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Ceftobiprole: in-vivo profile of a bactericidal H. F. Chambers

University of California, San Francisco School of Medicine, San Francisco, California, USA

ABSTRACT Resistance to antimicrobials is a significant and growing problem, limiting treatment options, especially for serious Gram-positive infections. Ceftobiprole is a novel broad-spectrum cephalosporin that is active in vitro against streptococci and staphylococci, including -resistant strains of pneumococci and -resistant Staphylococcus aureus (MRSA). It maintains the activity of extended-spectrum against Gram-negative bacteria, including Enterobacteriaceae. The in-vivo activity of ceftobiprole has been demonstrated in mouse sepsis and subcutaneous abscess models of infection. Its activity also has been examined in several discriminative models of infection that mimic specific diseases in humans and permit testing of antimicrobial activity under a variety of defined pharmacokinetic conditions. These include experimental pneumonia in mice, a tissue cage model of foreign body infection in rats, and endocarditis models in rats and rabbits. In these models, ceftobiprole exhibits activity equivalent or superior to that of comparators against MRSA, including - intermediate strains. These models also confirm the in-vivo activity of ceftobiprole against Gram- negative bacteria that are susceptible in vitro. The results from animal models support the evaluation of the clinical efficacy of ceftobiprole in humans and also predict clinical efficacy in the empirical treatment of severe infections. The broad spectrum of activity may allow ceftobiprole to be used as monotherapy for serious hospital-acquired infections where combination therapy would otherwise be required. Keywords Antimicrobial resistance, ceftobiprole, in vivo, MRSA

Clin Microbiol Infect 2006; 12 (Suppl. 2): 17–22

cate that the percentage of Staphylococcus aureus INTRODUCTION isolates in hospitals that are resistant to methi- Since the mid-1970s, resistance to antimicrobials cillin, or (collectively referred has become a significant and escalating problem, to as MRSA) increased from 2% in 1975 to 29% limiting treatment options for serious Gram- in 1991 and further to 46% by 2004 [3,4]. In 2004, positive infections in particular. The emphasis 60% of Staph. aureus isolates from intensive care placed on controlling Gram-negative infections unit patients were resistant to these agents, an over recent decades may have unintentionally increase of 11% compared with the period from contributed to the emergence of Gram-positive 1998 to 2002 [3]. If this trend continues, nosoco- bacteria as clinically significant nosocomial path- mial MRSA rates in the USA could exceed 70% ogens. Thus, hospitals increasingly have to deal by the end of the decade. Although MRSA rates with infections caused by multidrug-resistant vary between countries, similar increases are organisms, particularly methicillin-resistant sta- evident worldwide and, furthermore, most phylococci, penicillin- and erythromycin-resist- strains are also resistant to other classes of ant pneumococci, and vancomycin-resistant [5–7]. The use of vancomycin, previ- enterococci [1,2]. Data from the US National ously an effective antibiotic against MRSA, has Nosocomial Infections Surveillance System indi- led to the development of isolates with reduced susceptibility [8,9]. Cases of vancomycin-resist- ant Staph. aureus infections have been reported in Corresponding author and reprint requests: H. F. Chambers, the medical literature and are of particular University of California, San Francisco School of Medicine, 505 Parnassus Avenue, San Francisco, CA 94143, USA concern [8,9]. Against such a background, there E-mail: [email protected] is a need for new antimicrobial agents that are

2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases 18 Clinical Microbiology and Infection, Volume 12 Supplement 2, 2006

effective against not only MRSA but also other Screening models antibiotic-resistant organisms. Several new agents with Gram-positive activ- The activity of ceftobiprole against a range of ity, such as , , , Gram-positive and Gram-negative organisms has quinupristin–dalfopristin, and tigecycline, have been investigated in a mouse experimental septi- or soon will reach the clinic [2]. Some, such as caemia model, using comparators such as ceftri- tigecycline and linezolid, however, are bacterio- axone, vancomycin, and [15]. In static rather than bactericidal [2,10,11]. Bacteri- this model, MIC values measured in vitro corre- cidal activity is important for therapeutic efficacy lated well with in-vivo efficacy, as assessed by the in certain infections, such as endocarditis, men- 50% effective dose (ED50) (the dose required for ingitis, and infections in neutropenic patients [12], survival of 50% of the animals on the fourth day and bactericidal agents are often preferred in the after infection). Ceftobiprole showed high in-vivo treatment of serious infections in hospitalised activity in infections caused by strains with MIC patients [2]. Furthermore, none of the new agents values £ 2mg⁄ L (Table 2). These included meth- listed above, apart from tigecycline, has a broad icillin-susceptible Staph. aureus, MRSA, Streptococ- spectrum of activity including both Gram-positive cus pyogenes, , Escherichia and Gram-negative pathogens, frequently restrict- coli, , Citrobacter freundii, Ser- ing their use to combination therapy [13,14]. ratia marcescens, and . Ceftobiprole Ceftobiprole is a novel broad-spectrum, was superior to and vancomycin b-lactamase-stable parenteral cephalosporin with against methicillin-susceptible Staph. aureus, with a strong affinity for the penicillin-binding pro- an ED50 below 0.2 mg ⁄ kg. The MIC90 obtained for teins PBP2a and PBP2x responsible for resistance ceftobiprole against 77 isolates of MRSA was in staphylococci and pneumococci, respectively. £ 4mg⁄ L, as compared to > 64, > 32, > 32, > 8 and Ceftobiprole also can bind to relevant penicillin- >2 mg⁄ L, respectively, for , , binding proteins of resistant Gram-positive and , ciprofloxacin, and vancomycin. Gram-negative bacteria and has a low ability to Ceftobiprole exhibited good in-vivo activity select for resistance [15,16]. On the basis of against group A streptococci and penicillin- antimicrobial activity shown in animal models of infection, ceftobiprole is undergoing further Table 2. Activity of ceftobiprole and comparators in clinical development. experimental mouse sepsis

Organism Agent MIC (mg ⁄ L) ED50 (mg ⁄ kg)

ANIMAL MODELS OF INFECTION IN Gram-positives MSSA Ceftobiprole 0.25 < 0.2 THE EVALUATION OF Ceftriaxone 4 0.89 CEFTOBIPROLE Vancomycin 1 0.73 MRSA Ceftobiprole 2 2.4 Vancomycin 2 6.7 Several animal models have been used in the GAS Ceftobiprole £ 0.06 < 0.2 evaluation of ceftobiprole, including mouse sep- Ceftriaxone £ 0.06 < 0.2 PSSP Ceftobiprole £ 0.06 < 0.2 sis, abscess and pneumonia models, rat endocar- Benzylpenicillin £ 0.06 < 0.4 PRSPa Ceftobiprole 1 1.0 ditis and tissue cage models, and a rabbit Ceftriaxone 4 8.8 endocarditis model (Table 1). Gram-negatives Ceftobiprole £ 0.06 < 0.2 Ceftriaxone £ 0.06 < 0.2 Enterobacter cloacae Ceftobiprole 4 3.8 Cefepime 2 1.1 Table 1. Animal models of infection in the evaluation of Meropenem £ 0.06 0.22 Serratia marcescens Ceftobiprole 0.25 0.68 ceftobiprole Meropenem £ 0.06 0.45 Proteus vulgaris Ceftobiprole > 32 > 12 Animal Model Infective agent Meropenem £ 0.06 < 0.4 Pseudomonas aeruginosa Ceftobiprole 8 4.0 Mouse Sepsis Gram-positive and Gram-negative Cefepime 4 1.0 Mouse Abscess MRSA, VISA Meropenem 2 < 0.4 Mouse Pneumonia Haemophilus influenzae, Enterobacter cloacae, Klebsiella pneumoniae Adapted from Hebeisen et al. [15] with permission. Rat Endocarditis MRSA aStrain 23 F-CTR. Rat Tissue cage MRSA ED50, dose at which 50% of animals survived, assessed on the fourth day after Rabbit Endocarditis MRSA, VISA infection; MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin- resistant Staph. aureus; GAS, group A streptococci (Streptococcus pyogenes); PSSP, MRSA, methicillin-resistant Staphylococcus aureus; VISA, vancomycin-intermediate penicillin-susceptible Streptococcus pneumoniae; PRSP, penicillin-resistant Strep. Staph. aureus. pneumoniae.

2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 12 (Suppl. 2), 17–22 Chambers In-vivo profile of ceftobiprole 19 susceptible Strep. pneumoniae, as expected since was more effective than vancomycin and amoxy- b-lactams are effective against these organisms, cillin– [17]. Ceftobiprole was also but was also active against penicillin-resistant highly effective against the VISA strain, com- streptococci, including a strain (23 F-CTR) with a pletely eliminating the pathogen from most ani- reduced in-vitro (MIC = 4 and 8 mg ⁄ L for ceftri- mals, whereas vancomycin and linezolid effected axone and cefotaxime, respectively, vs. 1 mg ⁄ L only a minor reduction (0.13 and 0.64 log10 units for ceftobiprole) and in-vivo activity (ED50 =8.8 in comparison with untreated controls, respect- and > 12 mg ⁄ kg, respectively, vs. 1 mg ⁄ kg sub- ively; n = 5 for all four groups) [17]. This outcome cutaneously) susceptibility to extended-spectrum was in accordance with the in-vitro finding that cephalosporins. Results with Enterobacteriaceae the MIC of ceftobiprole for the VISA strain was were also encouraging. Low ED50 values with the same as that for the vancomycin-susceptible ceftobiprole were comparable to those obtained strain of Staph. aureus [15]. Linezolid, a bacterio- with cefepime and superior to those with ceftri- static rather than bactericidal agent [10,12], was axone against Enterobacter cloacae and C. freundii unable to eliminate the infecting organisms in this strains that produce class C chromosomal b-lacta- model. mase. However, the activity of all b-lactamases against Gram-negative pathogens depends on Discriminative models the class and amount of b-lactamase produced. Meropenem was superior to both cefepime and Although it is impossible to exactly duplicate a ceftobiprole in this model because of its stability human infection and the process for drug absorp- towards b-lactamases produced by selected bac- tion and clearance in an animal model, discrimi- teria. Ceftobiprole was inactive against P. vulgaris native animal models attempt to do so by as a result of hydrolysis by the broad-spectrum incorporating pharmacokinetic parameters. The K1 b-lactamase of this organism. Ceftobiprole, critical pharmacokinetic factor with b-lactamase like cefepime and ceftriaxone, is hydrolysed by is time rather than concentration, such extended-spectrum b-lactamases and inactive that the duration for which the MIC value for a against strains producing these enzymes. particular organism is exceeded is a better predic- The bactericidal properties of ceftobiprole have tor of efficacy than peak concentration. A 750-mg been demonstrated in a mouse model in which dose of ceftobiprole administered as an intraven- subcutaneous abscesses were induced using two ous infusion over 30 min in single- and multiple- MRSA strains, a vancomycin-intermediate (VISA) dose studies resulted in a mean peak plasma strain (Mu50) and a vancomycin-susceptible concentration of 0.60–0.61 mg ⁄ L per hour, a mean strain (I-6) [15]. Ceftobiprole (10 mg ⁄ kg) was AUC value of 135–165 mg ⁄ L per hour, and a mean bactericidal compared with vancomycin half-life of 3–4 h. The value of T > MIC at which (10 mg ⁄ kg) and linezolid (20 mg ⁄ kg) against the 100% of MRSA isolates were inhibited (< 4 mg ⁄ L) vancomycin-susceptible strain, achieving a med- was approximately 7–9 h (Table 3) [18,19]. ian decrease in log10 CFU in comparison with In mice, the half-life of ceftobiprole is shorter untreated controls of 5.12 (n = 21) vs. decreases in than in humans, such that in the mouse pneumonia comparison with untreated controls (n = 21) of model in which ceftobiprole has been evaluated 3.42 with vancomycin (n = 21) and 0.80 with [Rouse M, Anguı´ta-Alonso P, Han M, Steckelberg J, linezolid (n = 5). The bactericidal properties of Patel R. Activity of BAL5788 in Haemophilus ceftobiprole against MRSA have also been dem- influenzae, Enterobacter cloacae or Klebsiella pneumo- onstrated in an endocarditis rat model, where it niae experimental murine pneumonia. 44th

Table 3. Pharmacokinetic parame- AUC T >4 ters of ceftobiprole in humans and Dose (mg) Peak (lg ⁄ mL) (lgh⁄ mL) T1 ⁄ 2 (h) (lg ⁄ mL) (h) discriminative animal models of infection Human [18,19] 750 60–61 135–165 3–4 7–9 (single dose) Mouse pneumonia [20] 50 four times daily 25 22.5 0.25–0.5 1.5 Rat tissue cage [21] 150 twice daily 16–25 120 3 9 Rat endocarditis [17] Constant 5.5–6.8 144 NA ¥ infusion 11.9–14.5 290 24.2–27.3 600 Rabbit endocarditis [22] 19 three times daily 29 NA 1 3–4

2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 12 (Suppl. 2), 17–22 20 Clinical Microbiology and Infection, Volume 12 Supplement 2, 2006

ICAAC 2004, abstract B-1177] the AUC value is >4 lg ⁄ mL was similar to that obtained in humans lower than in humans and the 4 mg ⁄ L MIC (Table 3). Ceftobiprole and vancomycin 50 mg ⁄ kg concentration is exceeded for only 1.5 h (Table 3). twice daily were equally efficacious in this model, This means that the experimental conditions are achieving mean decreases in log10 CFU ⁄ mL biased against ceftobiprole. In other models (± SEM) of 0.7 ± 0.3 (n = 29) and 0.9 ± 0.2 [17,21,22], the concentrations and time above MIC (n = 28), respectively, compared with an increase are more comparable with what would be achieved of 0.2 ± 0.2 (n = 30) in untreated rats. However, in humans, but towards the lower range (Table 3). the reductions achieved are relatively low com- In none of the models, therefore, are the pharma- pared with the 2–6 log10 changes seen in other cokinetic conditions preferential to ceftobiprole. animal infection models, such as the mouse In the mouse pneumonia model, ceftobiprole pneumonia model described above (Table 4), (50 mg ⁄ kg four times daily) administered 24 h reflecting the difficulty of treating foreign body after infection and continued for 48 h showed in- infections. vivo activity against Haemophilus influenzae, Ceftobiprole has shown superiority to vanco- Ent. cloacae, and extended-spectrum b-lactamase- mycin in a model in which endocarditis is negative K. pneumoniae (Table 4) (Rouse M, induced in rats via aortic catheterisation [17]. Anguita-Alonso P, Hein MH, Steckelberg JM, Patel Two MRSA strains were investigated, COL Bla+ R. Activity of BAL5788 in Haemophilus influenzae, and P8-Hom, both homogeneously methicillin- Enterobacter cloacae or Klebsiella pneumoniae Experi- resistant, b-lactamase-producing strains. Rats mental Murine Pneumonia. 44th ICAAC 2004, were given a constant infusion of ceftobiprole to abstract B-1177). Ceftobiprole, ceftriaxone achieve a steady-state concentration of 5, 10 or 50 mg ⁄ kg twice daily and cefepime 50 mg ⁄ kg 20 mg ⁄ L (Table 3) or 1 g of vancomycin every four times daily were effective compared with 12 h at a flow rate designed to mimic intermittent untreated animals (p < 0.05), and there were no intravenous treatment in humans. Treatment significant differences among the three treatments. began 12 h after bacterial challenge and contin- All three antibiotics produced a significant reduc- ued for 3 days. Ceftobiprole was effective against tion in viable counts for all isolates except exten- both strains of MRSA, sterilising > 90% of cardiac ded-spectrum b-lactamase-positive K. pneumoniae, vegetations. Against the COL Bla+ strain, all three for which no effect was observed for any agent. infusion regimens were effective compared with Foreign body infections, the majority of which untreated animals (p < 0.05), with the two higher are caused by staphylococci, are extremely resist- steady-state levels (10 and 20 mg ⁄ L) rendering ant to antibiotics, even those with in-vitro activity, significantly more animals culture-negative than and contribute significantly to the problem of vancomycin treatment (p < 0.05). Against the P8- nosocomial infections [23,24]. The tissue cage Hom strain, where only the ceftobiprole 5 mg ⁄ L model is a foreign body infection model in which level was investigated, 100% of animals were MRSA is injected into preimplanted Teflon tissue rendered sterile, a significantly better result than cages [25]. In the evaluation of ceftobiprole using that achieved with vancomycin (p < 0.05). this model, rats were treated 2 weeks after bac- Ceftobiprole has also demonstrated in-vivo terial infection with ceftobiprole or vancomycin activity in a rabbit model of aortic valve endocar- for 7 days [21]. The dose of ceftobiprole, equival- ditis using MRSA (strain 76) and VISA (New ent to 150 mg ⁄ kg twice daily, was chosen such Jersey strain HIP5836). Ceftobiprole 19 mg ⁄ kg that the time for which plasma concentration was three times daily for 4 days significantly

Table 4. Activity of cephalosporins Haemophilus Enterobacter ESBL– Klebsiella ESBL+ Klebsiella influenzae cloacae pneumoniae pneumoniae in a mouse pneumonia model [Rouse M, Anguı´ta-Alonso P, Han Sterile Log10 CFU Sterile Log10 CFU Sterile Log10 CFU Sterile Log10 CFU M, Steckelberg J, Patel R. Activity of BAL5788 in Haemophilus influenzae, Untreated 0 ⁄ 15 4.9 0 ⁄ 16 6.0 0 ⁄ 16 6.8 0 ⁄ 16 6.1 Ceftobiprolea 9 ⁄ 15 < 2.5b 4 ⁄ 16 3.6 2 ⁄ 15 < 2.5b 0 ⁄ 16 6.4 Enterobacter cloacae or Klebsiella pneu- Ceftriaxone 11 ⁄ 15 < 2.5b 5 ⁄ 18 3.6 1 ⁄ 15 < 2.5b 0 ⁄ 16 6.2 moniae experimental murine pneu- Cefepime 15 ⁄ 15 < 2.5b 4 ⁄ 15 3.4 2 ⁄ 14 2.7 0 ⁄ 16 6.0 monia. 44th ICAAC 2004, abstract ESBL, extended-spectrum b-lactamase. B-1177] aCeftobiprole (50 mg ⁄ kg twice daily), ceftriaxone (50 mg ⁄ kg twice daily) or cefepime (50 mg ⁄ kg four times daily) were commenced 24 h after infection and continued for 48 h. b Limit of detection, 2.5 log10 CFU ⁄ g lung.

2006 Copyright by the European Society of Clinical Microbiology and Infectious Diseases, CMI, 12 (Suppl. 2), 17–22 Chambers In-vivo profile of ceftobiprole 21

Fig. 1. Activity of ceftobiprole and vancomycin in a rabbit aortic valve endocarditis model using methicillin-resistant Staphylococcus aureus (MRSA) strain 76 (n = 34) or vancomycin-intermediate S. aureus (VISA) New Jersey strain HIP5836 (n = 21) [22]. Rabbits were treated with ceftobiprole (25 mg ⁄ kg three times daily, n = 24, 13 in the strain 76 group, 11 in the VISA group) or intravenous vancomycin (30 mg ⁄ kg twice daily, n = 18, 13 in the strain 76 group, five in the VISA group) or left untreated (n = 13, eight in the strain 76 group, five in the VISA group) for 4 days. Bacterial titres were assessed at the site of infection (Veg) and in the spleen and kidney. *p < 0.001 vs. control; †p < 0.01 vs. ceftobiprole; ‡p < 0.0001 vs. ceftobiprole; §p < 0.05 vs. control. decreased vegetations of both strains in compar- taining the activity of extended-spectrum ison with controls (Fig. 1) [22]. Significant reduc- cephalosporins against Gram-negative organisms. tions in comparison with controls were evident in The activity of ceftobiprole is based on inhibition the spleen and kidney, and at the site of infection of penicillin-binding proteins, including those (Fig. 1). Vancomycin was effective only against responsible for resistance in MRSA, and stability MRSA strain 76 in this model. The mortality rate against hydrolysis by b-lactamases. In vivo, for animals infected with MRSA strain 76 approa- screening models predict good activity for cefto- ched 50% in both the ceftobiprole and vanco- biprole against Gram-positive and many Gram- mycin groups, but this probably reflected the negative bacteria, including some important overwhelming nature of the infection rather than Enterobacteriaceae. Under a variety of pharma- treatment failure. In animals infected with VISA, cokinetic conditions, discriminative models of mortality was significantly lower in the ceftobi- infection have confirmed that ceftobiprole is prole group than in the vancomycin group (8% vs. active against MRSA, including vancomycin- 67%,p= 0.022). Given the absence of decrease of intermediate strains. These findings in animal bacterial burden in surviving animals treated with models support the evaluation of ceftobiprole in vancomycin, the higher death rate is probably human infections. Furthermore, these results may attributable to treatment failure with vancomycin. predict the clinical efficacy of ceftobiprole both as In the tissue cage rat model of foreign body empirical therapy while culture results are awai- MRSA (MRGR3, isolated from catheter-related ted and as a definitive therapy for infections sepsis) infection, MIC ⁄ MBC values for ceftobi- caused by methicillin-resistant staphylococci. The prole and vancomycin obtained in vitro were 1 ⁄ 4 results of a phase II study in patients with and 1 ⁄ 2, respectively [21]. Treatment for 7 days complicated skin and skin structure infections significantly reduced tissue cage counts of viable were reported recently [25], and multicentre, MRGP3 by 0.68 ± 0.28 log10 CFU ⁄ mL, which was randomised, controlled phase III studies to deter- not significantly different from values obtained mine the efficacy and safety of ceftobiprole have for ceftobiprole-treated rats. No resistant colonies been initiated. The broad spectrum of activity of were observed. ceftobiprole may permit its use as monotherapy in situations where a combination antibacterial regimen might otherwise be required. CONCLUSIONS Ceftobiprole is an investigational novel cepha- REFERENCES losporin that is active in vitro against streptococci and staphylococci, including penicillin-resistant 1. Low DE, Nadler HL. A review of in-vitro antibacterial strains of pneumococci and MRSA, while main- activity of quinupristin ⁄ dalfopristin against methicillin-

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