DailyFinance.com, January 18, 2010, by Melly Alazraki  —  As Haiti reels from the 7.0 earthquake that devastated its capital, Port-au-Prince, on Tuesday, relief efforts are beginning to make headway. Early estimates suggest as many as 100,000 may have died, and the quake crushed the country’s fragile infrastructure and added to its monumental health-care problems. But the world comes together during crises, and the heartbreaking images coming out of Haiti are prompting companies, governments and citizens to donate skills, products, money, and time to help.

Private American contributions after Hurricanes Katrina, Rita and Wilma struck in 2005 totaled $6.47 billion , and American citizens donated nearly $2 billion after the 2004 Asian tsunami. Already, The American Red Cross has raised millions via text messages for the Haiti relief efforts. While credit-card companies waive fees on donations and phone carriers permit donations via text messages, the crisis also gives Big Pharma ample opportunity to help relief efforts.

As the crisis deepens, access to clean water, antibiotics, and basic health supplies are top concerns, Giuseppe Annunziata, coordinator of the World Health Organization’s emergency response and recovery operations, told Bloomberg: resources that would combat life-threatening diarrhea, measles, and malaria among Haiti’s malnourished population.

Cash and Medicine

To provide immediate relief and combat potential long-term problems, the Red Cross and other organizations have been coordinating efforts on the ground and have been in contact with Direct Relief, AmeriCares, and other non-governmental organizations with specialist skills and established disaster-response and coordination processes to coordinate aid from pharmaceutical companies.

Big Pharma quickly responded with cash and medicine donations. Although the logistics have been daunting, the industry has gained experience in recent years, responding to a devastating earthquake in China, a tsunami in Indonesia, and other calamities.

Pfizer (PFE), a representative says, is working with global partners to assess what’s needed most in Haiti, most likely antibiotics to fight bacteria and fungal infections, and other medicines as requested. With operations in the neighboring Dominican Republic, Pfizer is in a good position to help and overcome logistical hurdles, the representative says. It has also made a cash donation of undisclosed size and has pledged to match employee contributions.

Increasing Donations as Efforts Unfold

Merck (MRK) says it’s making an initial $350,000 cash donation to several organizations, and will match employee contributions, to support the deployment of emergency response units, disaster specialists, blankets, clean water, therapeutic food, medical supplies, and temporary shelter. Merck says it also plans to immediately ship $200,000 of its products, including Coricidin, Lotrimin, Noroxin, Pepcid and other drugs.

GlaxoSmithKline’s (GSK) support includes a cash donation and sent medicine, mainly oral and topical antibiotics, on the first airlifts into Haiti since the disaster. The company says it will increase donations as the local infrastructure is repaired. Abbott (ABT) has committed to provide $1 million in initial humanitarian aid, including $100,000 in grants to aid partners and donations of nutritional products, antibiotics, rehydration fluids, and other products.

Eli Lilly and Co. (LLY) has pledged $250,000 in cash for short-term relief and longer-term rebuilding efforts and will match up to $250,000 in U.S. employees’ contributions, and it will work with first responders, partners, and the military on appropriate donations. Bristol-Myers Squibb (BMY) has shipped medicines to Haiti, primarily antibiotics and pain medicines, and will donate $200,000 and match two-for-one employee contributions in the U.S. AstraZeneca (AZN) donated antibiotic and respiratory medicines and made a donation of $162,500 (£100,000) to the British Red Cross. And Amgen (AMGN) has contributed $2 million to Haiti relief efforts.

BiologyNews.net, January 18, 2010  —  People with impaired mobility after a stroke soon may have a therapy that restores limb function long after the injury, if a supplemental protein works as well in humans as it does in paralyzed rats.

Two new studies by UC Irvine biologists have found that a protein naturally occurring in humans restores motor function in rats after a stroke. Administered directly to the brain, the protein restores 99 percent of lost movement; if it’s given through the nose, 70 percent of lost movement is regained. Untreated rats improve by only 30 percent.

“No drugs exist that will help a stroke after a few days. If you have a stroke, you don’t have many treatment options,” said James Fallon, psychiatry & human behavior professor and senior co-author of the studies. “Now we have evidence there may be therapies that can repair damage to a significant degree long after the stroke. It’s a completely unexpected and remarkable finding, and it’s worth trying in humans.”

The studies, carried out by UCI postdoctoral researcher Magda Guerra-Crespo, chronicle the success of a small protein called transforming growth factor alpha, which plays critical tissue-forming and developmental roles in humans from just after conception through birth and into old age.

“TGF alpha has been studied for two decades in other organ systems but never before has been shown to reverse the symptoms of a stroke,” Guerra-Crespo said. No lasting side effects were observed.

In the first study, published in the journal Neuroscience, scientists sought to learn whether TGF alpha administered directly to the brain could help rats with stroke-induced loss of limb function, typically on one side – as is seen in humans.

When put inside a cylinder, healthy rats will jump up with both front legs, but stroke-impaired rats will use just one leg, favoring the injured side. When given a choice of directions to walk, impaired rats will move toward their good side.

One month after the study rats suffered an induced stroke (equal to about a year for humans), some were injected with TGF alpha. Within a month, they had regained nearly all their motor function, hopping up with both legs in the cylinder exercise and not favoring a side in the directional test. Rats that did not receive treatment improved just 30 percent.

Scientists examined the rats’ brains and found that TGF alpha was stimulating neuron growth. First, it prompted adult stem cells in the brain to divide, creating more cells. Those cells then turned into brain cells and moved to the injured part of the brain, replacing neurons lost to the stroke. These new neurons, the scientists believe, helped restore motor function.

“It’s becoming more and more clear that the brain is like any other organ: It has a lot of potential to regenerate,” said Darius Gleason, a developmental & cell biology graduate student who worked on the study. “We are just emulating nature by giving a little nudge to what the brain is trying to do itself.”

In the second study, appearing online Jan. 11 in the Journal of Stroke & Cerebrovascular Diseases, scientists placed TGF alpha in the rats’ noses, simulating a nasal spray. They used a slightly different chemical version of the protein to render it more stable on its journey to the brain. After a month, the injured rats had regained 70 percent of their function, indicating that the intranasal method also works well.

“We saw the same phenomena,” Fallon said. “It wasn’t as profound, but we still ended up with very significant behavioral improvements and the same regenerative anatomical process.”

Source : University of California – Irvine



Boston University Henry M. Goldman School of Dental Medicine studies show regenerative power of dental stem cells and tissues.

(Boston) – To all those who have made deals with the tooth fairy in the past: you probably sold your teeth below their fair value.

Dr. George Huang, Chair of Endodontics at the Boston University Henry M. Goldman School of Dental Medicine (GSDM), says those baby teeth and extracted third molars we are throwing away hold valuable dental stem cells.

“Our team found for the first team that we can reprogram dental stem cells into human embryonic-like cells called induced pluripotent stem (iPS) cells, which may be an unlimited source of cells for tissue regeneration,” Dr. Huang says.

So far, scientists have had luck creating iPS cells from various cells in mice easily, but this hasn’t been as easy in humans, until more recently. All three types of human dental stem cells the GSDM team tested are easier to reprogram than fibroblasts, which previously seemed to be the best way to make human iPS cells.

In a related study, Dr. Huang regenerated two major human tooth components—dental pulp and dentin—for the first time in a mouse experimental model. The mouse was used to supply nutrition for human tissue regeneration.

Using tissue engineering, researchers saw empty root canal space fill with pulp-like tissue with ample blood supplies. Dentin-like tissue regrew on the dentinal wall.

“The finding will revolutionize endodontic and dental clinical practice by helping to preserve teeth,” Dr. Huang says.”

The studies, iPS cells reprogrammed from mesenchymal-like stem/progenitor cells of dental tissue origin and Stem/progenitor cell–mediated de novo regeneration of dental pulp with newly deposited continuous layer of dentin in an in vivo model, appear in Stem Cells and Development and Tissue Engineering.

The mission of Boston University Henry M. Goldman School of Dental Medicine is to provide excellent education to dental professionals throughout their careers; to shape the future of dental medicine and dental education through research; to offer excellent health care services to the community; to participate in community activities; and to foster a respectful and supportive environment.

Contact: Jackie Rubin, 617/638-4892, jackier@bu.edu

Source: Boston University

Ask anyone who suffers from migraine headaches what they do when they’re having an attack, and you’re likely to hear “go into a dark room.” And although it’s long been known that light makes migraines worse, the reason why has been unclear.

Now scientists at Beth Israel Deaconess Medical Center (BIDMC) have identified a new visual pathway that underlies sensitivity to light during migraine in both blind individuals and in individuals with normal eyesight. The findings, which appeared January 11, 2010, in the Advance On-line issue of Nature Neuroscience, help explain the mechanism behind this widespread condition.

A one-sided, throbbing headache associated with a number of symptoms, including nausea, vomiting, and fatigue, migraines are notoriously debilitating and surprisingly widespread, affecting more than 30 million individuals in the U.S. alone. Migraine pain is believed to develop when the meninges, the system of membranes surrounding the brain and central nervous system, becomes irritated, which stimulates pain receptors and triggers a series of events that lead to the prolonged activation of groups of sensory neurons.

“This explains the throbbing headache and accompanying scalp and neck-muscle tenderness experienced by many migraine patients,” explains the study’s senior author Rami Burstein, PhD, Professor of Anesthesia and Critical Care Medicine at BIDMC and Harvard Medical School.

In addition, for reasons that were unknown, nearly 85 percent of migraine patients are also extremely sensitive to light, a condition known as photophobia.

“Migraine patients may wear sunglasses, even at night,” he notes, adding that the dimmest of light can make migraine pain worse. Extremely disabling, photophobia prevents patients from such routine activities as reading, writing, working or driving.

It was the observation that even blind individuals who suffer from migraines were experiencing photophobia that led Burstein and first author Rodrigo Noseda, PhD, to hypothesize that signals transmitted from the retina via the optic nerve were somehow triggering the intensification of pain.

The investigators studied two groups of blind individuals who suffer migraine headaches. Patients in the first group were totally blind due to eye diseases such as retinal cancer and glaucoma; they were unable to see images or to sense light and therefore could not maintain normal sleep-wake cycles. Patients in the second group were legally blind due to retinal degenerative diseases such as retinitis pigmentosa; although they were unable to perceive images, they could detect the presence of light and maintain normal sleep-wake cycles.

“While the patients in the first group did not experience any worsening of their headaches from light exposure, the patients in the second group clearly described intensified pain when they were exposed to light, in particular blue or gray wavelengths,” explains Burstein. “This suggested to us that the mechanism of photophobia must involve the optic nerve, because in totally blind individuals, the optic nerve does not carry light signals to the brain.

“We also suspected that a group of recently discovered retinal cells containing melanopsin photoreceptors [which help control biological functions including sleep and wakefulness] is critically involved in this process, because these are the only functioning light receptors left among patients who are legally blind.”

The scientists took these ideas to the laboratory, where they performed a series of experiments in an animal model of migraine. After injecting dyes into the eye, they traced the path of the melanopsin retinal cells through the optic nerve to the brain, where they found a group of neurons that become electrically active during migraine.

“When small electrodes were inserted into these ‘migraine neurons,’ we discovered that light was triggering a flow of electrical signals that was converging on these very cells,” says Burstein. “This increased their activity within seconds.”

And even when the light was removed, he notes, these neurons remained activated. “This helps explain why patients say that their headache intensifies within seconds after exposure to light, and improves 20 to 30 minutes after being in the dark.”

The discovery of this pathway provides scientists with a new avenue to follow in working to address the problem of photophobia.

“Clinically, this research sets the stage for identifying ways to block the pathway so that migraine patients can endure light without pain,” adds Burstein.

Source : Beth Israel Deaconess Medical Center

Visual migraine aura

Seeing zig zags is common during the migraine aura.  

Ceftobiprole: First Cephalosporin with Activity Against Methicillin-resistant Staphylococcus aureus

Abstract and Introduction

Abstract

Ceftobiprole medocaril is the first member of a new series of advanced cephalosporins with activity against methicillin-resistant Staphylococcus aureus (MRSA). The drug received an approvable letter from the United States Food and Drug Administration (FDA) in March 2008 and from Health Canada in June 2008 for the treatment of complicated skin and skin structure infections including diabetic foot infections. Ceftobiprole exerts its antibacterial activity by inhibiting the penicillin-binding proteins (PBPs) involved in cell wall synthesis. It has an established stability against hydrolysis by many gram-positive β-lactamases and a higher affinity for various PBPs (such as PBP2a of MRSA or PBP2x of Streptococcus pneumoniae), which leads to a wider spectrum of activity compared with older (β-lactams. Ceftobiprole activity does not cover extended-spectrum (β-lactamase-producing Enterobacteriaceae and some other pathogens, including Enterococcus faecium or Acinetobacter baumanii. Generally well tolerated, with nausea and taste disturbance being the most common adverse events, ceftobiprole appeared noninferior to empiric therapy in several clinical trials. Ceftobiprole is available only for intravenous administration; recommended dosage regimens have not been approved by the FDA as of this writing. However, based on the Canadian package insert, expected dosage recommendations are 500 mg as a 1-hour intravenous infusion every 12 hours for the treatment of complicated skin and skin structure infections caused by certain gram-positive pathogens, and 500 mg as a 2-hour infusion every 8 hours when susceptible gram-negative or both gram-positive and susceptible gram-negative pathogens are involved. Dosage adjustments are indicated for patients with moderate or severe renal impairment, and dosage recommendations are expected to be 500 or 250 mg, respectively, as a 2-hour infusion every 12 hours. Several precautions regarding hypersensitivity and drug incompatibility are reported. Ceftobiprole represents a promising option for the treatment of mono- and polymicrobial infections caused by multidrug-resistant gram-positive and susceptible gram-negative pathogens, but further toxicity and safety studies are warranted.

Introduction

Methicillin-resistant Staphylococcus aureus (MRSA) represents one of the most common pathogens involved in serious hospital- and community-acquired infections, with a high risk of mortality and morbidity.[1] A significant increase in MRSA infections has been reported worldwide, with a prevalence greater than 60% in the United States in 2003 (vs 2% in 1974 and 22% in 1995) and almost 50% in some European countries in 2008.[2–4] Methicillin resistance is due to the presence of the staphylococcal cassette chromosome mec (SCCmec) and the mecA gene, acquired by horizontal transfer from another species and integrated into the chromosome.[5] The mecA gene encodes a 78-kD penicillin-binding protein (PBP) called PBP2a, which has the faster rate of drug release compared with the unaltered PBP2 and the lowest binding affinity for methicillin and other β-lactams.[5] For many years, vancomycin alone or combined with gentamicin or rifampin was considered empiric therapy for MRSA infections. However, the emergence of vancomycin heteroresistance in S. aureus has markedly compromised the drug’s utility, leading to an urgent need for new anti-MRSA agents.[6]

Ceftobiprole medocaril (developed jointly by Basilea Pharmaceutical AG, Basel, Switzerland, and Johnson & Johnson Pharmaceutical Research and Development LLC, Raritan, NJ) is a new parenteral broad-spectrum cephalosporin with activity against MRSA.[7] The drug was approved in Canada in June 2008 and in Switzerland in November 2008 for the treatment of complicated skin and skin structure infections (cSSSIs) including diabetic foot infections. The United States Food and Drug Administration (FDA) issued an approvable letter for ceftobiprole in March 2008 for the treatment of cSSSIs; final FDA approval is pending. We performed a review of the available literature on ceftobiprole by conducting a search of the MEDLINE database (2001–2008) using the search terms ceftobiprole, BAL9141, BAL5788, RO63-9141, and RO65-5788. We also reviewed the data presented in recent conferences regarding ceftobiprole’s in vitro and in vivo activity, mode of action, potential mechanisms of resistance, pharmacokinetic and pharmacodynamic properties, safety, and clinical trials.

Chemistry, Structure, and Functions of Ceftobiprole

Ceftobiprole (also referred to as BAL9141 or RO63-141) is a new pyrrolidinone cephalosporin, with a chemical formula of C20H22N8O6S2 and a molecular weight of 534.6 g/mol.[7] Because of its poor solubility in water, ceftobiprole was developed as a methylcarbamate prodrug known as ceftobiprole medocaril or BAL5788 (Figure 1). After intravenous administration, the prodrug is rapidly hydrolyzed by plasma esterases into three compounds: ceftobiprole, an inactive diacetyl metabolite, and carbon dioxide.[8] Like other cephalosporins, ceftobiprole’s chemical structure consists of a (β-lactam ring condensed with a six-membered heterocycle and three variable side chain substituents (Figure 1). Planar geometry, unflexibility of the bicyclic system, and chemical functions in position C3 (R2), C4 (R3), and C7 (R1) are deemed largely involved in the overall biologic activity of cephalosporins.[9] Thus, for ceftobiprole, the large hydrophobic side chain in position R1 was found more deeply enclosed into the binding pocket of PBP2a compared with nitrocefin, leading to a stronger interaction and the formation of a stable acyl-enzyme complex.[10]

Figure 1. Chemical structures of ceftobiprole and its water-soluble prodrug ceftobiprole medocaril.

Mechanism of Action

The mechanism of action for ceftobiprole is common to that of the β-lactam class in general. In both gram-positive and gram-negative bacteria, ceftobiprole exerts its antibacterial activity by binding and inhibiting one or more high-molecular-weight PBPs, acting as trans-peptidases in cell wall synthesis.[11] Ceftobiprole exhibits potent binding to most gram-positive PBPs, including those with decreased β-lactam susceptibility such as PBP2a in MRSA, PBP2x in Streptococcus pneumoniae, or many PBPs in Enterococcus faecalis.[7,12–14] Ceftobiprole also displays strong binding to many gram-negative PBPs, such as PBP2 and PBP3, the most important PBPs of Escherichia coli, and PBP1a-b, PBP2, PBP3, and PBP4 of Pseudomonas aeruginosa.[14–15] In contrast, ceftobiprole like cefepime or ceftazidime does not bind to PBP5/6 expressed by P. aeruginosa isolates.[14–15]

Antimicrobial Activity

Ceftobiprole exhibits a broad spectrum of activity against many gram-positive organisms, including MRSA, vancomycin-intermediate S. aureus (VISA), and heterogeneous VISA (hVISA), as well as various gram-negative pathogens. Its anaerobic coverage is generally limited. Based on the Canadian package insert, expected susceptibility breakpoints for S. aureus (including MRSA) and Streptococcus species (other than S. pneumoniae) should be less than or equal to 4 and 0.5 μg/ml (corresponding to zone diameters > 16 and 19 mm), respectively.[16] For Entero-bacteriaceae, strains should be characterized as susceptible if the minimum inhibitory concentration (MIC) is 1 μg/ml or less (i.e., > 20 mm), intermediate if the MIC is 2 μg/ml (i.e., 18–20 mm), and resistant if the MIC is greater than 4 μg/ml (i.e., < 18 mm).[16] The MIC for 50% (MIC50) and 90% (MIC90) of tested strains and MIC ranges for the most common clinical pathogens are reported in Table 1 .[7,15,17–23]

[

Table 1. In Vitro Susceptibility of Ceftobiprole

Organism No. of Isolates MIC50(μg/ml) MIC90(μg/ml) MIC Range(μg/ml)
Gram-positive
Staphylococcus aureus
Methicillin susceptible[7, 15, 17, 19] 7889 0.25 0.5 ≤ 0.125–2
Methicillin resistant[7, 15, 17–19] 6270 1 2 ≤ 0.125–4
Coagulase-negative staphylococci
Methicillin susceptible[17–19] 854 0.125 0.25 ≤ 0.125–1
Methicillin resistant[17, 19] 2632 1 2 ≤ 0.015–8
Streptococcus pneumoniae
Penicillin susceptible[7, 15, 19] 686 0.008 0.015 ≤ 0.002–0.06
Penicillin intermediate[15, 19] 206 0.06 0.125 0.008–0.5
Penicillin resistant[7, 15, 19] 193 0.25 0.25 ≤ 0.015–2
Enterococcus faecalis 2975 0.5 4 0.125 to > 32
Enterococcus faecium
Ampicillin susceptible[7] 16 4 8 1–8
Ampicillin resistant[7,19] 71 > 32 > 32 0.25 to > 32
Gram-negative
Escherichia coli
Wild type[7, 15, 18, 19] 5792 0.03 0.125 0.03 to > 32
ESBL-producing strains[7, 15, 18] 443 > 32 > 32 0.03 to > 32
Klebsiella pneumoniae
Wild type[7, 15, 18, 20] 2669 ≤ 0.06 0.125 ≤ 0.015 to > 32
ESBL-producing strains[7,15,18, 20] 676 > 32 > 32 0.125 to > 32
Enterobacter sp[18, 19] 1435 ≤ 0.06 > 8 ≤ 0.06 to > 8
Enterobacter cloacae
AmpC-nonderepressed strains[15] 286 0.06 4 0.03 to > 32
AmpC-derepressed strains[15] 120 8 > 32 0.125 to > 32
Pseudomonas aeruginosa
All[7, 18, 19, 21] 2237 2 > 8 0.003 to > 32
Ceftazidime susceptible[15] 621 4 8 0.03 to > 32
Ceftazidime resistant[15] 130 16 > 32 0.03 to > 32
Proteus mirabilis
Wild type[7, 15, 18, 19] 876 0.03 0.06 ≤ 0.015 to > 32
ESBL-producing strains[15] 16 > 32 > 32 0.5 t o > 32
Acinetobacter sp
All[7, 18, 19, 21] 1220 8 > 32 ≤ 0.015 to > 32
Imipenem susceptible[15] 220 0.5 > 32 ≤ 0.015 to > 32
Imipenem resistant[15] 58 > 32 > 32 0.25 to > 32
Haemophilus influenzae [19, 20] 445 ≤ 0.06 ≤ 0.06 ≤ 0.06–0.5
Neisseria meningitidis [19] 24 ≤ 0.002 0.004 ≤ 0.002–0.008
Neisseria gonorrheae [19] 32 0.003 0.06 0.008–0.06
Anaerobic
Clostridium difficile [22] 30 4 8 1–8
Clostridium perfringens [22] 30 ≤ 0.016 ≤ 0.016 ≤ 0.016
Bacilus fragilis [19, 22, 23] 164 8 > 128 ≤ 0.025 to > 128

aMIC50 and MIC90 = minimal inhibitory concentrations for 50% and 90% of tested strains, respectively; ESBL = extended-spectrum βlactamase.

Gram-positive Organisms

Ceftobiprole has been evaluated against a large number of isolates from various international surveillance programs, including the SENTRY Antimicrobial Surveillance Program.[18,19] Against methicillin-susceptible S. aureus (MSSA), ceftobiprole MIC50 and MIC90 values were reported at 0.25 and 0.5 μg/ml, respectively (MIC range < 0.125-2 μg/ml). Ceftobiprole appeared slightly less efficient (or active) against MRSA, with MIC50 and MIC90 values at 1 and 2 μg/ml, respectively (MIC range < 0.125-4 μg/ml; Table 1 ).[7,17–19]

[]

Table 1. In Vitro Susceptibility of Ceftobiprole

Organism No. of Isolates MIC50(μg/ml) MIC90(μg/ml) MIC Range(μg/ml)
Gram-positive
Staphylococcus aureus
Methicillin susceptible[7, 15, 17, 19] 7889 0.25 0.5 ≤ 0.125–2
Methicillin resistant[7, 15, 17–19] 6270 1 2 ≤ 0.125–4
Coagulase-negative staphylococci
Methicillin susceptible[17–19] 854 0.125 0.25 ≤ 0.125–1
Methicillin resistant[17, 19] 2632 1 2 ≤ 0.015–8
Streptococcus pneumoniae
Penicillin susceptible[7, 15, 19] 686 0.008 0.015 ≤ 0.002–0.06
Penicillin intermediate[15, 19] 206 0.06 0.125 0.008–0.5
Penicillin resistant[7, 15, 19] 193 0.25 0.25 ≤ 0.015–2
Enterococcus faecalis 2975 0.5 4 0.125 to > 32
Enterococcus faecium
Ampicillin susceptible[7] 16 4 8 1–8
Ampicillin resistant[7,19] 71 > 32 > 32 0.25 to > 32
Gram-negative
Escherichia coli
Wild type[7, 15, 18, 19] 5792 0.03 0.125 0.03 to > 32
ESBL-producing strains[7, 15, 18] 443 > 32 > 32 0.03 to > 32
Klebsiella pneumoniae
Wild type[7, 15, 18, 20] 2669 ≤ 0.06 0.125 ≤ 0.015 to > 32
ESBL-producing strains[7,15,18, 20] 676 > 32 > 32 0.125 to > 32
Enterobacter sp[18, 19] 1435 ≤ 0.06 > 8 ≤ 0.06 to > 8
Enterobacter cloacae
AmpC-nonderepressed strains[15] 286 0.06 4 0.03 to > 32
AmpC-derepressed strains[15] 120 8 > 32 0.125 to > 32
Pseudomonas aeruginosa
All[7, 18, 19, 21] 2237 2 > 8 0.003 to > 32
Ceftazidime susceptible[15] 621 4 8 0.03 to > 32
Ceftazidime resistant[15] 130 16 > 32 0.03 to > 32
Proteus mirabilis
Wild type[7, 15, 18, 19] 876 0.03 0.06 ≤ 0.015 to > 32
ESBL-producing strains[15] 16 > 32 > 32 0.5 t o > 32
Acinetobacter sp
All[7, 18, 19, 21] 1220 8 > 32 ≤ 0.015 to > 32
Imipenem susceptible[15] 220 0.5 > 32 ≤ 0.015 to > 32
Imipenem resistant[15] 58 > 32 > 32 0.25 to > 32
Haemophilus influenzae [19, 20] 445 ≤ 0.06 ≤ 0.06 ≤ 0.06–0.5
Neisseria meningitidis [19] 24 ≤ 0.002 0.004 ≤ 0.002–0.008
Neisseria gonorrheae [19] 32 0.003 0.06 0.008–0.06
Anaerobic
Clostridium difficile [22] 30 4 8 1–8
Clostridium perfringens [22] 30 ≤ 0.016 ≤ 0.016 ≤ 0.016
Bacilus fragilis [19, 22, 23] 164 8 > 128 ≤ 0.025 to > 128

aMIC50 and MIC90 = minimal inhibitory concentrations for 50% and 90% of tested strains, respectively; ESBL = extended-spectrum βlactamase.

Few studies report activity of ceftobiprole against VISA and vancomycin-resistant S. aureus (VRSA) isolates, with MIC values of 2 μg/ml or less, which suggests the potential role for ceftobiprole in the treatment of infections caused by MRSA with reduced susceptibility to vancomycin.[24,25] Like other cephalosporins, the MIC of ceftobiprole may be reduced at intra-cellular pH of 5.5. Thus, the MRSA ATCC33591 strain exhibits an MIC of 2 μg/ml at pH 7.4 and 0.5 μg/ml at pH 5.5. In a model of THP1-macrophage, except ceftazidime, all tested cephalosporins prevented MSSA growth, whereas MRSA growth was only inhibited by ceftobiprole.[26] In contrast, ceftobiprole MICs appeared not to be influenced by the SCCmec type, by susceptibility profile to vancomycin, oxacillin, or cefoxitin and the origin of isolates (endocarditis or bone infections).[7, 12, 27, 28]

Ceftobiprole is also efficient against coagulase-negative staphylococci, both methicillin susceptible and methicillin resistant, as well as against strains with small-colony variant phenotypes, S. pneumoniae (including penicillin-resistant strains) and other streptococcal species ( Table 1 ).[7, 13, 14, 17–21, 29, 30] Susceptibility values appeared to be affected by addition of 2% sodium chloride, which induces the unreliable PBP2a expression.[7]

[

Table 1. In Vitro Susceptibility of Ceftobiprole

Organism No. of Isolates MIC50(μg/ml) MIC90(μg/ml) MIC Range(μg/ml)
Gram-positive
Staphylococcus aureus
Methicillin susceptible[7, 15, 17, 19] 7889 0.25 0.5 ≤ 0.125–2
Methicillin resistant[7, 15, 17–19] 6270 1 2 ≤ 0.125–4
Coagulase-negative staphylococci
Methicillin susceptible[17–19] 854 0.125 0.25 ≤ 0.125–1
Methicillin resistant[17, 19] 2632 1 2 ≤ 0.015–8
Streptococcus pneumoniae
Penicillin susceptible[7, 15, 19] 686 0.008 0.015 ≤ 0.002–0.06
Penicillin intermediate[15, 19] 206 0.06 0.125 0.008–0.5
Penicillin resistant[7, 15, 19] 193 0.25 0.25 ≤ 0.015–2
Enterococcus faecalis 2975 0.5 4 0.125 to > 32
Enterococcus faecium
Ampicillin susceptible[7] 16 4 8 1–8
Ampicillin resistant[7,19] 71 > 32 > 32 0.25 to > 32
Gram-negative
Escherichia coli
Wild type[7, 15, 18, 19] 5792 0.03 0.125 0.03 to > 32
ESBL-producing strains[7, 15, 18] 443 > 32 > 32 0.03 to > 32
Klebsiella pneumoniae
Wild type[7, 15, 18, 20] 2669 ≤ 0.06 0.125 ≤ 0.015 to > 32
ESBL-producing strains[7,15,18, 20] 676 > 32 > 32 0.125 to > 32
Enterobacter sp[18, 19] 1435 ≤ 0.06 > 8 ≤ 0.06 to > 8
Enterobacter cloacae
AmpC-nonderepressed strains[15] 286 0.06 4 0.03 to > 32
AmpC-derepressed strains[15] 120 8 > 32 0.125 to > 32
Pseudomonas aeruginosa
All[7, 18, 19, 21] 2237 2 > 8 0.003 to > 32
Ceftazidime susceptible[15] 621 4 8 0.03 to > 32
Ceftazidime resistant[15] 130 16 > 32 0.03 to > 32
Proteus mirabilis
Wild type[7, 15, 18, 19] 876 0.03 0.06 ≤ 0.015 to > 32
ESBL-producing strains[15] 16 > 32 > 32 0.5 t o > 32
Acinetobacter sp
All[7, 18, 19, 21] 1220 8 > 32 ≤ 0.015 to > 32
Imipenem susceptible[15] 220 0.5 > 32 ≤ 0.015 to > 32
Imipenem resistant[15] 58 > 32 > 32 0.25 to > 32
Haemophilus influenzae [19, 20] 445 ≤ 0.06 ≤ 0.06 ≤ 0.06–0.5
Neisseria meningitidis [19] 24 ≤ 0.002 0.004 ≤ 0.002–0.008
Neisseria gonorrheae [19] 32 0.003 0.06 0.008–0.06
Anaerobic
Clostridium difficile [22] 30 4 8 1–8
Clostridium perfringens [22] 30 ≤ 0.016 ≤ 0.016 ≤ 0.016
Bacilus fragilis [19, 22, 23] 164 8 > 128 ≤ 0.025 to > 128

aMIC50 and MIC90 = minimal inhibitory concentrations for 50% and 90% of tested strains, respectively; ESBL = extended-spectrum βlactamase.

Against E.faecalis, ceftobiprole displays similar activity as that of ampicillin and amoxicillin-clavulanic acid, with MIC50 and MIC90 values of 0.5 and 4 μg/ml, respectively. In a recent study that evaluated 17 E. faecalis isolates obtained from two phase III clinical trials, the authors reported the same MIC50 and MIC90 values of 0.5 μg/ml.[17] In contrast and due to a poor affinity for the PBP5, ceftobiprole is less active than linezolid against Enterococcus faecium isolates and should not be used to treat infections due to these pathogens.[7, 12, 16, 19, 31]

Gram-negative Organisms

Promising activity has been demonstrated against a variety of susceptible gram-negative pathogens such as E. coli, Klebsiella species, Proteus mirabilis, Salmonella species, Haemophilus influenzae, and Shigella species, frequently with MIC values of 4 μg/ml or less ( Table 1 ).[7, 14, 17–21, 29] Against Paeruginosa, ceftobiprole activity has been reported comparable to or slightly higher than that of cefepime and ceftazidime, with an MIC90 greater than 8 μg/ml.[7, 15, 18, 19, 21] Its activity against Acinetobacter baumanii is also limited, with MIC90 values greater than 32 μg/ml.

]

Table 1. In Vitro Susceptibility of Ceftobiprole

Organism No. of Isolates MIC50(μg/ml) MIC90(μg/ml) MIC Range(μg/ml)
Gram-positive
Staphylococcus aureus
Methicillin susceptible[7, 15, 17, 19] 7889 0.25 0.5 ≤ 0.125–2
Methicillin resistant[7, 15, 17–19] 6270 1 2 ≤ 0.125–4
Coagulase-negative staphylococci
Methicillin susceptible[17–19] 854 0.125 0.25 ≤ 0.125–1
Methicillin resistant[17, 19] 2632 1 2 ≤ 0.015–8
Streptococcus pneumoniae
Penicillin susceptible[7, 15, 19] 686 0.008 0.015 ≤ 0.002–0.06
Penicillin intermediate[15, 19] 206 0.06 0.125 0.008–0.5
Penicillin resistant[7, 15, 19] 193 0.25 0.25 ≤ 0.015–2
Enterococcus faecalis 2975 0.5 4 0.125 to > 32
Enterococcus faecium
Ampicillin susceptible[7] 16 4 8 1–8
Ampicillin resistant[7,19] 71 > 32 > 32 0.25 to > 32
Gram-negative
Escherichia coli
Wild type[7, 15, 18, 19] 5792 0.03 0.125 0.03 to > 32
ESBL-producing strains[7, 15, 18] 443 > 32 > 32 0.03 to > 32
Klebsiella pneumoniae
Wild type[7, 15, 18, 20] 2669 ≤ 0.06 0.125 ≤ 0.015 to > 32
ESBL-producing strains[7,15,18, 20] 676 > 32 > 32 0.125 to > 32
Enterobacter sp[18, 19] 1435 ≤ 0.06 > 8 ≤ 0.06 to > 8
Enterobacter cloacae
AmpC-nonderepressed strains[15] 286 0.06 4 0.03 to > 32
AmpC-derepressed strains[15] 120 8 > 32 0.125 to > 32
Pseudomonas aeruginosa
All[7, 18, 19, 21] 2237 2 > 8 0.003 to > 32
Ceftazidime susceptible[15] 621 4 8 0.03 to > 32
Ceftazidime resistant[15] 130 16 > 32 0.03 to > 32
Proteus mirabilis
Wild type[7, 15, 18, 19] 876 0.03 0.06 ≤ 0.015 to > 32
ESBL-producing strains[15] 16 > 32 > 32 0.5 t o > 32
Acinetobacter sp
All[7, 18, 19, 21] 1220 8 > 32 ≤ 0.015 to > 32
Imipenem susceptible[15] 220 0.5 > 32 ≤ 0.015 to > 32
Imipenem resistant[15] 58 > 32 > 32 0.25 to > 32
Haemophilus influenzae [19, 20] 445 ≤ 0.06 ≤ 0.06 ≤ 0.06–0.5
Neisseria meningitidis [19] 24 ≤ 0.002 0.004 ≤ 0.002–0.008
Neisseria gonorrheae [19] 32 0.003 0.06 0.008–0.06
Anaerobic
Clostridium difficile [22] 30 4 8 1–8
Clostridium perfringens [22] 30 ≤ 0.016 ≤ 0.016 ≤ 0.016
Bacilus fragilis [19, 22, 23] 164 8 > 128 ≤ 0.025 to > 128

aMIC50 and MIC90 = minimal inhibitory concentrations for 50% and 90% of tested strains, respectively; ESBL = extended-spectrum βlactamase.

Ceftobiprole activity is reduced in the presence of extended-spectrum β-lactamase (ESBL) or carbapenemase enzymes, and MIC values for multidrug-resistant gram-negative organisms have been reported between 0.03 and greater than 32 μg/ml, depending on the enzymes produced.[32] Like cefepime, but in contrast to other advanced-generation cephalosporins such as ceftazidime or ceftriaxone, ceftobiprole is a weak inducer and a poor substrate for AmpC cephalosporinases, and its activity against Enterobacter cloacae isolates therefore may be limited ( Table 1 ).[19, 20, 32] Several ceftobiprole cross-resistance phenomena have been observed; examples include ceftazidime, cefepime, imipenem, and piperacillin-tazobactam in P.aeruginosa or Acinetobacter species isolates.[7, 15, 18, 33]

]

Table 1. In Vitro Susceptibility of Ceftobiprole

Organism No. of Isolates MIC50(μg/ml) MIC90(μg/ml) MIC Range(μg/ml)
Gram-positive
Staphylococcus aureus
Methicillin susceptible[7, 15, 17, 19] 7889 0.25 0.5 ≤ 0.125–2
Methicillin resistant[7, 15, 17–19] 6270 1 2 ≤ 0.125–4
Coagulase-negative staphylococci
Methicillin susceptible[17–19] 854 0.125 0.25 ≤ 0.125–1
Methicillin resistant[17, 19] 2632 1 2 ≤ 0.015–8
Streptococcus pneumoniae
Penicillin susceptible[7, 15, 19] 686 0.008 0.015 ≤ 0.002–0.06
Penicillin intermediate[15, 19] 206 0.06 0.125 0.008–0.5
Penicillin resistant[7, 15, 19] 193 0.25 0.25 ≤ 0.015–2
Enterococcus faecalis 2975 0.5 4 0.125 to > 32
Enterococcus faecium
Ampicillin susceptible[7] 16 4 8 1–8
Ampicillin resistant[7,19] 71 > 32 > 32 0.25 to > 32
Gram-negative
Escherichia coli
Wild type[7, 15, 18, 19] 5792 0.03 0.125 0.03 to > 32
ESBL-producing strains[7, 15, 18] 443 > 32 > 32 0.03 to > 32
Klebsiella pneumoniae
Wild type[7, 15, 18, 20] 2669 ≤ 0.06 0.125 ≤ 0.015 to > 32
ESBL-producing strains[7,15,18, 20] 676 > 32 > 32 0.125 to > 32
Enterobacter sp[18, 19] 1435 ≤ 0.06 > 8 ≤ 0.06 to > 8
Enterobacter cloacae
AmpC-nonderepressed strains[15] 286 0.06 4 0.03 to > 32
AmpC-derepressed strains[15] 120 8 > 32 0.125 to > 32
Pseudomonas aeruginosa
All[7, 18, 19, 21] 2237 2 > 8 0.003 to > 32
Ceftazidime susceptible[15] 621 4 8 0.03 to > 32
Ceftazidime resistant[15] 130 16 > 32 0.03 to > 32
Proteus mirabilis
Wild type[7, 15, 18, 19] 876 0.03 0.06 ≤ 0.015 to > 32
ESBL-producing strains[15] 16 > 32 > 32 0.5 t o > 32
Acinetobacter sp
All[7, 18, 19, 21] 1220 8 > 32 ≤ 0.015 to > 32
Imipenem susceptible[15] 220 0.5 > 32 ≤ 0.015 to > 32
Imipenem resistant[15] 58 > 32 > 32 0.25 to > 32
Haemophilus influenzae [19, 20] 445 ≤ 0.06 ≤ 0.06 ≤ 0.06–0.5
Neisseria meningitidis [19] 24 ≤ 0.002 0.004 ≤ 0.002–0.008
Neisseria gonorrheae [19] 32 0.003 0.06 0.008–0.06
Anaerobic
Clostridium difficile [22] 30 4 8 1–8
Clostridium perfringens [22] 30 ≤ 0.016 ≤ 0.016 ≤ 0.016
Bacilus fragilis [19, 22, 23] 164 8 > 128 ≤ 0.025 to > 128

aMIC50 and MIC90 = minimal inhibitory concentrations for 50% and 90% of tested strains, respectively; ESBL = extended-spectrum βlactamase.

Anaerobic Bacteria

Some anaerobic bacteria, such as Propioni-bacterium acnes or Clostridium perfringens, have proved to be susceptible to ceftobiprole with an MIC90 less than 1 μg/ml (Table 1).[19, 34] In contrast, Bacillus species, Bacteroides species, Clostridium difficile, Peptostreptococcus anaerobius, Prevotella species, and Lactobacillus species appear less susceptible to ceftobiprole, with MIC90 values that range from 8 to greater than 128 μg/ml.[19, 23, 34] In a recent study evaluating 463 anaerobes, ceftobiprole activity appeared to be affected by most of the β-lactamase enzymes of anaerobic organisms, which therefore displayed higher MIC50 values (1–16 μg/ml).[22, 34]

[

Table 1. In Vitro Susceptibility of Ceftobiprole

Organism No. of Isolates MIC50(μg/ml) MIC90(μg/ml) MIC Range(μg/ml)
Gram-positive
Staphylococcus aureus
Methicillin susceptible[7, 15, 17, 19] 7889 0.25 0.5 ≤ 0.125–2
Methicillin resistant[7, 15, 17–19] 6270 1 2 ≤ 0.125–4
Coagulase-negative staphylococci
Methicillin susceptible[17–19] 854 0.125 0.25 ≤ 0.125–1
Methicillin resistant[17, 19] 2632 1 2 ≤ 0.015–8
Streptococcus pneumoniae
Penicillin susceptible[7, 15, 19] 686 0.008 0.015 ≤ 0.002–0.06
Penicillin intermediate[15, 19] 206 0.06 0.125 0.008–0.5
Penicillin resistant[7, 15, 19] 193 0.25 0.25 ≤ 0.015–2
Enterococcus faecalis 2975 0.5 4 0.125 to > 32
Enterococcus faecium
Ampicillin susceptible[7] 16 4 8 1–8
Ampicillin resistant[7,19] 71 > 32 > 32 0.25 to > 32
Gram-negative
Escherichia coli
Wild type[7, 15, 18, 19] 5792 0.03 0.125 0.03 to > 32
ESBL-producing strains[7, 15, 18] 443 > 32 > 32 0.03 to > 32
Klebsiella pneumoniae
Wild type[7, 15, 18, 20] 2669 ≤ 0.06 0.125 ≤ 0.015 to > 32
ESBL-producing strains[7,15,18, 20] 676 > 32 > 32 0.125 to > 32
Enterobacter sp[18, 19] 1435 ≤ 0.06 > 8 ≤ 0.06 to > 8
Enterobacter cloacae
AmpC-nonderepressed strains[15] 286 0.06 4 0.03 to > 32
AmpC-derepressed strains[15] 120 8 > 32 0.125 to > 32
Pseudomonas aeruginosa
All[7, 18, 19, 21] 2237 2 > 8 0.003 to > 32
Ceftazidime susceptible[15] 621 4 8 0.03 to > 32
Ceftazidime resistant[15] 130 16 > 32 0.03 to > 32
Proteus mirabilis
Wild type[7, 15, 18, 19] 876 0.03 0.06 ≤ 0.015 to > 32
ESBL-producing strains[15] 16 > 32 > 32 0.5 t o > 32
Acinetobacter sp
All[7, 18, 19, 21] 1220 8 > 32 ≤ 0.015 to > 32
Imipenem susceptible[15] 220 0.5 > 32 ≤ 0.015 to > 32
Imipenem resistant[15] 58 > 32 > 32 0.25 to > 32
Haemophilus influenzae [19, 20] 445 ≤ 0.06 ≤ 0.06 ≤ 0.06–0.5
Neisseria meningitidis [19] 24 ≤ 0.002 0.004 ≤ 0.002–0.008
Neisseria gonorrheae [19] 32 0.003 0.06 0.008–0.06
Anaerobic
Clostridium difficile [22] 30 4 8 1–8
Clostridium perfringens [22] 30 ≤ 0.016 ≤ 0.016 ≤ 0.016
Bacilus fragilis [19, 22, 23] 164 8 > 128 ≤ 0.025 to > 128

aMIC50 and MIC90 = minimal inhibitory concentrations for 50% and 90% of tested strains, respectively; ESBL = extended-spectrum βlactamase.

Mechanisms of Resistance

In both in vitro and in vivo studies, ceftobiprole demonstrated a low mutation frequency (1.4 × 10−10 reported for S. aureus).[7, 13, 35–38] The highest MIC found against S. aureus, after 50 serial passages with ceftobiprole at subinhibitory concentrations, was 8 μg/ml.[24] The same result was demonstrated for pneumococcal isolates, H. influenzae, and Moraxella catarrhalis in animal infection models.[38, 39] As with other β-lactams, mutation frequency was higher at lower concentrations against gram-negative bacteria, and resistant colonies displayed increased levels of β-lactamase enzymes.[40] Although there is no clinical evidence, ceftobiprole, like other β-lactams, may be affected by the three major mechanisms of resistance developed by bacteria: antibiotic inactivation by enzyme degradation, target modification, and default of the antibiotic accumulation within the cell by impermeability or efflux.[41]

Enzymatic Degradation

Ceftobiprole activity is not affected by class A and class C β-lactamase enzymes from gram-negative organisms, nor by the penicillinase PC1, present in almost 90% of S. aureus strains.[32] In contrast, ESBL and carbapenemase enzymes are able to hydrolyze ceftobiprole at high rates, and this property seems common to β-lactams bearing a 2-aminothiazol-4-yl-oxime moiety.[11, 19, 32] Ceftobiprole is also reported to be unstable in the presence of the chromosomal β-lactamases of Proteus vulgaris, Bacteroides fragilis, and other Bacteroides species, which therefore appear naturally resistant.[42]

Decreased Affinity or Modification of the Target

Decreased affinity of ceftobiprole is reported for some PBPs, such as PBP1b and PBP2b of penicillin-resistant S. pneumoniae, PBP5 of E. coli and E. faecium, and PBP5/6 of P. aeruginosa. [12, 14, 15] This may partially explain the limited activity of ceftobiprole for most of these species. Also, increased ceftobiprole MIC values were reported to closely correlate with an increase in the number of mutations in the PBP.[43] Recently, a group of authors demonstrated that resistance to ceftobiprole may be mediated by mutations in mecA and suggested that these modifications led to three different mechanisms: inhibition of acylation, inhibition of substrate binding, and interference with protein-protein interactions.[44] Briefly, they selected ceftobiprole mutants of three isogenic strains, only differing by mecA expression or mutations, and demonstrated emergence of new mutations in mecA after 9 days of passaging. Molecular modeling of PBP2a mutants allowed the design of three groups of mutations. The first group corresponded to modifications nearby the active site of the protein, by addition of charged and polar groups, therefore affecting the acylation rate of β-lactam substrates and inhibitors. The second group of mutations concerned substitutions within the protein or nearby the active site, playing a role in ceftobiprole binding and leading to conformational changes of the active protein. The third group of mutations, considered as secondary, corresponded to addition of a positive charge in a non-penicillin-binding domain, placed far from the active site and likely involved in interactions with other proteins.[44]

Efflux

Ceftobiprole has been demonstrated to be a substrate of the MexXY efflux pump.[45] A 4-fold increase in ceftobiprole MIC value (from 4 to 16 μg/ml) was observed for one P. aeruginosa isolate after ceftobiprole exposure. Increase in mexX and mexY RNA levels were reported, and sequence analysis demonstrated a single mutation in the mexZ repressor, leading to the overexpression of the MexXY transporter. However, this apparent resistance did not lead to a treatment failure.[46] Considering that cephalosporins are known to be substrates of efflux pumps, especially from the resistance nodulation division (RND) superfamily, it is expected that ceftobiprole will lose activity in case of overexpression of RND efflux pumps.[46]

Tolerance and the Eagle Effect

The Eagle effect is widely recognized and documented among β-lactam antimicrobials as a paradoxical bactericidal effect, which occurs in heteroresistant populations.[47] This effect is due to the activation of the mecI regulator under exposure to a high concentration of methicillin (128 μg/ml), leading to the decrease of the mecA transcription. This mechanism has also been observed with ceftobiprole against many S. aureus strains harboring various antimicrobial susceptibility profiles.[24, 29] Tolerance has also been reported for S. aureus, S. pneumoniae, and Serratia marcescens isolates.[48] For S. aureus isolates, tolerance was associated with the lower specific activity of autolytic enzymes after exposure to high concentrations of methicillin, as well as the inhibition of RNA and protein synthesis.[48]

Pharmacokinetics

Table 2 summarizes the pharmacokinetic parameters of ceftobiprole, which were derived mainly from single-dose and multiple-dose pharmacokinetic studies, involving 40 and 16 healthy male subjects, respectively.[8, 49] After intravenous administration, the water-soluble prodrug BAL5788 is quickly converted by the type A plasma esterases into the active cephalosporin (ceftobiprole or BAL9141), the inactive diacetyl metabolite, and carbon dioxide.[8, 50] Ceftobiprole exhibits linear pharmacokinetics for peak plasma concentration and area under the concentration-time curve with ascending single doses from 125–1000 mg as well as multiple doses.[50] Peak plasma concentration is observed at the end of the 30-minute infusion, and the degree of plasma protein binding is low (estimated at 16%).[8, 49] Like other cephalosporins, elimination mainly occurs by the renal route, and the half-life is approximately 3–4 hours in subjects with normal renal function.[8, 49, 51, 52] The peak concentration of ceftobiprole in urine is rapidly observed (0–2 hrs after start of the infusion) as unchanged drug at more than 80%, suggesting its potential utility in urinary tract infections.[8] In the multiple-doses study, no drug accumulation was observed, suggesting that the treatment did not affect renal function.[49] The volume of distribution approximates the volume of the extracellular water compartment in healthy adults (12–20 L).[50]

[

Table 2. Pharmacokinetic and Pharmacodynamic Parameters of Intravenous Ceftobiprole After Single- or Multiple-Dose Administration of Ascending Doses Over 30 Minutes Every 24 Hours[8, 49]

Parameter Single-Dose Administration Multiple-Dose Administration
125 mg 250 mg 500 mg 750 mg 1000 mg Day 1 Day 8
500 mg 750 mg 500 mg 750 mg
Cmax (μg/ml) 9.87 ± 0.78 19.5 ± 2.75 35.5 ± 6.79 59.6 ± 10.7 72.2 ± 8.78 40.6 ± 7.38 60.7 ± 4.55 44.2 ± 10.8 60.6 ± 9.99
AUC0–∞ (μg·hr/ml) 20.3 ± 2.82 43.7 ± 5.99 76.6 ± 3.88 135 ± 27.6 151 ± 9.04 101 ± 9.04 156 ± 19.3 108 ± 22.2 165 ± 12.8
T1/2,α (hrs) 0.37 ± 0.14 0.47 ± 0.15 0.57 ± 0.22 0.48 ± 0.27 0.56 ± 0.36 1.06 ± 0.46 0.96 ± 0.59 1.03 ± 0.42 0.99 ± 0.50
T1/2,β (hrs) 2.84 ± 0.21 3.42 ± 0.29 3.44 ± 0.30 3.47 ± 0.37 3.25 ± 0.20 3.63 ± 0.48 3.64 ± 0.32 4.04 ± 0.31 4.11 ± 0.41
Cls (L/hr/kg) 6.27 ± 0.97 5.81 ± 0.84 6.54 ± 0.34 5.74 ± 1.13 6.64 ± 0.41 4.99 ± 0.46 4.85 ± 0.57 5.05 ± 0.95 4.84 ± 0.34
Clr (L/hr/kg) 4.60 ± 0.38 4.35 ± 0.57 5.07 ± 0.22 4.08 ± 0.75 4.16 ± 0.57 4.12 ± 0.75 4.05 ± 0.47 4.47 ± 1.07 4.09 ± 2.20
Vss (L/kg) 17.9 ± 2.00 17.8 ± 3.11 19.8 ± 1.95 18.4 ± 2.63 18.9 ± 2.31 16.4 ± 2.11 16.3 ± 1.82 16.7 ± 3.58 16.1 ± 2.20
% n i urine at 24 hrs 74.2 (62.1 –86.1) 76.1 (67.4–97.6) 77.5 (53.8–81.7) 71.3 (69.5–73.5) 62.5 (53.7–70.6) 82.2 (70.5–94.8) 87.8 (76.9 –104.2) 83.7 (76–87.1) 84.4 (73.1–100.2)
T>MIC (hrs)
Total 1.5 3.5 5.0 7.0 7.0
Unbound 0.75 2 3.5 5.0 5.0
T>MIC (%)
Total 13 29 42 58 58
Unbound 6 17 29 42 42

Data are mean, mean ± SD, or mean (range).
Cmax = maximum plasma concentration; AUC0-∞ = area under the concentration-time curve from time zero extrapolated to infinity; t1/2, α = halflife-in the distribution phase; t1/2, β = half-life in the postdistribution phase; Cls = total systemic clearance; Clr = total renal clearance; Vss = volume of distribution at steady state; T>MIC = percentage of the dosing interval or time that the drug concentration remains above an MIC of 4 μg/ml using a 12-hr dosing interval.

Ceftobiprole undergoes minimal hepatic metabolism, resulting in an open-ring compound and few unidentified metabolites. In addition, ceftobiprole does not affect the cytochrome P450 system or hepatic enzyme activity, and its intracellular concentration in cell monolayers appears not to be affected by the efflux transporter P-glycoprotein.[50] Results of a small study that included 12 male and 12 female subjects showed that systemic exposure to ceftobiprole was slightly higher in the female group, who had a lower body weight:size ratio and therefore a smaller volume of distribution.[52] The percentage of the dosing interval that free drug concentration remains above the MIC (fT>MIC) was therefore considered not significantly affected by sex, and no dosage adjustment was required. In contrast, dosage adjustment does appear necessary for a population with renal impairment, since ceftobiprole concentrations in plasma and terminal elimination half-life increase with the degree of renal impairment (see Expected Recommended Dosage Regimens and Dosage Adjustments section).[53]

Pharmacodynamics

Ceftobiprole’s pharmacodynamic profile is similar to that of other compounds in the cephalosporin class. Ceftobiprole exhibits time-dependent and concentration-independent killing, and fT>MIC is considered as the main parameter to predict its efficacy.[49, 54] Target attainment rates were studied by using Monte Carlo simulations for several dosage regimens of ceftobiprole (500 mg as a 30-minute-2-hour infusion every 12 or 24 hours and 750 mg as a 30-minute infusion twice/day).[54–56] In a small study involving only 12 patients, a dosage regimen of 750 mg as a 30-minute infusion every 12 hours or 500 mg as a 30-minute infusion every 8 hours had a high probability of target attainment and therapeutic efficacy against MRSA with an MIC of 4 μg/ml or less.[55] A recent and more extensive analysis was conducted in 150 subjects, including 29 older patients from a phase II pharmacokinetic study of ceftobiprole, intravenous drug users with higher clearances, and patients with renal functional impairment.[56] For staphylococci with MIC values less than 1 μg/ml, targets for stasis and maximal killing were 30% and 50% fT>MIC, respectively.[56] Against MRSA with MIC values of 2 ug/ml or less, a target attainment rate greater than 90% was observed for 40% fT>MIC with dosage regimens of 500 mg as a 30-minute-2-hour infusion every 8 hours and 500 mg as a 1-hour infusion every 12hours with a creatinine clearance of 80 ml/minute. For an MIC of 4 μg/ml, fT>MIC ranges from 40–58% or 58–75% were achieved in a multiple-dose study using ceftobiprole 500 or 750 mg as a 1–2-hour infusion twice/day or 500 mg as a 1–2-hour infusion every 8 hours.[49, 56] Against gram-negative pathogens, a dosage of 500 mg as a 2-hour infusion every 8 hours led to bacteriostatic (40% fT>MIC) and bactericidal (60% fT>MIC) effects against susceptible bacilli, suggesting its utility for the treatment of polymicrobial infections. Target attainment rates from 87.8–89.8% were reported for 40–60% fT>MIC against AmpC-producing gram-negative bacilli and from 62–71% against P. aeruginosa.[56]

Postantibiotic Effect

The postantibiotic effect (PAE), or the length of time between inhibition of bacterial growth and antibiotic exposure, is a pharmacodynamic parameter that allows the selection of the most optimal antibiotic dosing schedule. The postantibiotic sub-MIC effect (PA-SME), defined as the length of time that includes the PAE and the time interval during which bacterial growth is still suppressed by subinhibitory concentrations, was also studied.[57] A recent study evaluated ceftobiprole’s in vitro PAE for 12 gram-positive pathogens (including S. pneumoniae, S. aureus, and E.faecalis). For all tested isolates, in vitro PAE values varied from 0–3.1 hours and was modest for MRSA strains (˜0.5 hr).[13, 57] The PA-SME appeared longer than PAE and increased with subinhibitory concentrations of ceftobiprole, suggesting that continued exposure to sub-MIC levels of ceftobiprole after a suprainhibitory concentration may allow a greater suppression of growth in vivo. In a recent in vivo study using a murine thigh and lung infection model, average PAE was 4.3 hours for MRSA and 0.5 hours for penicillin-resistant S. pneumoniae isolates.[58]

Synergy

Synergy is defined as a greater than or equal to 2 log10-colony-forming units/ml increase in killing at 24 hours with a combination of drugs compared with the most active single agent. Ceftobiprole’s in vitro potential for synergy has been mainly investigated against multidrug-resistant gram-positive organisms, such as S. pneumoniae, enterococci, and MRSA isolates. Against community- and hospital-acquired MRSA, ceftobiprole alone demonstrated potent bactericidal activity, but no synergy was observed in combination with tobramycin.[59] Combination with vancomycin also did not lead to a synergistic effect, and differences between monotherapy and combination therapy were not significant either in vitro or in vivo.[60] Combination with gentamicin appeared mainly indifferent against staphylococci and enterococci, but synergistic effect was demonstrated for two coagulase-negative staphylococci and 50% of tested E.faecium.[48] Against (β-lactamase-producing and vancomycin-resistant E.faecalis strains, combinations of ceftobiprole plus streptomycin or gentamicin exhibited synergistic effect at subinhibitory concentrations.[61] Against some gram-negative pathogens, few studies refer to a synergistic effect for the combination of ceftobiprole with aminoglycosides (amikacin and tobramycin) or fluoroquinolones (ciprofloxacin and levofloxacin).[62, 63] Against P. aeruginosa, although most combinations displayed an additive effect (68–90%), a synergistic effect was observed with tobramycin for 27% of isolates, with amikacin for 12%, and with levofloxacin or ciprofloxacin for 10%.[63] More recently, the combination of ceftobiprole with levofloxacin appeared synergistic against P. aeruginosa isolate ATCC27853 in a neutropenic mouse model, and also suppressed emergence of resistance.[62] Although further investigations are required, these results suggest that the combination of ceftobiprole and aminoglycosides or fluoro-quinolones might be useful to treat infections caused by multidrug-resistant gram-positive pathogens or polymicrobial infections, involving both gram-positive and susceptible gram-negative organisms.

Animal Infection Models

Ceftobiprole has been compared with several empiric therapies in a large variety of animal infection models. Antiinfective doses used in these experiments generally simulated human pharmacokinetics but were different because of the varying pharmacokinetic profiles in animal models.

Endocarditis

Two studies have evaluated ceftobiprole activity in experimental endocarditis models, in comparison with vancomycin and/or amoxicillin-clavulanate.[37,64] In one of the studies, ceftobiprole was administered 12 hours after inoculation, by continuous infusion for 3 days, at 72, 144, and 288 mg/kg every 24 hours to attain steady-state target levels in serum 1.25, 2.5, and 5 times higher than the MIC90 of tested MRSA.[64] Amoxicillin-clavulanate 164.4 mg/kg every 6 hours and vancomycin 23.2 mg/kg every 12 hours were used as comparators. Ceftobiprole demonstrated excellent activity against homo-geneously methicillin-resistant and penicillinase-positive S. aureus and appeared equal to or more active than amoxicillin-clavulanate or vancomycin. The consistent activity of ceftobiprole was correlated to its high affinity for PBP2a, as well as a better diffusion into vegetations compared with vancomycin.[64]

The other study evaluated ceftobiprole efficacy at 25 mg/kg intramuscularly every 8 hours in an experimental rabbit model of aortic valve endo-carditis infected with MRSA and VISA isolates.[37] Vancomycin 30 mg/kg every 12 hours was used as the comparator. Ceftobiprole appeared bactericidal against both isolates, which is consistent with previous in vitro experiments, and its activity was found superior to that of vancomycin against the VISA isolate or equivalent against the MRSA strain. Nevertheless, ceftobiprole MIC was 2-fold higher for the MRSA strain than that for the VISA isolate.[37] To our knowledge, no clinical trials have evaluated ceftobiprole for endocarditis in humans.

Osteomyelitis

A recent study evaluated ceftobiprole activity compared with vancomycin and linezolid against MRSA by using an experimental tibial osteomyelitis rabbit model over a 4-week period.[65] Ceftobiprole 40 mg/kg was administered by subcutaneous injection every 6 hours. Comparators were linezolid 60 mg/kg administered orally every 8 hours and vancomycin 30 mg/kg administered by subcutaneous injection. As with vancomycin, ceftobiprole demonstrated a higher penetration rate in infected bones than in noninfected bones, and concentrations in bone matrix and marrow of noninfected rabbits after 4 days ranged from 13–20% and 47–80% of the 1-hour serum concentration, respectively. Ceftobiprole appeared more active than vancomycin and linezolid, with bacterial counts under the limit of detection for 100% of infected tibias treated with ceftobiprole compared with 73% for those treated with linezolid or vancomycin. Ceftobiprole has not been evaluated in the treatment of osteomyelitis in humans, and further investigations need to be done to clarify its utility in the treatment of osteomyelitis.

Tissue Cage Fluid

The therapeutic potential of ceftobiprole 150 mg/kg every 12 hours and its propensity for emergence of resistance were evaluated in a rat tissue cage model infected with MRSA.[36] Vancomycin 50 mg/kg every 12 hours was used as the comparator. Outcomes of antibiotic therapy were evaluated after 7 days of treatment after disrupting the biofilm and phagocytic cells by sonication. The pharmacokinetic study identified the dosage of 150 mg/kg every 12 hours sufficient to achieve bactericidal levels in tissue cage fluids. Ceftobiprole and vancomycin reached comparable peak and trough concentrations in the model and also had similar degrees of protein binding (38% and 30%, respectively). No development of endogenous resistant subpopulations was reported, which represents a significant advantage of ceftobiprole over glycopeptide therapy for foreign-body infections.

Pneumonia

Ceftobiprole activity was investigated over a 3-day period in leukopenic mice infected with penicillin- and cephalosporin-resistant pneumococcal strains, exhibiting MIC values from 0.008–1 μg/ml (i.e., 4–8 times less than MICs for ceftriaxone).[38] Ceftobiprole and ceftriaxone were administered twice/day at doses of 1.05–37.5 mg/kg and 5.3–200 mg/kg, respectively, depending on the MIC of the strain. Ceftobiprole, like ceftriaxone but at lower concentrations, appeared highly efficient in this model of pneumonia against both penicillin-susceptible and -resistant tested strains. Against the most susceptible strain (ceftriaxone and ceftobiprole MICs < 0.06 μg/ml), a 100% survival rate was attained for both cephalosporins, but with a 5-fold lower total daily dose of ceftobiprole. Although both drugs were administered at comparable doses, a significant difference in the survival rates (93% for ceftobiprole vs 13% for ceftriaxone) was observed against the strain displaying an intermediate MIC value (0.25 μg/ml). In terms of pharmacokinetic and pharmacodynamic parameters, fT>MIC required for the efficacy of ceftobiprole was 9–18% of the dosing interval versus 30–50% for ceftriaxone against most pneumococci, including some resistant strains. These results are consistent with recent observations in murine thigh and lung infections models.[58]

Another recent study that used an immuno-competent experimental mouse pneumonia model compared ceftobiprole activity with that of ceftriaxone or cefepime against one H.influenzae, one E.cloacae, and two Klebsiella pneumoniae ESBL-producing and non-ESBL-producing strains.[66] In vivo activities of tested antimicrobials were equal against H. influenzae, non-ESBL-producing K. pneumoniae, and E.cloacae strains. All agents, including ceftobiprole, were inactive against the ESBL-producing K. pneumoniae, which is consistent with previous data.[20] Ceftobiprole appeared noninferior to comparators and displayed a high penetration rate into lung tissue and epithelial lining fluid, which accounted for its activity. In addition, no emergence of resistance was observed with ceftobiprole.[38, 67]

Peritonitis

Ceftobiprole activity was assessed in a mouse peritonitis model against E.faecalis, including (β-lactamase-producing and vancomycin-resistant strains.[12] Single doses of ceftobiprole 1.56–25 mg/kg and ampicillin 6.25–100 mg/kg were administered by subcutaneous injection. In contrast to ampicillin, low doses of ceftobiprole exhibited an excellent activity against (β-lactamase-producing E.faecalis, which confirms that ceftobiprole is a poor substrate of entero-coccal β-lactamase. Ceftobiprole showed comparable results to those of ampicillin against ampicillin-susceptible-vancomycin-resistant E.faecalis.

Central Nervous System

Antimicrobial activity and penetration into inflamed meninges were recently evaluated in a rabbit meningitis model that compared cefto-biprole with cefepime against one K. pneumoniae strain with MIC values at 0.25 μg/ml for both drugs.[68] Dosage regimens were one dose of ceftobiprole 40 mg/kg and two doses of cefepime 100 mg/kg. Experiments were conducted over an 8-hour period. Ceftobiprole displayed higher activity than cefepime in the treatment of meningitis caused by susceptible K. pneumoniae, and its penetration rate into inflamed meninges ranged from 10–23%.

Septicemia

Ceftobiprole activity was compared with that of several antiinfective agents in an experimental septicemia mouse model infected with MSSA, MRSA, Streptococcus pyogenes, S. pneumoniae, and gram-negative organisms.[7] Ceftobiprole appeared highly effective against MSSA after subcutaneous administration, whereas its in vivo activity was only minimal after oral administration. Cefto-biprole and comparators (ceftriaxone, cefepime, benzylpenicillin, meropenem, vancomycin, and linezolid) were administered by subcutaneous injection at 1, 3, and 5 hours after the bacterial inoculation. Doses were calculated to attain steady-state level at 4–10 times higher than the MIC50 of each species, and experiments were run over 4 days. Ceftobiprole appeared more active than comparators against MSSA, MRSA, and penicillin-resistant S. pneumoniae and equivalent to cefepime and ceftriaxone against S. pyogenes and penicillin-susceptible S. pneumoniae. Against gram-negative pathogens, ceftobiprole was noninferior to comparators for susceptible E.coli and K. pneumoniae, but inferior to cefepime and meropenem for E.cloacae and P. aeruginosa.

Clinical Efficacy Trials

Skin and Skin Structure Infections

Two international, double-blind, randomized trials have been conducted to demonstrate noninferiority of ceftobiprole versus vancomycin (trial 1)[69] or vancomycin plus ceftazidime (trial 2)[70] and to assess clinical cure rates, efficacy, and safety of ceftobiprole in the treatment of cSSSI. In both trials, noninferiority was defined as a difference in clinical cure rates of less than 10%. Eligible patients were 18 years or older with a diagnosis of cSSSI caused exclusively by gram-positive organisms (trial 1) or by gram-positive and/or gram-negative organisms (trial 2). In both studies, exclusion criteria were hypersensitivity to cephalosporins or vancomycin, renal or hepatic functional impairments, neutropenia or immunodeficiency, pregnancy or lactation. The definition of cSSSI in both trials was an infection involving subcutaneous tissues or requiring surgical intervention with intravenous therapy plus one or more of the following characteristics: infection after trauma or surgery within 30 days, complicated by purulent drainage or three or more infection symptoms; diagnosis of abscess for less than 1 week with purulent drainage or aspirate and presence of fluid requiring surgery, erythema, or extended induration; or cellulitis for less than 1 week with advancing edema, erythema, or induration complicated by signs of infections. In the second trial, foot infection was included as an additional characteristic of cSSSI and was defined as an ulcer of the inframalleolar full-skin-thickness, cellulitis, myositis, or tendonitis complicated by three or more signs of infection.

The first trial involved 784 patients with a diagnosis of cSSSI caused by gram-positive bacteria.[69] Ceftobiprole 500 mg and vancomycin 1000 mg were administered as 1-hour infusions every 12 hours for 7–14 days. The most common pathogens were S. aureus, one third of which were MRSA with a ceftobiprole MIC of 2 μg/ml (vs 0.5 μg/ml for MSSA), and S. pyogenes (< 10%). Among the microbiologically evaluable population, ceftobiprole was as effective as and noninferior to vancomycin, with a clinical cure rate of 94.6% versus 94.2% for vancomycin. Differences between clinical cure rates observed against MSSA and MRSA were less than 2%. Against Panton-Valentine leukocidin-positive MRSA infections, ceftobiprole demonstrated a higher clinical cure rate compared with vancomycin (93.1% vs 84.6%).

In the second trial, ceftobiprole was compared with vancomycin plus ceftazidime or placebo.[70] Ceftobiprole 500 mg as a 2-hour infusion every 8 hours was administered, and comparator therapy consisted of vancomycin 1000 mg as a 1-hour infusion every 12 hours plus ceftazidime 1000 mg as a 2-hour infusion every 8 hours. Based on a total of 828 patients enrolled in the study, 66% (547 patients) received ceftobiprole monotherapy. Four hundred thirty-four subjects (79%) were screened for microbiologic intent to treat, 485 (89%) were considered clinically evaluable, 391 (71%) were microbiologically evaluable, and 543 (99%) were analyzed for safety. The most common pathogen in both groups was MSSA (41_45%) followed by MRSA (18–22%). The frequencies of gram-negative bacteria were 13% or lower, with a higher likelihood of E.coli in both groups, followed by P.aeruginosa in the ceftobiprole group and E.cloacae or P. mirabilis in the vancomycin group. Ceftobiprole and vancomycin plus ceftazidime demonstrated similar cure rates against both gram-positive and gram-negative pathogens. The greatest difference was observed for P.aeruginosa, with a clinical cure rate of 86.7% with ceftobiprole and 100% with vancomycin plus ceftazidime. However, only nine patients were evaluated for vancomycin plus ceftazidime versus 30 patients for ceftobiprole.

Community-acquired Pneumonia

Ceftobiprole is in phase III trials for the treatment of community-acquired pneumonia, and results of one clinical trial were recently reported.[71] The primary end point of the study was to demonstrate noninferiority of ceftobiprole compared with ceftriaxone with or without linezolid regarding clinical cure rates at the test-of-cure visit. Secondary end points were microbiologic eradication, clinical cure rates, whether the patients required mechanical ventilation within the first 2 days of enrollment, and 30-day pneumonia-specific mortality rates. A difference of 10% or less between clinical cure rates in clinically evaluable and intent-to-treat (ITT) populations defined noninferiority of ceftobiprole therapy versus ceftriaxone with or without linezolid. Patients were eligible for this trial if they were 18 years or older and had clinical and radiologic criteria for acute bacterial community-acquired pneumonia that required intravenous therapy for more than 3 days. Patients were excluded if community-acquired pneumonia was suspected or known to be secondary to aspiration or caused by viruses or atypical bacteria, such as Legionella species, Mycoplasma pneumoniae, or Chlamydia pneumoniae. Other exclusion criteria were systemic anti-microbial therapy for more than 24 hours in the previous 3 days before enrollment (except if pathogens were resistant to the previous therapy), residence in a nursing home or chronic care facility, and severe renal functional impairment or dialysis.

Antimicrobial therapies were ceftobiprole 500 mg as a 2-hour infusion every 8 hours with or without placebo as a 1-hour infusion every 12 hours, and ceftriaxone 2000 mg as a 30-minute infusion every 24 hours plus linezolid 600 mg as a 1-hour infusion every 12 hours or placebo as previously described. Linezolid was administered to patients with suspected or detected MRSA or S. pneumoniae resistant to ceftriaxone. The study involved randomization of 666 ITT patients (328 in the ceftobiprole group and 338 in the comparator group). Clinically evaluable and ITT with valid pathogen populations, as well as demographics and baseline characteristics, were similar between groups. The main difference was observed for the type of infection, since 80% of patients had monomicrobial infection in the ceftobiprole group versus 92% in the comparator group. Differences between clinical cure rates and microbiologic eradication were found to be less than 3% for both the clinically evaluable and ITT populations, demonstrating the noninferiority of ceftobiprole in the treatment of community-acquired pneumonia and at the test-of-cure visit. Clinical cure rates for gram-positive and gram-negative pathogens were similar. However, a higher rate of efficacy was observed for ceftobiprole against S. aureus coagulase-positive organisms. In spite of some study limitations (e.g., exclusion of atypical pathogens), ceftobiprole was clinically efficient and therapeutically noninferior to ceftriaxone with or without linezolid in the treatment of community-acquired pneumonia.

A clinical trial for treatment of hospital-acquired pneumonia was completed recently. Results were presented at an international conference and showed promising data for ceftobiprole being noninferior to a comparator.[72] A clinical trial for S. aureus bacteremia was withdrawn due to the difficulty of finding an appropriate population, and a phase III study for the treatment of neutropenia was also suspended for a reevaluation of the comparator.[73]

Safety, Contraindications, and Precautions

Ceftobiprole safety and efficacy have been evaluated in many studies.[8, 49, 69–71, 74] In a phase I study, 27% of patients experienced adverse events, and 88% of them reported a caramel-like taste disturbance (dysgeusia), attributed to the diacetyl compound released during the degradation of ceftobiprole medocaril.[8] In phase III clinical trials conducted with a larger number of patients, nausea was the most common adverse event. Other adverse events such as vomiting, diarrhea, headache, insomnia, hypokalemia, infusion-site reactions, and hypersensitivity were reported at rates of less than 12%.[69–71] Overall, adverse events were mild and did not require treatment.

In many cases, adverse events appeared more frequent in trials that used a 60-minute infusion versus a 120-minute infusion.[69, 70] Discontinuation due to adverse events (especially vomiting) was reported for 4% of patients, but the frequency was not correlated to the dose.[50]

No electrocardiographic abnormalities and no clinically relevant changes in hematologic results, biochemical results, urinalysis results, or vital signs were reported with ceftobiprole.[78, 75]

Patients with known serious hypersensitivity to β-lactams or any excipient contained in the formula should not be treated with ceftobiprole, and careful inquiry should be made before starting therapy to verify the patient’s medical history. Caution is also advised for patients at risk for hyponatremia and patients with pre-existing central nervous system disorders, since these events have been observed previously in clinical trials with ceftobiprole. In addition, since no clinical studies have been performed in pregnant or nursing women or in children (< 18 yrs), ceftobiprole should not be used in these populations.

Incompatibility of ceftobiprole 2 mg/ml, diluted in 5% dextrose injection, 0.9% sodium chloride injection, or Ringer’s lactate solution injection, with 70 drugs (e.g., antiinfectives, antivirals, antidepressants, diuretics) was evaluated recently.[76] Of the 70 tested combinations, 32 were found to be incompatible in all three of the infusion solutions, and seven other combinations were found to be incompatible depending on the infusion solution. Caution is advised if simultaneous administration through a Y-site is considered.

Expected Recommended Dosages and Dosage Adjustments for Special Populations

Recommended dosage regimens had not been approved by the FDA as of this writing. However, based on the Canadian package insert for ceftobiprole medocaril,[16] expected dosage recommendations are 500 mg as a 1-hour intravenous infusion every 12 hours for the treatment of cSSSIs caused by gram-positive pathogens (MSSA, MRSA, and S. pyogenes). The dosing interval should be reduced to every 8 hours with a 2-hour intravenous infusion given when the infection is caused by susceptible gram-negative pathogens such as E.cloacae, E. coli, K. pneumoniae, P. mirabilis, both gram-positive and susceptible gram-negative pathogens, or when the cSSSI is associated with a diabetic foot infection.

Dosage adjustments for patients with moderate or severe renal impairment are also expected to be similar to those recommended in the Canadian package insert: 500 or 250 mg, respectively, as a 2-hour intravenous infusion every 12 hours.[16] No data are available regarding patients with end-stage renal disease or those receiving dialysis, or in obese patients.

Conclusion

  1. Ceftobiprole medocaril is a new parenteral cephalosporin that exhibits a distinctively wide spectrum of activity, encompassing MRSA, multidrug-resistant S. pneumoniae, and susceptible gram-negative organisms, including most Enterobacteriaceae. Ceftobiprole has a low potential to select mutants, and emergence of resistance was not reported during its development. With the emergence of hVISA and VRSA, new anti-MRSA agents need to be added to the available antiinfective drugs, and despite the world concept that MRSA pathogens are considered uniformly resistant to all β-lactam antimicrobials, ceftobiprole represents a promising alternative treatment for infections caused by these pathogens. Pharmacokinetic and pharmacodynamic characteristics were widely investigated and revealed a high penetration rate into various tissues, as well as a low protein binding in plasma, which accounts for its in vivo activity. Clinical studies demonstrate that ceftobiprole is generally well tolerated; overall, adverse events were mild and did not require treatment. Extensive studies of target attainment rates showed that a dosage regimen of 500 mg as a 1–2-hour infusion every 8 hours would be optimal against susceptible gram-positive and gram-negative pathogens, and based on the Canadian package insert, this dosage should be recommended in most cases.

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Authors and Disclosures

Céline Vidaillac, Pharm.D., Ph.D., and Michael J. Rybak, Pharm.D., M.P.H., FCCP

From the Anti-Infective Research Laboratory, Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Sciences (both authors), and the School of Medicine, Wayne State University (Dr. Rybak), and the Detroit Receiving Hospital (Dr. Rybak), Detroit, Michigan.

Address reprint requests to
Michael J. Rybak, Pharm.D., M.P.H., FCCP, Anti-Infective Research Laboratory, Pharmacy Practice-4148, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48201; e-mail: m.rybak@wayne.edu.

Pharmacotherapy. 2009;29(5):511-525. © 2009