 0.5 × MIC.

In our in vitro model we focused on the pharmacodynamic parameter T > MIC for ceftobiprole, simulating pharmacokinetics after typical doses used for complicated skin and skin structure infections.^2,11–13 Other investigators simulating ceftobiprole pharmacodynamics in animals have reported that T > MIC is the pharmacodynamic parameter that is associated with bacterial killing.^13,19 Using the neutropenic mouse thigh infection model, Craig and Andes¹³ reported that ceftobiprole T > MIC of ∼24% and ∼32% were required to achieve a static dose and 2 log₁₀ kill, respectively, for MRSA. In an immunocompromised murine pneumonia model, Laohavaleeson et al.¹⁹ studied the pharmacodynamics of ceftobiprole against a diverse collection of S. aureus strains including MSSA, CA-MRSA and HA-MRSA. These investigators reported that the fT > MIC to achieve a static dose, effective dose 50 (ED₅₀), ED₈₀ and maximal bacterial killing were 11.0%, 11.9%, 14.6% and ∼20%, respectively.¹⁹ Consistent with the data in our study, these investigators reported no difference in ceftobiprole bacterial killing between MSSA, CA-MRSA and HA-MRSA (Table 4).¹⁹ Yin et al.²⁰ attested to the bactericidal properties of ceftobiprole versus MRSA by studying a rabbit osteomyelitis model and reported that ceftobiprole was able to eradicate MRSA from all infected tibiae. In contrast, these investigators found that only 73% of infected tibiae from vancomycin- and linezolid-treated rabbits had MRSA eradicated.²⁰ The rapid bactericidal nature of ceftobiprole compared with the lack of bactericidal activity of vancomycin against MRSA is consistent with our study (Tables 4 and 5). The good pharmacodynamic properties demonstrated by ceftobiprole against MRSA in vitro are reflected in clinical trials in which rates of clinical and bacteriological eradication of MRSA from patients with complicated skin and skin structure infections of >90% were achieved.^21,22

Several investigators have reviewed the pharmacokinetic and pharmacodynamic properties of ceftobiprole.^23–26 Lodise et al.,²³ assessed the probability of target attainment (PTA) for ceftobiprole as derived from population pharmacokinetic analysis in 150 subjects. These investigators reported that the PTA of 30% for fT > MIC for pathogens with an MIC of ≤2 mg/L using ceftobiprole 500 mg every 8 h was ∼98% and 99% when infused over 30 min or 2 h, respectively. In a recently published report all 1095 S. aureus and 385 MRSA demonstrated ceftobiprole MICs of ≤2 mg/L.¹⁵ As ceftobiprole is primarily renally eliminated, the PTA will only increase with a decline in renal clearance of the drug.²⁶ Ceftobiprole's potent activity against S. aureus genotypes including MSSA, MRSA, VISA and VRSA has to be tempered with the report that MRSA can ultimately be made resistant to ceftobiprole in the laboratory.²⁷ Whether ceftobiprole-resistant MRSA will develop clinically needs to be closely monitored.

The second major observation in this study was that vancomycin was bacteriostatic against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA. Previous work both in vitro and in vivo have repeatedly demonstrated that vancomycin is bacteriostatic versus CA-MRSA and HA-MRSA, and that MRSA re-growth occurs rapidly with vancomycin administration, especially when a high inoculum is used.^11,28 Rose et al.¹¹ reported that at high inoculum, MRSA re-growth occurred rapidly even when vancomycin was dosed at 5 g every 12 h. As well, as vancomycin MICs increase from 0.5 to 1–2 mg/L successful treatment of MRSA bacteraemia has been reported to decrease from 55.6% to 9.5%.²⁹ As vancomycin is not bactericidal against MRSA, it is not surprising that vancomycin is only marginally better than the growth control (no drug) versus VISA strains and provides no benefit at all for VRSA (Table 5).

Limitations of the current study include that the pharmacodynamic model did not simulate a 2 h infusion of ceftobiprole as is used in patients in Canada.² Simulating a bolus dose as we did in our model and not optimizing the pharmacodynamics by extending the infusion time to 2 h may have underestimated the bacterial killing of ceftobiprole. Despite this limitation, the ceftobiprole pharmacodynamics simulated resulted in ceftobiprole concentrations exceeding the MIC at all time points and proved to be bactericidal against all strains studied. In addition, as we could not locate an S. aureus strain of any genotype for which the ceftobiprole MIC was >2 mg/L, this precluded a full assessment of ceftobiprole pharmacodynamic activity against strains for which MICs are elevated.

In conclusion, ceftobiprole T > MIC of ≥100% (ceftobiprole MICs, ≤2 mg/L) resulted in bactericidal (≥3 log₁₀ killing) activity against MSSA, CA-MRSA, HA-MRSA, VISA and VRSA at 16 and 24 h with no re-growth over the 24 h study period. Vancomycin was bacteriostatic against MSSA, MRSA and VISA, while demonstrating no activity versus VRSA.

Funding

This study was supported in part by the University of Manitoba and Janssen Ortho Inc.

Transparency declarations

G. G. Z. and D. J. H. have received research funding from Janssen Ortho Inc. Other authors: none to declare.