Summary Basis of Decision for Zeftera

3.2.1 Pharmacodynamics

The in vivo bacterial efficacy of ceftobiprole on gram-positive and gram-negative bacteria has been demonstrated in various experimental animal models. The pharmacokinetic/pharmacodynamic studies indicate that the time above the minimum inhibitory concentration (MIC) is the most important pharmacokinetic parameter that correlates with in vivo efficacy. The value for this parameter was two-fold higher for gram-negative bacteria as compared to gram-positive bacteria. Therefore the dosing schedule for gram-positive and gram-negative bacteria is expected to differ in clinical studies. Animal model studies also indicate that the activity of ceftobiprole is markedly influenced by the presence of neutrophils. The efficacy of ceftobiprole in animal model studies is either comparable or better than linezolid and vancomycin in treatment of both methicillin-susceptible and resistant strains of Staphylococcus aureus. Staphylococcus aureus which is the predominant pathogen in diabetic foot is one of the requested indications in this drug submission. The in vivo animal model study presented supports the proposed indication.

Safety Pharmacology

In vitro and in vivo studies were conducted to characterize the cardiovascular, central nervous system (CNS), and respiratory safety of ceftobiprole medocaril and ceftobiprole. The in vivo cardiovascular and CNS studies were not conducted according to the ICH guidelines as the studies were conducted early in the development of the non-clinical program, prior to finalization of the guidance. However, due to the absence of relevant findings in non-clinical and clinical studies, Janssen-Ortho did not repeat the studies.

The potential for QT/QTc delayed ventricular repolarization was examined in vitro by membrane currents in HEK293 cells stably transfected with the human ether-à-go-go-related gene (HERG). Treatment with 5 µM concentration of ceftobiprole (highest concentration attainable under the conditions of the assay) produced no statistically significant effects.

The in vivo effects of ceftobiprole on mean arterial blood pressure (MAP) and heart rate (HR) were related to high maximum plasma concentration (C_max) values achieved in conscious rats [number (n) =4] and marmosets (n=3) with a single bolus administration of 100 mg/kg. A slight persistent increase in MAP was noted in rats and marmosets with a delayed onset following administration of a single intravenous (IV) bolus injection of ceftobiprole medocaril at 100 mg/kg. No effect was seen with single slow bolus IV administrations of 50 mg/kg in rats and 35 mg/kg dose in marmosets.

Dogs (n=1/sex) receiving a 4-hour infusion of 50 mg/kg or 100 mg/kg of ceftobiprole medocaril demonstrated transient effects on blood pressure, as well as ventricular premature complex in the male dog at 100 mg/kg. Ventricular premature complex was considered unlikely to be test drug-related as it can occur spontaneously in beagle dogs. Moreover, a toxicokinetic study in beagle dogs revealed a dose-related exposure to both ceftobiprole and ceftobiprole medocaril at the end of the 4-hour infusion period in dogs with an average C_max of ceftobiprole of 45.0 ug/mL and 89.5 µg/mL at doses of 50 and 100 mg/kg, respectively, and 30.1 µg/mL and 46.0 µg/mL of ceftobiprole medocaril respectively. This indicates a relatively slow cleavage of the prodrug in this species. 

Ceftobiprole produced clonic and tonic convulsions in mice after IV and intra-cerebroventricular (ICV) administrations. Signs of nephrotoxicity (related to drug precipitation in distal and collecting tubules) and incidences of mortality were noted at doses ≥250 mg/kg. Delayed convulsions were observed in mice at IV doses ≥250 mg/kg were attributed to high levels of drug exposure caused by marked nephrotoxicity, which was considered to have led to reduced renal clearance of ceftobiprole, and thus, sustained elevated plasma and brain levels. Manifestation of kidney toxicity was clearly time- and dose-related, and was overall rated as minimal to moderate at 250 mg/kg IV and moderate to marked at 500 mg/kg IV.

The median effective dose (ED₅₀) of ceftobiprole for centrally-mediated convulsions was determined to be 2.55 µg in a CNS safety study in mice. Mice were administered single ICV injections of 0.3-30 μg ceftobiprole.

IV administration over a 4-hour infusion period at doses equivalent to 125, 250, and 500 mg/kg ceftobiprole, did not affect airway resistance (R_L) or dynamic lung compliance (C_dyn) when compared to vehicle-treated Sprague-Dawley rats.

3.2.2 Pharmacokinetics

Absorption

In animals and in humans, it was demonstrated both in vivo and in vitro that ceftobiprole medocaril was converted within minutes quantitatively to ceftobiprole, the active drug. In all species after IV dosing with ceftobiprole medocaril, the C_max of ceftobiprole occurred at the first sampling point, which was five minutes post-dose. Absolute bioavailability appeared to be approximately 100%.

After administration of a single IV dose of the active drug ceftobiprole to mice, rats, rabbits, and cynomolgus monkeys, plasma concentration-time profiles showed a bi-exponentialdecline with a slight initial distribution phase.

Distribution

The volume of distribution at steady state (V_dss) was approximately 0.3-0.4 L/kg and was comparable to the extracellular space, which is typical for cephalosporins with low plasma protein binding. The in vitro binding of ceftobiprole to human plasma protein was low and concentration-independent. The in vitro plasma protein binding of ceftobiprole was 21.1% in rats, 20.5% in rabbits, 44.9% in cynomolgus monkeys, 30.2% in marmosets, and 18.9% in dogs and remained fairly constant over the concentration range tested. After IV administration of 20 mg/kg radiolabelled ¹⁴C-ceftobiprole medocaril in albino mice and pigmented rats, ceftobiprole-related radioactivity was widely distributed, with maximum concentrations at the first sampling time (0.25 hours post-dose) in all tissues. The highest radioactivity levels were found in the coagulating gland, kidney, liver, skin, and lung. As reported in mice, tissue/plasma concentration ratios were below unity in virtually all tissues except for the kidney, in which a ratio of 1.3 was observed. Penetration into the brain was minimal. Drug-related material was not retained in melanin-containing organs in pigmented rats.

Metabolism

Metabolism of ceftobiprole medocaril in vitro with heptocytes of different species revealed a very rapid hydrolytic cleavage of the carbamate group of ceftobiprole medocaril. The main metabolic reaction of ceftobiprole was the hydrolysis of the ß-lactam ring of the drug to RO65-2070; a small percentage of the drug appeared to be transformed into unknown metabolites. Starting with ceftobiprole medocaril, the metabolism of ceftobiprole within 24 hours appeared to be species-dependent: 69% in mice, 64% in marmosets, 51% in humans, 48% in rats, and 43% in dogs.

Metabolic profiles obtained in vitro in rats, dogs, marmosets, and mice were more or less similar and comparable to man. Metabolic profiles from rat liver, kidney, and brain were comparable and revealed no formation of organ-specific metabolites.

The metabolic profiles in vivo in the plasma, urine, and bile of rats and the urine of marmosets, obtained after administration of ceftobiprole and its ceftobiprole medocaril indicated that the major drug-related material excreted was unchanged ceftobiprole, together with the ring-opened product RO65-2070 and 2-3 minor metabolites of unknown structure (<5% of the dose each). Metabolic profiles of rat bile were similar to the urine.

Brain homogenates obtained from in vivo studies in mice and rats having received IV doses of ceftobiprole or ceftobiprole medocaril contained predominantly unchanged drug and very few other components in small amounts. In mice receiving ICV administration of ceftobiprole medocaril, more than 40% of ceftobiprole medocaril was cleaved to the active drug within a few minutes, but no additional peaks were observed. Since the brains were obtained when the mice showed tonic seizures, the drug itself, rather than a potential metabolite, appeared to be responsible for the observed effect on the CNS.

Excretion

The elimination half-life (t_1/2) ranged from 0.29 hours in the mouse to 1.7 hours in the cynomolgus monkey. Ceftobiprole was mainly eliminated by renal excretion of unchanged drug. In rats and dogs, about 70% of the administered dose was recovered in the urine. In rats, renal excretion of ceftobiprole was shown to proceed via glomerular filtration since renal clearance of the unbound fraction was similar to the glomerular filtration rate (GFR) in this species. This finding was confirmed by the lack of effect on the clearance of ceftobiprole when probenecid was co-administered. Plasma clearance of ceftobiprole in other species was consistent with renal excretion via glomerular filtration.

The apparent clearance of ceftobiprole was 5.05 and 2.59 mL/min/kg in the marmoset and cynomolgus monkey, respectively. In the rat however, clearance was 13.0 mL/min/kg, which exceeded the GFR, and which was also higher than the value obtained after administration of ceftobiprole itself. This finding indicates a somewhat incomplete conversion of ceftobiprole medocaril to ceftobiprole, which would decrease the bioavailability of ceftobiprole.

IV administration of ¹⁴C-labelled ceftobiprole medocaril in albino mice demonstrated that elimination of radioactivity from the body was very rapid; by two hours post-dose, tissue concentrations declined on average by a factor of ten. At 24 hours post-dose, only the kidney cortex and liver still contained quantifiable levels of radioactivity. In pigmented rats, at seven hours after administration of ¹⁴C-labelled ceftobiprole medocaril, the tissue concentrations declined on average by a factor of ten. At 48 hours post-dose, most of the tissues showed radioactivity levels below or close to the quantitation limit. In rats, excretion of radioactivity in the feces was 17%. Levels of radioactivity in cage wash, gastrointestinal tract, and residual carcass were below 3% of the administered dose by 96 hours post-dose.

High exposures to ceftobiprole were achieved in plasma and urine. No significant deviations from dose-proportionality were observed at the dose range of ceftobiprole medocaril used in toxicity studies, and no apparent accumulation of ceftobiprole was noted after repeated dosing, even at the highest dose tested of ceftobiprole medocaril. In general, the pharmacokinetics (PK) of ceftobiprole were independent of time. No apparent gender-related differences with respect to plasma or urinary exposures were observed.

Drug Interactions

Under the test conditions, ceftobiprole did not seem to be a P-glycoprotein (P-gp) substrate or P-gp inhibitor and the bi-directional permeability of ceftobiprole in MDR-MDCK cell monolayers was very low.

The inhibitory potential of ceftobiprole was investigated in vitro on several cytochrome P450 isozyme-catalyzed reactions, using human liver microsomes, one substrate concentration, and several concentrations of ceftobiprole. Ceftobiprole showed slight to no inhibitory potential of CYP1A2, 2C9, 2C19, 2D6, and 3A4 in the high dose range (50-100 µM).

The effect of probenecid on the PK of ceftobiprole and ceftobiprole medocaril was studied in rats to evaluate the excretion process in the kidney. Concomitant administration of probenecid with ceftobiprole or ceftobiprole medocaril showed no significant effects on the plasma clearances and area under the curve (AUC) parameters of ceftobiprole or its prodrug ceftobiprole medocaril, suggesting a lack of relevant PK interaction. Since probenecid is known to inhibit active renal secretion processes, it appears unlikely that ceftobiprole is significantly excreted by active transport processes in the kidney, which is consistent with the fact that total plasma clearances in animals and humans after administration of ceftobiprole or ceftobiprole medocaril were similar to their respective glomerular filtration rates.

Therefore, the potential of ceftobiprole to affect the P450-dependent metabolic clearance of potential co-administered drugs is not anticipated.

3.2.3 Toxicology

Acute Toxicity

No single-dose studies with ceftobiprole were conducted. The initial bolus dose selection was based on kinetic studies in rats with single-dose administration and subsequent computer simulations of expected exposures with C_max values in the range of 700 µg/mL for a dose of 200 mg/kg. This dose was well tolerated in an exploratory single-dose study in mice.

Studies in rats demonstrated nephrotoxicity with ≥150 mg/kg thrice daily (TID) bolus administration of ceftobiprole medocaril, while nephrotoxicity was seen at >250 mg/kg twice daily (BID) doses of ceftobiprole when administered slowly for four hours. The nephrotoxicity observed in both cases was of similar effect.

Repeat-Dose Toxicity

The repeat-dose IV toxicity of ceftobiprole medocaril was evaluated in rats, dogs, and primates for up to 13 weeks duration.

Ceftobiprole medocaril was well tolerated up to 360 mg/kg infusion (four hours, twice a day) study in male rats. At doses ≥250 mg/kg, pigment deposits and amorphous precipitates were present in the distal renal tubules and collecting tubules. At the end of the administration period, hyaline droplets in the proximal renal tubules of almost all animals administered ceftobiprole medocaril may have reflected facilitated re-uptake of excreted test article, and were considered to be toxicologically insignificant since no necrotic or degenerative changes were observed in the tubules. The treatment-related findings exhibited a trend towards complete reversibility following the 4-week recovery period. Mean plasma concentrations were dose-related.

In a four-week infusion (four hours, once daily) study, minimally increased levels of urinary N-acetyl-beta-glucosiminidase (NAG) seen in high-dose (360 mg/kg/day) male rats at Weeks 2 and 4 were comparable to levels seen in control animals at the end of the recovery period. Dose-dependent minimal to slight cytoplasmic inclusions seen in renal proximal tubules at doses ≥250 mg/kg/day were not associated with any functional or other morphological changes in the kidneys. The renal toxicity observed in rats and marmosets showed reversibility after cessation of dosing. Safety margins for renal toxicity ranged from approximately 2-7 for plasma exposures, and from approximately 4-34 for urine exposures, based on clinical exposure data for the 500 mg dose administered as a 2-hour infusion. Enlargement of the cecum, seen in rats at 360 mg/kg, was related to the pharmacological activity of the drug.

In contrast to its benign profile in the proximal tubule, ceftobiprole medocaril shows dose-related adverse effects in the distal tubule and collecting duct. These effects were more pronounced for a bolus dose, compared to the same dose administered as a four-hour infusion, indicating a relationship to C_max. The effects were associated with the presence of precipitate in the distal tubules and collecting ducts, and were considered to be due to precipitation of the active drug within the distal tubules. The active drug was present at very high levels in the urine due to this being the predominant route of elimination. During IV infusion, there is rapid conversion of ceftobiprole medocaril to ceftobiprole in the plasma, which is then filtered and concentrated in the distal tubules resulting in urine concentrations that are higher than concentrations measured in plasma, and causing the occurrence of drug precipitates in the distal tubules and collecting ducts. At a dose level of 175 mg/kg/h a precipitate was observed in the urine during a two-week marmoset study in which dosing was performed as a four-hour infusion every 12 hours.

The precipitate was confirmed as ceftobiprole by bioanalysis. This is consistent with the microscopic observations and supports the conclusion that the precipitate observed in the distal tubules is comprised of ceftobiprole.

The renal toxicity observed in rats and marmosets showed reversibility after cessation of dosing.

Dose-dependent convulsions were observed for ceftobiprole following direct administration (ICV) into the brain in mice. In contrast to the high potency for convulsions when administered directly into the brain, convulsions were rare after systemic administration of ceftobiprole medocaril and ceftobiprole, and were associated with overdosing. Doses ≥ 250 mg/kg showed dose-related incidences of convulsions associated with signs of renal toxicity.

Incidences of convulsions were also observed in rats and marmosets. The convulsions occurred at high doses that were associated with sustained elevated plasma levels (attributed in some cases to renal toxicity and reduced clearance). In a three-day marmoset pilot study, an animal showed convulsions approximately eight hours after the second IV bolus dose of 200 mg/kg ceftobiprole medocaril. The plasma concentration for this animal was 77.4 µg/mL, which is approximately two-times higher than the concentration observed two hours after the end of a four-hour infusion dose of 200 mg/kg ceftobiprole medocaril. The prolonged elevation of plasma levels after the IV bolus dose at 200 mg/kg is attributed to reduced clearance due to renal toxicity.

In a two-week marmoset study, convulsions were observed in two animals from the high dose group (360 mg/kg , administered as four-hour infusions twice daily) after the first infusion on Day 1. The plasma concentration of ceftobiprole in these two animals ranged from 317-355 µg/mL, which is approximately ten times greater than the clinical C_max.

In a 13-week rat study, convulsions were observed in an animal from the high-dose group (750 mg/kg, administered as an eight-hour infusion once daily) on Day 34, approximately one hour before the end of infusion. The plasma concentration in this animal was 511 µg/mL at 1.5 hours after the end of infusion, which is about 15 times greater than the clinical C_max.

Treatment-related infusion site reactions were observed during repeat dose studies in marmosets and rats, including the presence of a yellowish-white fibrinous material with thrombus formation at the catheter tip and around the catheter, and signs of vascular irritation (thickening of the vessel wall, erosion of the endothelium, localized thrombosis and chronic active inflammation with fibrosis of the vein wall). These local vascular effects at the infusion site and associated thromboembolic effects, were attributed as the cause of mortality in the 13-week marmoset study and as a cause of incidences of mortality in the 13-week rat study. The infusion site reactions were further evaluated in two-week rat bridging toxicity studies that were conducted subsequent to the 13-week studies. Local vascular irritation by the test article occurred mainly in the region of the vessel apposed to the catheter, with little effect in the region of the vessel distal to the catheter. Thus, damage by the catheter may play a permissive role in these animals, with test article-related effects occurring only in the damaged regions.

Thromboembolic effects were not observed in a 13-week dog study that included serial sectioning of the brain, kidney, and heart which indicated that the test article-related effects for thromoembolic reactions appear to be more prominent in small animals.

Genotoxicity

The genotoxic potential of ceftobiprole medocaril and/or ceftobiprole was assessed by a battery of in vitro and in vivo assays: Ames test, Mouse Lymphoma Cell Mutation Test (ML/TK), human chromosome aberration assay, mouse micronucleus test, and measurement of unscheduled DNA synthesis in rat liver. In comparison to ceftobiprole, only ceftobiprole medocaril and cleavage product "diacetyl" were found to possess genotoxic activies in the ML/TK test. This genotoxic activity was presumed to have been attributable to the formation of the cleavage product 2,3-butan-dione. In the confirmatory in vivo mouse micronucleus assay, ceftobiprole medocaril did not induce chromosomal aberrations in bone marrow of the mouse. Under the above-mentioned experimental conditions, ceftobiprole medocaril did not show genotoxic potential.

Carcinogenicty

No carcinogenicity studies were conducted to evaluate the carcinogenic potential of ceftobiprole medocaril. This was considered acceptable due to the intended short-term clinical duration of therapy and the low potential for genotoxicity.

Reproductive and Developmental Toxicity

The potential effects of ceftobiprole medocaril on fertility were examined in two separate studies in male and female rats. Dose levels of 0, 175, 250, and 360 mg/kg/day ceftobiprole equivalent were used in both these studies, administered as once daily IV infusions (four hours). There was no effect on male or female reproductive performance or on early embryonic development. Abnormally coloured urine was observed, as well as a slightly suppressed body weight gain in males. The no observable adverse effect level (NOAEL) for general toxicity was 250 mg/kg/day in males, and 360 mg/kg/day in females. In both studies, the NOAEL for reproductive performance and early embryonic development was 360 mg/kg/day. Toxicokinetic data demonstrated a dose-proportional increase in mean plasma concentration of ceftobiprole between doses of 175 mg/kg/day and 360 mg/kg/day.

Embryo-foetal development toxicity studies were conducted in rats and cynomolgus monkeys. The NOAEL for dams and embryo-fetal development in rats was 360 mg/kg/day. The NOAEL for pregnant monkeys was 60 mg/kg/day, and 120 mg/kg/day for fetuses. No teratogenic potential or embryo-fetal effects were noted up to 120 mg/kg/day.

In a pre- and post-natal developmental toxicity study, doses of ceftobiprole medocaril (0, 175, 250, and 360 mg/kg/day) were administered to pregnant female rats as a once daily IV infusion (four hours) from implantation to weaning of the first generation (F1) pups on Day 21 of lactation. The number of born and live pups (F1) was slightly reduced at 360 mg/kg/day, due to post-implantation loss associated with maternal toxicity. No effect on other reproductive parameters was observed. Functional and physical development of pups was normal in all groups; mating performance of F1 animals was not affected by treatment and no effect on reproductive parameters was observed for the F1 animals. No treatment-related effect on F2 animals was observed.

The NOAEL for ceftobiprole medocaril in dams was 175 mg/kg/day for general maternal toxicity with no effects noted in body weight or food consumption, 250 mg/kg/day for reproductive toxicity with no effects noted in live birth or viability indices in Fl, and 360 mg/kg/day for developmental toxicity in the Fl and F2 generations. Enlargement of the cecum was observed in the 175 mg/kg/day groups due to general maternal toxicity.

Ceftobiprole was excreted in milk with levels amounting to approximately one fifth of the corresponding maternal plasma levels. Nursing pups were not exposed systemically to ceftobiprole, which was consistent with low absorption via the oral route of administration.

No studies in which the offspring were dosed with ceftobiprole medocaril have been conducted to date.

Local Tolerance

Two local tolerance studies were conducted in rabbits. There was a slight decrease in adverse events (AEs) between the irritancies of freshly prepared ceftobiprole medocaril (within six hours of preparation) and that of formulation prepared 30 hours previously.

Antigenicity

The antigenicity of ceftobiprole medocaril was investigated in the guinea pig in a Maximization Test, an active systemic anaphylaxis (ASA) assay, and a four-hour passive cutaneous anaphylactic (PCA) assay. The low dose was approximately the intended clinical dose and the high dose was a 5X multiple.

Ceftobiprole medocaril was found to possess antigenic potential. The positive ASA reactions (scratching, piloerection) were present in animals receiving single IV bolus doses of ≥20 mg/kg ceftobiprole medocaril five times weekly for three weeks or 50 mg/kg ceftobiprole medocaril emulsified with Freund's complete adjuvant (FCA) or Freund's incomplete adjuvant (FIA) once weekly for three weeks.

Nephrotoxicity

No nephrotoxicity was observed in male rabbits that received a single IV administration of 160 mg/kg of ceftobiprole medocaril. There was red discolouration of renal papilla.

Phototoxicity

Ceftobiprole proved to be non-phototoxic in vitro after ultraviolet (UV) irradiation and ceftobiprole medocaril did not induce a phototoxic skin reaction in vivo under the experimental conditions used.

Potential for Hemolysis and Plasma Turbidity

No significant hemolysis and plasma turbidity or precipitation was seen in dog blood under in vitro conditions in a 13.3% test solution of RO65-5788 corresponding to 1.25% of ceftobiprole. At higher concentrations, hemolysis up to 7.3% and moderate to marked plasma turbidity and precipitation were observed and were attributed to the low solubility of ceftobiprole in plasma under physiological pH conditions.

The intravenous administration of ceftobiprole medocaril formulated in reconstitution solution, whilst causing no significant hemolysis, may cause increasingly significant adverse plasma interactions at infusion solution concentrations of 12.5 to 50 mg/mL, whichever species is used. The severity of adverse plasma interactions may be exacerbated with increasing infusion volume, repeated dosing, and/or increasing infusion duration.

3.2.4 Microbiology

Ceftobiprole is an expanded-spectrum cephalosporin with activity against gram-positive and gram-negative aerobic bacteria. Ceftobiprole exerts its antibacterial activity by binding to essential PBPs in both gram-positive [including methicillin-resistant Staphylococcus aureus (MRSA)] and gram-negative bacteria. In gram-positive bacteria, ceftobiprole differs from other cephalosporins and ß-lactams due to its unique high affinity for PBP2a from methicillin-resistant staphylococcus. Ceftobiprole has high affinity for the essential PBP3 and PBP2 of Escherichia coli.In vivo ceftobiprole treatment in animal models of infection did not produce resistant mutants of Staphylococcus aureus, Enterobacter cloacae, and extended spectrum b-lactamase (ESBL)-negative Klebsiella pneumoniae.

Ceftobiprole also appears to be hydrolyzed by b-lactamases from anaerobic bacteria. Ceftobiprole demonstrated reduced clinical efficacy against infections with Pseudomonasaeruginosa with a minimum inhibitory concentration (MIC) of >4 ug/mL, and as such, use of Zeftera against Pseudomonas aeruginosa is not recommended.

Ceftobiprole MICs against both gram-positive and gram-negative bacteria were not affected by more than one doubling dilution by such factors as divalent calcium, 2% sodium chloride, 5% carbon dioxide, and pH ranging from 6.4-8.2. Inoculum effects were generally not seen.

The efficacy of ceftobiprole was examined in skin and soft tissue infection models septicemia infection models, and in a rabbit model of MRSA osteomyelitis.

• Ceftobiprole achieved a >1.7 log10 colony forming units/gram (CFU/g) reduction of methicillin-sensitive Staphylococcus Aureus (MSSA) in skin tissue compared to the initial inoculum at doses of 1.6 to 100 mg/kg/day. Against MRSA, ceftobiprole showed similar or improved reduction in bacterial load at doses of 1.6 to 100 mg/kg/day against comparators. Ceftobiprole was effective in reducing the lesion volume at the infection site in animals infected with either MSSA or MRSA .
• Ceftobiprole was effective in treating experimental septicemia. The strains included MSSA, MRSA (except MRSA 8525), Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis.
• Ceftobiprole provided effective parenteral treatment of osteomyelitis caused by MRSA in the rabbit osteomyelitis infection model. Following ceftobiprole treatment bacterial titres in all infected left tibiae from evaluable rabbits were below the level of detection, whereas 73% of infected left tibiae from comparator treated animals had bacterial titres below the level of detection. Mean ceftobiprole titres were 3-5 times higher in the infected left tibias compared to the uninfected right tibiae.

3.2.5 Conclusion

Appropriate non-clinical toxicology studies were performed and are considered adequate. The toxicology findings were consistent with the pharmacological effects of ceftobiprole medocaril/ceftobiprole. The non-clinical pharmacology and toxicology studies support the use of Zeftera for the proposed indication.