Cephems Cephalosporins & Cephamycins

Cephems; Cephalosporins & Cephamycins Introduction • Cephems are a sub-group of β-lactam antibiotics- it includes cephalosporins & cephamycins. • Cephalosporins are β-lactam antibiotics closely related structurally and functionally to penicillins. • Have the same mechanism of action & affected by the same resistance mechanisms. • Cephalosporins produced semisynthetically by the chemical attachment of side chains to 7-aminocephalosporanic acid. • More stable to many bacterial β-lactamases than penicillins  • Have a broader spectrum of activity. • Cephalosporins can be classified into five major groups or generations, depending on the spectrum of antimicrobial activity & resistance to β-lactamases. • Cephamycins are a group of β-lactam antibiotics very similar to cephalosporins- sometimes classified as cephalosporins. • Both cephalosporins & cephamycins sometimes called cephems. Cephems; Cephalosporins & Cephamycins • The core of the basic structure consists of a two ring system which includes a β-lactam ring condensed with dihydrothiazine ring. 7-aminocephalosporanic acid Core structure of the cephamycins Possess a methoxy group at the 7-alpha position Core structure of the cephalosporins Very efficient antibiotic against anaerobic microbes. Ex. Cefoxitin, Cefotetan, Cefmetazole Classification of Cephalosporins I. First generation • Agents: Cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, & cephradine • Penicillin G substitutes. • Have good activity against gram-positive cocci. • They are resistant to the staphylococcal penicillinase (they cover MSSA). • Modest activity against gram-negative microorganisms  Active against Proteus mirabilis, E. coli, and Klebsiella pneumonia (acronym PEcK has been suggested). I. First generation…. Continued • Cefazolin penetrates well into most tissues the drug of choice for surgical prophylaxis. • • Cefazolin does not penetrate the central nervous system and can't be used to treat meningitis Orally effective drugs (Cephalexin) are used in treating susceptible bacteria that cause: • Skin and soft tissue. • Uncomplicated UTI. II. Second Generation • Agents: • Cephalosporins: cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil, loracarbef & ceforanide • Cephamycins: cefoxitin, cefmetazole and cefotetan. • Display greater activity against gram-negative microorganisms: – H. influenzea – Enterobacter areogenes – Some Niesseria species • Activity against gram-positive organisms is weaker (acronym HENPEcK has been suggested with the second generation’s increased coverage). • Antimicrobial coverage of cefotetan and cefoxitin also includes the anaerobe, Bacteroides fragilis. • However, neither is the preferred treatment because of the increasing prevalence of resistance amongst to both agents. • Like 1st generation: none is active against enterococci or P. aeuroginosa. II. Second Generation …. Continued 1. 2. Used to treat otitis media, sinusitis & lower RTI (H. influenza & B. catarrhallis) Cefoxitin, cefotetan or cefmetazole: used to treat mixed anaerobic infections such as peritonitis or diverticulitis. 3. Cefuroxime: used in treating community acquired pneumonia, particularly in cases where β-lactamase- producing H. influenzae or K. pneumoniae is a consideration. • Cefuroxime axetil is an acetoxyethyl ester prodrug of cefuroxime which is effective when taken by mouth. III. Third Generation • Agents: • Ceftriaxone, cefotaxime, ceftazidime, cefoperazone, cefdinir, cefixime, ceftibutin, etc. • More effective against gram-negative bacteria than the first and second generations. • They are usually effective against bacteria that may be resistant to previous generations of cephalosporins. • Inferior to first-generation cephalosporins against MSSA. • Important for treating infectious diseases (Intra-abdominal infection, CNS infections, skin and soft tissue infections, UTIs, lower RT infections, Gynecological infections, Bone & joint infections, Sepsis) • Enhanced activity against gm -ve bacilli, most enteric organisms and Serratia marcescens. • Active against B-lactamase producing strains of haemophilus and Neisseria spp. III. Third Generation …. Continued • Able to cross the BBB -Ceftriaxone and cefotaxime are agents of choice in treating meningitis. • Most widely used parenteral 3rd-generation cephalosporins is ceftriaxone. • Vancomycin and a 3rd-generation cephalosporin recommended as initial therapy for meningitis until culture susceptibility results are available. • Ceftriaxone offers convenient once daily dosing to treat most infections. • Ceftazidime active against P. aeureginosa resistance is increasing and appropriate use should be evaluated on a case-by-case basis. • Third generation cephalosporins can produce "collateral damage,“ induction and spread of antimicrobial resistance [fluoroquinolones also cause collateral damage.] IV. Fourth Generation • Agents: • Cefepime, cefpirome. • Cefepime must be administered parenterally. • Has a wide antibacterial spectrum • Active against streptococci and staphylococci (only MSSA). • Effective against aerobic gram-negative organisms • Enterobacter species • E. coli • K. pneumonia • P. mirabilis • P. aeruginosa • When treating P. aeruginosa, clinicians should refer to their local antibiograms (laboratory testing for sensitivity of the isolated bacterial strain to different antibiotics). V. Fifth Generation • Agents: 5th generation cephalosporins ceftaroline, ceftobiprole. • Known as advanced- generation cephalosporins. • Activity is similar to 3rd-generation cephalosporins, except it is not effective against Pseudomonas aeruginosa. • Used to treat bacteria, including: • Resistant Staphylococcus aureus (MRSA). • Streptococcus species resistant to penicillin antibiotics. Resistance to Cephalosporins • Resistance to cephalosporins is similar to penicillins. Pharmacokinetics of Cephalosporins 1. Administration: Many of the cephalosporins must be administered IV or IM because of their poor oral absorption. • Exceptions noted in next slides. 2. Distribution: All cephalosporins distribute very well into body fluids. • Adequate therapeutic levels in the CSF - only with select a few cephalosporins. • Ceftriaxone or cefotaxime  treatment of neonatal and childhood meningitis caused by H. influenza. • Cefazolin finds application as a single prophylaxis dose prior to surgery because of its 1.8-hour half-life and its activity against penicillinaseproducing S. aureus. • Additional intra-operative doses may be required if the surgical procedure lasts longer than 3 hours. • Cefazolin is effective for most surgical procedures, including orthopedic surgery because of its ability to penetrate bone. • All cephalosporins cross the placenta. 3. Elimination: • Biotransformation by the host is not clinically important. • Elimination occurs through tubular secretion and/or glomerular filtration.  Dose adjusted in severe renal failure (Exception ceftriaxone excreted in bile to feces- use in cases of renal insufficiency). Summary of therapeutic advantages of some clinically useful cephalosporins • Drugs administered orally are shown in reverse type. • More useful drugs shown in bold. Adverse effects of cephalosporins • Allergy: Patients who have had an anaphylactic response, stevens-Johnson syndrome, toxic epidermal necrolysis to penicillins should not receive cephalosporins.  Avoid cephalosporins or use with caution in individuals who are allergic to penicillins (8 to 10% cross-sensitive).  Cross-reactivity between penicillin and cephalosporins determined by similarity in the side chain, not the β-lactam structure.  Highest allergic cross sensitivity is between penicillin and 1st generation cephalosporins.  Symptoms of anaphylaxis: hives, flushed skin, swollen tongue and throat, breathing difficulties, low blood pressure, rapid or weak pulse, nausea or vomiting, diarrhea, dizziness, fainting. Adverse effects of cephalosporins … continued • Pain if given IM, thrombophelebitis if given IV. • Renal toxicity. • Hypo-prothrombinemia. • Disulfiram like reaction. • Superinfection- Oral thrush Pseudomembranous colitis (Clostridium difficile) • Yeast infection or oral thrush. • One serious side effect is C. difficile infection. • Occurs after a long course of antibiotics • Can be life-threatening Thrombophelebitis • Symptoms: watery diarrhea, abdominal pain, fever, nausea, ↓ appetite… • Prevent stomach upset and diarrhea by: • Probiotics, add good bacteria to your digestive tract. • Follow instructions for medication antibiotics should be taken with food vs. should be taken on an empty stomach. • Avoid foods that produce stomach upset (spicy or greasy foods). OTHER β-LACTAM ANTIBIOTICS Monobactams: Aztreonam (Only commercially available monobactam) • Disrupt bacterial cell wall synthesis- the β-lactam ring is not fused to another ring. • Spectrum of activity is limited to aerobic gramnegative rods, (Enterobacteriaceae) including P. aeruginosa. • Has no activity against gram-positive bacteria or anaerobes. • Cannot be used alone in empiric therapy • Resist the action of most β-lactamases except extended-spectrum β-lactamases (ESBLs). • • • • Given IV or IM and excreted in urine (accumulate in renal failure). Shows little cross-reactivity with other β-lactam antibiotics. ADRs: phlebitis, skin rash, and abnormal liver function tests. Low immunogenic potential- little cross-reactivity with antibodies induced by other β-lactams- a safe alternative in patients allergic and cannot tolerate penicillins and/or cephalosporins. Carbapenems • Synthetic β-lactam antibiotics…. • Sulfur atom of the thiazolidine ring in penicillins has been externalized and replaced by a carbon atom. • Agents: Imipenem, meropenem, doripenem and ertapenem. Backbone of carbapenems • • • Imipenem Resists hydrolysis by most to β-lactamses -Wide spectrum • Resists most β-lactamases producing bacteria, gram -ve rods, including P. aeruginosa, gram +ve organisms, and anaerobes) Used in empiric treatment…. • Imipenem drug of choice for enterobacter infections • Meropenem and doripenem have similar spectrum. • Ertapenem does not cover P. aeruginosa, Enterococcus species and Acinetobacter species Given parenteral via IV or IM Imipenem rapidly metabolized by dehydropeptidase in brush border of the proximal renal tubule- nephrotoxic metabolite. • • • Cilastatin a peptidase inhibitor blocks renal dehydropeptidase  increases plasma half-life & inhibits nephrotoxic metabolite formation. Other carbopenemes do not require co-administration of cilistatin. ADE: GI distress, skin rash, CNS toxicity (confusion, encephalopathy and seizures)- Partial cross allergenicity with penicillins Summary of Antimicrobial Agents Affecting Cell Wall Synthesis *Cilastatin is not an antibiotic but a peptidase inhibitor that protects imipenem from degradation. Vancomycin • Tricyclic glycopeptide – • Active only against gram-positive bacteria, particularly staphylococci. • No activity against gram-negative organisms • Effective against multiple drug resistant organisms, such as MRSA and enterococci. • Inhibits synthesis of bacterial cell wall phospholipids and peptidoglycan polymerization in a time-dependant fashion by binding to the D-Ala-DAla side chain of the precursor pentapeptide (see next slide) • Poorly absorbed from the intestines. • Slow IV infusion (60–90 minutes) of vancomycin is employed for treatment of systemic infections or for prophylaxis. • Metabolism of the drug is minimal, and 90 to 100 percent is excreted by glomerular filtration (adjust in renal failure). Mechanism of Vancomycin Action & Resistance • The diagram shows one of two ways vancomycin acts against bacteria (inhibition of cell wall cross-linking) and one of many ways how bacteria becomes resistant. • Vancomycin is added to bacterial environment while it is synthesizing new cell wall. • Vancomycin recognizes and binds to the two D-ala residues on the end of the peptide chains. • Resistant bacteria last D-ala replaced by D-lactate vancomycin cannot bind. • In the sensitive bacteria, cross-links cannot be formed and the cell wall falls apart. • In the resistant bacteria, stable cross-links are formed. • This weakens the cell wall and damages the underlying cell membrane. • Resistance also occurs via plasmid-mediated changes in permeability to the drug. Clinical Uses of Vancomycin 1. 2. 3. 4. The drug is lifesaving in treatment of MRSA, methicillin-resistant staphylococcus epidermidis (MRSE) & enterococcal infections. Main indication: Sepsis or Endocarditis caused by MRSA. Methicillin-susceptible staphylococci (MSSA) in patients allergic to penicillins or cephalosporins. Oral vancomycin is limited to treatment for potentially lifethreatening, antibiotic-associated colitis due to C. difficile. 5. IV vancomycin used in patients with prosthetic heart valves and in patients undergoing implantation of prosthetic devices (decrease risk of MRSA or MRSE infection). 6. Vancomycin acts synergistic with aminoglycosides combined with gentamicin as an alternative regimen for treating enterococcal endocarditis in patients with serious penicillin allergy. Vancomycin combined with cefotaxime, ceftriaxone or rifampin to treat meningitis suspected or caused by a penicillin-resistant strain of pneumococcus (Inflammation allows meningeal penetration). 7. Adverse Reactions of Vancomycin • • • Fever, chills… Phlebitis at site of injection. Ototoxicity and Nephrotoxicity - rare with current preparations – • • • Dose-related hearing loss occurs in patients with renal failure due to drug accumulation. More common when co-administered with aminoglycosides. Red man or red neck syndrome: associated with rapid infusions  Flushing and shock as a result of excessive release of histamine • • • • Slow infusion rate so the dose is given over 2 hours. Increase the dilution volume Pretreat with antihistamine The red man syndrome is treated with antihistamines & steroids. Daptomycin • A cyclic lipopeptide antibiotic. • Binds the bacterial cytoplasmic membrane & induces rapid depolarization of the membrane  Disrupts membrane function • Inhibits intracellular synthesis of DNA, RNA, and protein. • Bactericidal (effect is concentration dependent). • Activity limited to gram-positive organisms  for treating infections caused by resistant gram-positive organisms, including MRSA and vancomycinresistant enterococci (VRE). • Indicated for treatment of bacteremia and endocarditis… • Daptomycin binds and inserts into the cell membrane. • It aggregates in the membrane. • It alters the shape of the membrane to form a hole, allowing ions in and out of the cell easily. Bacitracin • • • • • Bacitracin is a mixture of cyclic polypeptides that inhibits bacterial cell wall synthesis. Active against a wide variety of gram +ve organisms. Restricted to topical application because of potential for nephrotoxicity with systemic use. Safe when used topically… Bacitracin used to prevent wound infections, Bacitracin-containing topical treat pneumonia and empyema in infants, preparations remain a and to treat skin and eye infections. possible alternative to silver sulfadiazine for burn patients with a sulfa allergy. Bacitracin zinc salt, in combination with other topical antibiotics (usually polymyxin B and neomycin) as an ointment ("triple antibiotic ointment," with the brand name Neosporin)