1、Cephalosporin Antibiotics,First discovered in 1945 from a Cephalosporium fungi Commercial drugs derived semi-synthetically From 7-aminocephalosporanic acid - produced by fermentation Similar to penicillins 4 Generations Derivatives acylated at the 7-amino group Reasons for synthetic modification inc
2、lude: Increased acid stability Improved pharmacokinetics (oral absorption) Broaden antimicrobial spectrum Increased activity (decreased resistance due to destruction) Improved penetration Increased receptor affinity Decreased allergenicity Increased tolerance due to parenteral administration,Transit
3、ion from first generation to third generation agents reflects Broadening of the Gram (-) organism spectrum Loss of efficacy against Gram (+) organisms Greater efficacy against resistant organisms (but increased cost) MOA: Inhibit cell wall synthesis osmotically induced cell lysis Usually bactericida
4、l a function of dosage, organism susceptibility, tissue concentrations, and growth rate Cross allergenicity with penicillins is 5-16% Drug interactions: Alcohol use may produced a disulfiram like reaction - NMTT Aminoglycoside nephrotoxicity can be increased Anticoagulant effects can be potentiated
5、- NMTT Antacids can decrease plasma concentrations of oral agents Loop diuretic nephrotoxicity can be increased Monitor renal function since all are renally excreted Cefoperazone the exception,Cephalosporin Antibiotics,Classified by Generations - explosive advances First Generation Epitomized by cef
6、azolin Good activity against Gram(+) Modest Gram(-) activity Second Generation Increased Gram(-) activity Some active against baccillus fragilis (highly resistant anaerobe) Third Generation - cost vs. efficacy “Broad” spectrum with high penicillinase resistance Greater Gram (-) spectrum Less active
7、than G1 against most Gram(+) More active than G1 against enterobacter Fourth Generation - Cefepime Extended range of activity compared to G3 More Gram (+) Increased stability against b-lactamases VERY useful for Gram(-) strains resistant to G3,Cephalosporin Antibiotics,Cephalosporin Antibiotics,G1 P
8、O: Cephalexin, Cephradine, Cephadroxil Parenteral: Cefapirin, Cefazolin G2 PO: Cefaclor, Loracarbef, Cefprozil, Cefuroxime Parenteral: Cefmetazole, Cefotetan, Cefonacid, Cefamandol, Cefoxitin G3 PO: Cefpodoxime, Cefixime, Cefdinir, Ceftitbuten Parenteral: Cefotaxime, Ceftizoxime, Ceftriaxone, Ceftaz
9、idime, Cefaperazone G4 - Cefepime,Cephalosporin Antibiotics,Cephalosporin Deactivation,Deactivated Cephalosporin,1st Generation Cephalosporins,Indications: Respiratory tract infections, Otitis media, skin and skin structure infections, Bone infections, Gram (-) UTI. Used for staph or strep infection
10、 in patients with mild hypersensitivity to penicillins! Gram(+) aerobic bacteria - limited Gram(-) Oral use only, 10% protein bound, 90% excreted renally unchanged One of the Top 200Indications: Oral - Respiratory tract infections, Otitis media, skin and skin structure infections, Bone infections, G
11、U infections, UTI; Parenteral Septicemia; pre-, post- or intraoperative prophylaxis Oral or IV/IM use, 17% protein bound, 90% excreted renally unchanged,Generally all are inactivated by b-lactamases,Partial hydrogenation,1st Generation Cephalosporins,Generally all are inactivated by b-lactamases,Ind
12、ications: UTI, pharyngitis and tonsillitis due to group A b-hemolytic Streptococcus, skin and skin structure infections. Oral use only, 20% protein bound, 90% excreted renally unchanged Prolonged half-life allows once-a-day dosingIndications: Respiratory tract infections, skin and skin structure inf
13、ections, Osteomyelitis, UTI, Septicemia, pre-, post- or intraoperative prophylaxis IV/IM use only, 50% protein bound, 70% excreted renally unchanged Methicillin substitute. Comparatively resistant to Staph. penicillinase,1st Generation Cephalosporins,Generally all are inactivated by b-lactamases,Ind
14、ications: Respiratory tract infections, GU infections, skin and skin structure infections, Biliary tract infections, bone and joint infections, Septicemia, endocarditits; pre-, post- or intraoperative prophylaxis. Used for staph or strep infection in patients with mild hypersensitivity to penicillin
15、s! NOT for meningitis (cant cross BBB). IM/IV use only, adjust dose as a function of creatinine clearance with 80% excreted renally unchanged, 86% protein bound Longer half-life than Cephapirin, less irritating on injection, heat/light unstable,2nd Generation Cephalosporins,Indications: Respiratory
16、tract infections, Otitis media, skin and skin structure infections, UTI Extended release tabs: acute bacterial exacerbations of chronic bronchitis, secondary infections as a result of acute bronchitis, pharyngitis and tonsillitis Oral use only, 25% protein bound, 85% excreted unchanged renally Refri
17、gerate suspension MOST susceptible to b-lactamases in its class! Carbon Isostere of cefaclor Indications: Secondary bacterial infection of acute bronchitits, pneumonia; Otitis media, acute maxillary sinusitis, pharyngitis, tonsillitis, skin and skin structure infection, UTI such as cystitis and pyel
18、onephritis Oral use only, 25% protein bound, 90% excreted unchanged in the urine Store suspension at room temperature,Variable resistance to b-lactamase, more Gram (-) activity,2nd Generation Cephalosporins,Variable resistance to b-lactamase, more Gram (-) activity,Indications: pharyngitis, tonsilli
19、tis, otitis media, acute sinusitis, acute and chronic bronchitis, uncomplicated skin and skin structure infections Oral use only, 36% protein bound, 60% renal excretion unchanged - dosage adjustment necessary in renal failure - creatinine clearance 30 use 50% the usual dosage Similar to Cefaclor wit
20、h improved potency Top 200 drug,Amoxicillin like group,Trans form here imparts Gram(-) activity,2nd Generation Cephalosporins,Variable resistance to b-lactamase, more Gram (-) activity,Indications: Lower respiratory tract infections, UTI, intra-abdominal infections, GU infections, skin and skin stru
21、cture infections, bone and joint infections, Septicemia, pre-, post- or intraoperative prophylaxis Do NOT mix in the same IV as aminoglycosides, stability of reconstituted solution is a function of the diluent used, IV use only, 73% protein bound, 85% excreted unchanged in the urineIndications: ORAL
22、: Respiratory tract infections, UTI, early Lyme disease, uncomplicated gonorrhea, skin and skin structure infections; PARENTERAL: As above plus septicemia, meningitis, bone and joint infections, mixed infections. Community acquired pneumonia Oral or IV/IM use, 50% protein bound, up to 100% excreted
23、in the urine unchanged - reduce dosage in renal impairment based on creatinine clearance, may be taken with food, Do NOT mix in the same IV as aminoglycosides or use sodium bicarbonate injection as diluent, do NOT chew tablets due to very bad tasteswallow whole Top 200 drug,Can cross the BBB meningi
24、tis Not used as ceftriaxone & cefotaxime preferred,Cephamycin: Anaerobic activity,2nd Generation Cephalosporins,Variable resistance to b-lactamase, more Gram (-) activity,Indications: UTI, lower respiratory infections, skin and skin structure infections, intra-abdominal infections, pre-operative pro
25、phylaxis IM/IV use only, 65% protein bound, 85% recovered unchanged in the urine Do NOT mix in the same IV with aminoglycosides Indications: UTI, lower respiratory infections, skin and skin structure infections, intra-abdominal infections, peri-operative prophylaxis, GU infections, bone and joint in
26、fections Watch for nephrotoxicity when use with aminoglycosides - be sure to adjust dosage in renal failure based on creatinine clearance and do NOT mix in the same IV IM/IV only, 90% protein bound, 81% recovered unchanged from the urine,These agents + cefoxitin have reasonable anaerobic activity: P
27、eritonitis & diverticulitis,2nd Generation Cephalosporins,Variable resistance to b-lactamase, more Gram (-) activity,Indications: Lower respiratory infection, UTI, skin and skin structures, septicemia, bone and joint infections, pre-operative prophylaxis IV/IM use only, 90% protein bound, 99% excret
28、ed unchanged in the urine-dosage adjustment necessary in renal failure Admix incompatibility with aminoglycosides Longer half-life than other G2, lower Gram(+) potency Indications: Lower respiratory infection, UTI, peritonitis, skin and skin structures, septicemia, bone and joint infections; pre-, i
29、ntra- and post-operative prophylaxis Admix incompatibility with aminoglycosides IV/IM use only, dosage reduction necessary based on renal function NMTT bleeding and disulfuram problems,NMTT,Diester prodrug!-extended spectrum agent Indications: acute community-acquired pneumonia, chronic bronchitis,
30、acute otitis media, pharyngitis, tonsilllitis, acute uretheral, cervical or rectal gonorrhea but NOT pharyngeal disease; skin and skin structure infections, UTI Useful in cirrhosis patientsno dosage adjustment needed, renal failure necessitates dosage adjustment Oral use only, 29% protein bound, 33%
31、 excreted unchanged in the urineIndications: UTI, otitis media, pharyngitis, tonsillitis, acute and acute chronic bronchitis, cervical or urethral gonorrhea Oral use only, 65% protein bound, 50% excreted unchanged in the urine DOC gonorrhea single 400mg dose,3rd Generation Cephalosporins,Indications
32、: Community acquired pneumonia, acute exacerbation of chronic bronchitits, acute maxillary sinusitis, pharnygitis, tonsillitis, skin and skin structure infections, acute otitis media Oral use only, 70% protein bound, 17% excreted unchanged in the urine but dosage still needs reduced in renal failure
33、Indications: acute bacterial exacerbations of chronic bronchitis, acute bacterial otitis media caused by H. influenza, pharyngitis and tonsillitits caused by S. pyogenes Oral use only, 65% protein bound, 56% excreted unchanged in the urine - dosage adjustment as a function of creatinine clearance,3r
34、d Generation Cephalosporins,Ceftibuten,Indications: Lower respiratory infection, UTI, gynecological infection, bacteremia/septicemia, skin and skin structure infections, intra-abdominal infections, bone or joint infections, meningitis or other CNS infections, perioperative prophylaxis CDC recommende
35、d treatment for gonorrhea IM/IV, 40% protein bound, 60% renal excreted unchanged adjust with renal fx,3rd Generation Cephalosporins,Indications: Lower respiratory infection, UTI, gonorrhea and PID, septicemia, skin and skin structure infections, intra-abdominal infections, bone or joint infections,
36、meningitis IM/IV use only, 30% protein bound, 80% excreted unchanged in the urine-dosage reduction necessary in renal failureIndications: Lower respiratory infection, UTI, gonorrhea and PID, septicemia, skin and skin structure infections, intra-abdominal infections, bone or joint infections, meningi
37、tis, surgical prophylaxis, effective in treating Lyme disease infection causing neurological complications, arthritis and carditits refractory to PenG DOC Gonorrhea single injection IM/IV use only, 95% protein bound, 67% excreted unchanged in the urine,3rd Generation Cephalosporins,Indications: Lowe
38、r respiratory infections, skin and skin structure infections, UTI, bacterial septicemia, bone and joint infections, gynecological infections, intra-abdominal infections, CNS infections, concomitant antibiotic therapy in immunocompromised patients Renal excretion-adjust dosage as a function of GFR90%
39、 unchanged Sodium bicarbonate solution is NOT recommended as a diluent, do NOT mix with aminoglycosides IM/IV use only, 10% protein boundIndications: Respiratory tract infections, peritonitits and other intra-abdominal infections, bacterial septicemia, skin and skin structure infections, PID, endome
40、tritis, UTI IM/IV only, 93% protein bound, 30% excretion unchanged in the urineExtensively excreted in the bilemonitor serum concentrations in high doses in the case of hepatic disease or biliary obstructionRenal failure-no dose adjustment except in high doses,3rd Generation Cephalosporins,4th Gener
41、ation Cephalosporins,Indications: UTI, skin and skin structure infections, pneumonia (moderate to severe), complicated intra-abdominal infections, empirical therapy for febrile neutropenic patients, pediatric patients 2 months to 16 years of age: as above plus pyelonephritisIM/IV only, 20%protein bo
42、und, 85% excreted unchanged in the urinedosage adjustment needed in renal failureAdmixture stability can vary based on diluent,Cephalosporin Summary,Generation Cefazolin & Cephalexin Staph or Strep infections Surgical prophylaxus Many differences within this group watch for Superinfection Cefotetan
43、& Cefoxitin B. fragilis intraperotoneal and pelvic infection (surgery) Cefuroxime & Cefaclor H. influenza BIG guns reserved for SERIOUS infections Cross BBB (blood-brain barrier) Exceptions: Ceftriaxone (IV) & Cefixime (PO): DOC gonorrhea Ceftriaxone injection = 10d of amoxicillin (otitis media) Cef
44、ipime clinically like G3 Good Gram (+) and (-) activity,b-Lactam Bottom Line Gram(+),Bacteria DOC 2nd Line,Streptococcus Penicillin (G or VK) Cephalosporin G1Amoxicillin CeftriaxoneAmpicillin CefotaximeStaphylococcus Nafcillin Cephalosporin G1Oxacillin Vancomycin Enterococcus Penicillin (G or VK) VancomycinAmoxicillin GentamicinAmpicillin,+ CNS,GENERALLY(some exceptions) First Choice: Aminopenicillin + inhibitor Amoxicillin + clavulanate (Augmentin) Ampicillin + sulbactam (Unasyn) Next Option: Cephalosporin G2 or G3,b-Lactam Bottom Line Gram(-),
