Cephalosporins 5th generation

1. New Antibiotic Therapy 5 th cephalosporin generation KSMU – pharmacology Dep artment Fabio Grubba

2. Introduction Cephalosporins are structurally and pharmacologically related to the penicillins They have a beta- lactam ring structure that interferes with synthesis of the bacterial cell wall Bactericidal Activity

3. Mode of action Cephalosporins are bactericidal agents and have the same mode of action as other beta- lactam antibiotics (such as penicillins ). Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls, which causes the walls to break down and eventually the bacteria die.

4. USES Cephalosporins are bactericidal for most of the following: Gram-positive bacteria Gram-negative bacteria Cephalosporins are used to treat infections in different parts of the body—the ears, nose, throat, lungs, sinuses, and skin, for example. Cephalosporins are a newer class of antibiotics and often are seen as an alternative to penicillin

5. Generations Cephalosporins are grouped into "generations" based on their spectrum of antimicrobial activity. Each newer generation of cephalosporins has significantly greater gram-negative antimicrobial properties than the preceding generation, in most cases with decreased activity against gram-positive organisms. Fourth generation cephalosporins , however, have true broad spectrum activity.

6. The new generation: 5 th Cephalosporin Currently there are only two drugs in this category,  Ceftobiprole  and  Ceftaroline . These new drugs are also the only β- lactam antibiotics that are effective against  methicillin -resistant- Staphylococcus- aureus  (MRSA). They  inhibits the 2a penicillin-binding protein (PBP) of methicillin -resistant  Staphylococcus aureus  and the 2x PBP of  Streptococcus pneumoniae , as well as the classic PBP-2 of MSSA. Ceftobiprole is resistant to staphylococcal  β- lactamase .

7. MRSA STRAIN  MRSA is any strain of  Staphylococcus aureus  that has evolved resistance to beta- lactam antibiotics, which include the  penicillins  ( methicillin ,  dicloxacillin ,  nafcillin ,  oxacillin , etc.) and the  cephalosporins . Strains unable to resist these antibiotics are classified as methicillin -sensitive  Staphylococcus aureus , or MSSA. resistance does make MRSA infection more difficult to treat with standard types of antibiotics and thus more dangerous.

8. Ceftobiprole Ceftobiprole is a pyrrolidinone-3-ylidenemethyl  cephem . The C-3 side chain was specifically designed to have a strong binding affinity to PBP2a and PBP2x. PBP2a is known to give  staphylococci  resistance to other β- lactam drugs and PBPx does the same for  pneumococci . Ceftobiprole also has a aminothiazoylhydroxyimino side chain at the C-7 position which is known to give good resistance to β- lactamase from  S. aureus . Together these active groups make Ceftobiprole bactericidal to MRSA. Ceftobiprole has poor water solubility and is therefore administered intravenously. Clinical used: Methicillin -resistant Staphylococcus aureus associated with endocarditis and bone and joint infections Pneumonia caused by Penicillin-resistant Streptococcus pneumoniae Pseudomonas aeruginosa Enterococci .

9. Dosage gram- postive cSSSIs will be 500mg intravenously every 12 hours (1-h infusion) for 7–14 days. gram-negative pathogens are suspected or isolated, such as in a diabetic foot infection, may be 500mg intravenously every 8 hours (2-h infusion) for 7–14 days.

10. Distribuition Protein binding of ceftobiprole is approximately 16% and appears to be independent of ceftobiprole concentration. [28,29]  It is primarily bound to albumin (6.5–11.5%) and α 1 -acid glycoprotein (4.8–6.8%). Changes in the protein binding of ceftobiprole would not change the drug's activity or pharmacokinetic profile.

11. metabolism Ceftobiprole was slowly metabolized in an in vitro human hepatocyte model. Approximately 51% of the drug was metabolized in 24 hours and predominantly converted to an open-ring hydrolysis metabolite.

12. excretion ceftobiprole is primarily eliminated as unchanged drug by the kidneys, with up to 89% of the dose recovered in the urine. [10]  In a rat model, ceftobiprole elimination was not affected by the administration of probenecid , indicating that the predominant method of renal elimination is glomerular filtration, not active tubular secretion

13. Side effects Adverse Effects: Nausea Infusion –site reaction Diarrhea Headache Vomiting Dysgeusia ( Caramel-like taste, disturbances)

14. conclusion Ceftobiprole is a broad-spectrum, parenteral cephalosporin undergoing Phase III clinical trials. Its broad spectrum of activity makes it a candidate for monotherapy , either empirically or for treatment, of cSSSIs and pneumonias that have required combination therapy in the past.

15. Ceftaroline Ceftaroline was developed from the fourth generation cephalosporin  Cefozopran , It retains the alkoxyimino group at position C-7 from earlier generations so it is fairly stable in the presence of many β- lactamases . Since MRSA and penicillin resistant Streptococcus pneumoniae  have resistance dedicated to new types of PBP, PBP2a and PBP2x respectively, both Ceftaroline and Ceftobiprole have C-3 side chains specially engineered to bind these new PBP. In the case of Ceftaroline this side chain contains a 2-thioazolythio spacer linkage optimised for its anti-MRSA activity. ]

16. Dosage Acute Bacterial Skin and Skin Structure Infection (ABSSSI),600 mg , Every 12 hours,15-14 days Community-Acquired Bacterial Pneumonia (CABP),600 mg , Every 12 hours15-7 days

17. Distribution Distribution The average binding of ceftaroline to human plasma proteins is approximately 20% and decreases slightly with increasing concentrations over 1-50 mcg/ mL (14.5-28.0%).

18. Metabolism Metabolism Ceftaroline fosamil is converted into bioactive ceftaroline in plasma by a phosphatase enzyme and concentrations of the prodrug are measurable in plasma primarily during IV infusion. Hydrolysis of the beta- lactam ring of ceftaroline occurs to form the microbiologically inactive, open-ring metabolite ceftaroline M-1. The mean (SD) plasma ceftaroline M-1 to ceftaroline AUC0-∞ ratio following a single 600 mg IV infusion of ceftaroline fosamil in healthy adults (n=6) with normal renal function is 28% (3.1%).

19. Excretion Excretion Ceftaroline and its metabolites are primarily eliminated by the kidneys. Following administration of a single 600 mg IV dose of radiolabeled ceftaroline fosamil to healthy male adults (n=6), approximately 88% of radioactivity was recovered in urine and 6% in feces within 48 hours. Of the radioactivity recovered in urine approximately 64% was excreted as ceftaroline and approximately 2% as ceftaroline M-1. The mean (SD) renal clearance of ceftaroline was 5.56 (0.20) L/h, suggesting that ceftaroline is predominantly eliminated by glomerular filtration.

20. Side Effects Blood and lymphatic system disorders  - Anemia, Eosinophilia , Neutropenia , Thrombocytopenia Cardiac disorders  - Bradycardia , Palpitations Gastrointestinal disorders  - Abdominal pain General disorders and administration site conditions  - Pyrexia Hepatobiliary disorders -  Hepatitis Immune system disorders  - Hypersensitivity, Anaphylaxis Infections and infestations  -  Clostridium difficile  colitis Metabolism and nutrition disorders  - Hyperglycemia, Hyperkalemia Nervous system disorders  - Dizziness, Convulsion Renal and urinary disorders  - Renal failure Skin and subcutaneous tissue disorders  - Urticaria

21. conclusion Ceftaroline is an advanced-generation cephalosporin with gram-positive activity, including MRSA and drug-resistant  S. pneumoniae, and with gram-negative activity limited mainly to respiratory pathogens. Ceftaroline has demonstrated a low potential for the selection of resistance in vitro for gram-positive pathogens. Results of clinical trials at a dosage of 600 mg every 12 hours intravenously demonstrate that for complicated skin and skin structure infections and community-acquired pneumonia, ceftaroline fosamil is efficacious and well tolerated, Ceftaroline has the advantage of predictable pharmacokinetics, including after intramuscular administration, and pharmacodynamic and safety profiles similar to those of other cephalosporins . Ceftaroline's best feature and perhaps its useful clinical niche is its activity against drug-resistant gram-positive pathogens such as MRSA, hVISA , VISA, VRSA, daptomycin-nonsusceptible   S.aureus , and penicillin- and ceftriaxone -resistant  S. pneumoniae .  

22. THE END