Ceftobiprole: first cephalosporin with activity against MRSA

Ceftobiprole is the first member of a new series of advanced cephalosporins with activity against methicillin-resistant Staphylococcus aureus (MRSA). The drug received a letter of approval from the United States Food and Drug Administration (FDA) in March 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 is stable against hydrolysis by many gram-positive beta-lactamases and a has 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 beta-lactams. Ceftobiprole activity does not cover extended-spectrum beta-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. Several precautions regarding hypersensitivity and drug incompatibility are reported.
Ceftobiprole is available only for i.v. administration. 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.
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.

Patient Sharing Among Hospitals Common, Likely Source of spread of Infectious Pathogens

Patient sharing is common among hospitals, and it likely presents an avenue for infectious-disease transmission, according to a study presented here at the Society for Healthcare Epidemiology of America (SHEA) 19th Annual Scientific Meeting.

The study found that only 1 in 9 of these shared patients were directly transferred from one hospital to another; most of the patients were discharged and then readmitted to another hospital within 1 year. This amount of patient sharing between hospitals might increase the spread and transmission of infectious pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).

To assess the frequency of interfacility sharing in 1 county (Orange County, the third-most-populous and largely suburban county in California), the direct and indirect transfers among 31 acute-care hospitals were assessed in a retrospective evaluation using 2005 California hospital-discharge data. The study evaluated the likelihood that adult patients admitted to each hospital in 2005 would subsequently be transferred or admitted to another hospital in the county within 1 year of discharge.

Dr. Huang and colleagues found that in 2005, 239,456 adult patients were admitted to Orange County hospitals, with a median length of stay of 3 days. The study found that patients were widely shared among the hospitals, sharing at least 1 patient with a median of 28 other hospitals; only 16% of interfacility patient sharing occurred by direct patient transfer. Among those discharged, 22% were readmitted to a median of 2 hospitals in the subsequent year; median time to readmission was 23 days.

According to Dr. Rupp, the following bacilli are of concern:

• Pseudomonas aeruginosa is a gram-negative rod that belongs to the family Pseudomonadaceae, and is a pathogen of increasing clinical relevance and a frequent cause of nosocomial pneumonia, especially in intensive-care units. Several epidemiologic studies that have tracked its occurrence as a nosocomial pathogen indicate that antibiotic resistance is increasing in clinical isolates.
• Acinetobacter strains are nosocomial pathogens that have caused a number of American military casualties to develop serious infections.
• Klebsiella pneumoniae causes serious infections in the critically and chronically ill and is rapidly developing resistance to all available antibiotics.

Source:

Society for Healthcare Epidemiology of America (SHEA) 19th Annual Scientific Meeting: Abstract 59. Presented March 20, 2009.

Nanoparticles as Antimicrobial agents

Silver has long been used for its antimicrobial properties. However, the delivery systems available, often in the form of a salt, have been the limiting factor to successful biological use of this noble metal. Nanotechnology and the ability to deliver silver from a nanocrystalline structure has and will markedly improve the biologic value of silver. These advances in crystal chemistry will likely have a dramatic impact on the microbiology, as well as biology of wound healing and control of inflammation. This review will attempt to describe the past, present and future uses of silver in biologic systems focusing on its biological properties on “wounds”.

BIOLOGIC PROPERTIES OF NANOCRYSTALLINE SILVER COMPARED TO OTHER SILVER PRODUCTS
a) Antimicrobial Properties: The aqueous concentration of silver ions released from the nanocrystalline film is approximately 3% of that released from a 0.5% silver nitrate or a 1% silver sulfadiazine cream. However, the biological properties of the silver released from nanocrystals are much greater. Silver resistance has been reported in the literature and is mediated through one of two pathways. Either the silver is tied up in the cell wall and membranes, or it is actively transported out of the cell. Bacterial organisms that have either one of these resistance mechanisms, which are effective up to 1000 µg/mL Ag+, have been tested against the nanocrystalline silver coated dressing. These tests showed that these organisms were susceptible to the silver produced by the nanocrystals, but not to Ag+ from silver nitrate. These findings, as will be described, strongly suggest that other species of silver besides Ag+ are released from the nanocrystals.

The lower amount Ag+ released should also decrease the potential of silver toxicity to cells, if it exists, by a substantial margin when compared to the other silver agents. The nanocrystal coating contains 0.84-1.34 mg silver/cm2 of dressing, is resistant to abrasion, does not adhere to the wound and is flexible. In another study nanocrystalline silver was extracted from the silver delivery system Acticoat by incubating the dressing in nanopure water at 37°C in a shaking incubator, and silver concentrations were measured using atomic absorption spectrophotometry. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined using five bacterial isolates of clinical interest, and results were compared for nanocrystal silver, silver nitrate and silver sulfadiazine, based upon total silver. Nanocrystalline silver had similar MIC and MBC values when compared to three silver containing agents. Kill kinetics were also studied, using 2.0 cm x 2.0 cm pieces of silver dressing, and the same sized pieced of dressing impregnated with either silver nitrate (100µl of 1% solution. This results in a final concentration of 0.5% silver nitrate) or silver sulfadiazine (370mg of a 1% cream). Bacterial survival was measured using a plate counting technique. Nanocrystal silver demonstrated the fastest kill times for the five bacteria used. In most instances with Nanocrystal silver, bacterial survival was undetectable 30 minutes after inoculation, whereas at least 2-4 hours elapsed before no viable cells were detected with silver nitrate or silver sulfadiazine. These findings strongly suggest that silver species in addition to Ag+, are released from the nanocrystalline film which are responsible for the more potent antimicrobial properties. To date the nanocrystalline silver system kills all microbes found in a wound including fungi and all current antibiotic resistant strains such as vancomycin resistant enterococcus (VRE) and methicillin resistant Staphylococcus aureus (MRSA).

b) Pro-healing Properties: Although silver in an electro colloidal form, had been reported to improve the healing of indolent wounds in the early 20th century, that finding disappeared with the use of silver salts and complexes. Recently there have been several reported studies of improved re-epithelialization rates across partial thickness wounds with silver in the nanocrystalline form. The mechanism, although unknown at present, does not appear to be due to silver’s antimicrobial action.

c) Anti-inflammatory Properties: Increased wound inflammation not only accentuates pain but markedly impairs healing. Several heavy metals have been reported to decrease surface inflammation, the most recognized being gold. Wound surface inflammation has been reported to be decreased with the use of nanocrystalline silver. Excess metalloproteinases (MMP) are known to increase inflammation by both increasing inflammatory cell exudates and also leading to a non-healing chronic wound. A characteristic of this type of wound is excess surface MMP activity, decreased inhibitory MMP activity and degradation of growth factors by the MMP’s. Nanocrystalline silver has been shown both in vitro and in vivo to decrease but not prevent MMP activity as some activity is needed to remove devitalized tissue. The mechanism for this action also remains unknown. Decreasing the necessary zinc activity required for MMP’s, is one possibility. The other is an effect on the expression or release of pro-inflammatory cytokines.

SUMMARY

The application of nano-technology to develop nanocrystalline silver has led to a highly effective topical antimicrobial agent due not only to a more rapid release of silver cation onto a wound surface, compared to other available silver antimicrobial agents, but likely the release of other silver species as well. In addition, nanocrystalline silver appears to have overall positive biological effects on wound inflammation, healing and likely on a host of as yet undetermined reactions. Current available data only scratches the surface of the potential theoretical benefits of nanocrystalline silver.

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New Antimicrobial against Methicillin-resistant Staphylococcus aureus (MRSA)

ZEFTERA the only approved antibiotic in its class (cephalosporin) by Health Canada to demonstrate efficacy against Methicillin-resistant Staphylococcus aureus (
MRSA), a growing public health concern in both hospital and community settings.ZEFTERA is specially designed to tightly bind to and inhibit targets in both gram-positive (including MRSA) and gram-negative bacteria. The approval of ZEFTERA for the treatment of complicated skin and skin structure infections, including non-limb threatening diabetic foot infections without concomitant osteomyelitis, was based on results of two Phase III, double-blind, randomized, multi-centre, global trials involving 817 patients with cSSSI 2,3. The second Phase III trial included patients with non-limb threatening diabetic foot infections (mild, moderate or severe)3. Pathogens identified at baseline in this subpopulation included MSSA (38 per cent), MRSA (13 per cent), E. cloacae (9 per cent), and P. mirabilis (7 per cent). The results demonstrated the non-inferiority of ceftobiprole versus vancomycin plus ceftazidime in the treatment of diabetic foot infections. In both studies, ZEFTERA was well tolerated. The most common treatment-emergent adverse reactions were nausea (9 per cent) taste disturbance (6 per cent), diarrhea (5 per cent) and vomiting (5 per cent).