Beta-Lactam and Other Cell Wall- and Membrane-Active Antibioticsa. Penicillinsi. Penicillin G1. Greatest against Gram-positive organisms and Gram-neg cocci and non-beta-lactamase-producing anaerobes2. Susceptible to beta lactamasesii. Antistaphylococcal penicillins (nafcillin)1. Resistant to staph beta-lactamases2. Staphylococci and streptococci (Gram pos)3. Not for enterococci, anaerobic bacteria and gram neg cocci and rodsiii. Extended spectrum (ampicillin and antipseudomonal penicillins)1. Improved activity against Gram neg organisms2. Susceptible to beta lactamasesiv. Relatively stable in gastric acidv. I million units = 0.6 g1. Semisynthetic penicillins in weights rather than unitsvi. MIC in mcg/mLvii. Most penicillins are formulated as the sodium or potassium salt of the free acidviii. Procaine and benzathine salts of penicillin G provide repository for IM injectionix. Dry crystalline form stable for years at 4Cx. Solutions lose their activity rapidly (24 hrs at 20C)xi. MOA: interfere with transpeptidation reaction of bacterial cell wall synthesis, binds to penicillin-binding protein, beta lactam antibiotics only kill when cell is actively growing and synthesizing cell wallxii. Resistance: beta lactamase, modification of PBPs, impaired penetration of drug to target PBPs, efflux1. Beta lactamase: S. aureus, H flu, E coli prefer penicillins than cephalosporins2. AmpC beta lactamase (pseudomonas aeruginosa and enterobacter sp.) and extended spectrum beta lactamasesa. Hydrolyze ceph and pens3. Carbapenems are resistant to both penicillinases and cephalosporinases but susceptible to metallo-beta lactamases and carbapenemases4. Altered PBPsa. Basis of methicillin resistance in staphylococci and pen resistance in pneumococci and enterococcib. PBPs have low affinity for the antibiotics unless in higher not achievable concentrations5. Impaired penetrationa. Occurs in Gram neg only b. Not a very important mechanism to confer resistance unless beta lactamases are present (even a relatively inactive one) or with an efflux pumpxiii. Clinical Uses1. Penicillins should be given 1-2 hours before and after a meal, except amoxicillin. Blood levels of pen can be raised by simultaneously administering probenecid (0.5 g every 6hrs orally) to impair renal tubular secretion of beta lactam compounds.2. Penicillina. For streptococci, meningococci, some enterococci, penicillin-susceptible pneumococci, nonBlactamase producing staphylococci, treponema pallidum and certain other spirochetes, Clostridium sp, actinomyces and certain other gram pos rods, nonBlactamase producing gram neg anaerobesb. Penicillin V oral form of pen. Indicated only for minor infections because of poor bioavailability, narrow spectrum, and need to dose 4 times a day. Amoxicillin is used instead.c. Benz and procaine pen G for IM injection yield low but prolonged drug levels. 1.2M units benz pen for B-hemolytic strep pharyngitis. 2.4M units for syphilis. 3. Penicillins resistant to Staphylococcal B lactamase (methicillin, nafcillin, isoxazolyl pens)a. Semisyntheticb. Indicated for infection by staphylococcic. Listeria monocytogenes, enterococci, methicillin-resistant strains of staphylococcid. Drugs of choice for meth-susceptible pen-resistant staphylococcie. Isoxazolyl pen (oxacillin, cloxacillin, dicloxacillin)i. 0.25-0.5 g orally every 4-6 hoursii. For mild to moderate localized staphylococcal infectionsiii. Acid stable, reasonable bioavailabilityiv. Administered 1 hr before or after mealsf. For serious infections: oxacillin or nafcillin, 8-12 g/d, is given by intermittent IV infusion of 1-2g every 4-6 hrs4. Extended-Spectrum Penicillins (Aminopenicillins, Carboxypens, ureidopens)a. Better activity than pens against gram negb. Inactivated by many beta lactamasesc. Aminopens: ampicillin, amoxicillini. Amoxicillin better absorbed orallyii. Amoxicillin for UTI, sinusitis, otitis, lower resp tract infectionsiii. Ampicillin for shigellosis (not amoxicillin)iv. Both are the most active of beta lactam antibiotic against pneumococci with elevated MICsv. Ampicillin (4-12g/d) for anaerobes, enterococci, L monocytogenes, Blactamase-negative gram neg cocci and bacilli like E. coli. and Salmonella sp. Non beta-lactamase producing H flu are susceptiblevi. Ampicillin not for: Klebsiella sp., Enterobacter sp., P aeruginosa, Citrobacter sp., Serratia marcescens, indole-positive proteus species, other gram neg aerobes that are often encountered in hospital acquired infections these produce beta lactamases that inactivate ampicillind. Carboxypenicillinsi. Carbenicillin1. First antipseudomonal carboxypen2. Not used anymoreii. Ticarcillin1. Less active than ampicillin against enterococcie. Ureidopenicillins, Piperacillin, mezlocillin, azlocillini. Active against selected gram neg bacilli, such as Klebsiella pneumoniaef. In the treatment of P aeruginosa, aside from an antipseudomonal penicillin, an aminoglycoside or fluoroquinolone is used in combination for pseudomonal infections outside the urinary tractg. Ampicillin, amoxicillin, ticarcillin, piperacillin are available in combination with one or more B-lactamase inhibitorsi. Clavulanic acid, sulbactam, tazobactamii. Extends activity to b-lactamase producing S aureus and some B-lactamase producing gram neg bacteriaxiv. Adverse Reactions1. Hypersensitivity2. Allergic reactions include anaphylaxis (0.05%), serum-sickness type reactions (now rare urticarial, fever, joint swelling, angioneurotic edema, intense pruritus, respiratory compromise occurring 7-12 days after exposure), and a variety of skin rashes3. May occur: oral lesions, fever, interstitial nephritis (autoimmune reaction to penicillin-protein complex), eosinophilia, hemolytic anemia, hematologic disturbances, vasculitis4. Alternative drugs can be givena. Exception is for enterococcal endocarditis or neurosyphilis desensitization can be achieve by slowly increasing dosage5. Patients with renal failurea. High doses can cause seizures6. Nafcillin neutropenia7. Oxacillin hepatitis8. Methicillin interstitial nephritis (no longer used for this reason)9. Large doses GI upset, nausea, vomiting, diarrhea10. Ampicillin pseudomembranous colitis11. Secondary infections vaginal candidiasis12. Ampicillin and amoxicillin skin rashes not allergic in naturea. Usually occur when aminopens are prescribed for a viral infectionb. Cephalosporins and cephamycinsi. Similar to pens but more stable to many B-lactamases > broader spectrum1. However there are strains of Klebsiella and E. coli expressing extended-spectrum B-lactamases.ii. Not active against Enterococci and L monocytogenesiii. First Generation (Cefazolin, Cefadroxil, Cephalexin, Cephalothin, Cephapirin, Cephradine)1. Very active against Gram-pos cocci such as pneumococci, streptococci, staphylococci2. Traditional cephs are not active against methicillin-resistant strains of staphylococci but new compounds have been developed3. Active against: E coli, K pneumoniae, Proteus mirabilis, anaerobic cocci like peptococci and peptostreptococci (usually sensitive)4. Poorl against: P aeruginosa, indole-positive proteus species, Enterobacter sp, S marcescens, Citrobacter sp, Acinetobacter sp, Bacteroides fragilis5. Probenecid can increase serum levels6. Dosage must be reduced in pts with impaired renal function7. Orala. Cephalexin, cephradine, cefadroxil are absorbed in the gut to a variable extent. Filtered and secreted into urine.8. Parenterala. Cefazolin is the only first-gen parenteral ceph still in general use. IV infusion of 1 g and reach peak level of 90-120 mcg/mL. Can also be administered IM9. Clinical Usesa. Orali. UTI, staphylococcal and streptococcal infections like cellulitis and soft tissue abscessii. Not for serious systemic infectionsb. Cefazolini. Penetrates tissues wellii. Surgical prophylaxisiii. Alternative to an antistaphylococcal penicillin for patients allergic to penc. A choice in infections for which it is the least toxic drug (penicillinase-producing E coli or K pneumoniae) and in pts with staphylococcal and streptococcal infections with Hx of pen allergyd. Not for meningitis does not enter CNSiv. Second Generation (Cefaclor, Cefamandole, Cefonicid, cefuroxime, cefprozil, loracarbef, ceforanide and structurally related cephamycins cefoxitin, cefmetazole, cefotetan which have activity against anaerobs)1. Active against organisms inhibited by first-gen cephs with extended Gram-neg coverage2. Fora. Klebsiella sp (inc. resistant to cephalothin)b. Cefamandole, cefurozime, cefonicid, ceforanide, cefaclori. H flu but not serratia or B fragilisc. Cefoxitin, cefmetazole, cefotetani. B fragilis and some serratia but less for H flu3. Not for:a. Enterococci and P aeruginosa (like 1st gen)b. Enterobacter4. Orala. Cefaclor, cefuroxime axetil, cefprozil, loracarbefb. 10-15 mg/kg/d in two to four divided dosesc. Children: 20-40 mg/kg/d to a max of 1g/dd. Not predictably active against penicillin-non-susceptible pneumococcii. Except for cefuroxime axetile. Cefaclori. Susceptible to B-lactamase hydrolysis than other agents5. Parenterala. 1g IV infusion > serum levels 75-125 mcg/mL for most 2nd genb. IM administration is painful and avoidedc. All renally cleared6. Clinical Usesa. Oral - active against B-lactamase-producing H flu or Moraxella catarrhalis. Used to treat sinusitis, otitis, and lower resp tract infectionsb. Because of their activity against anaerobes (including many B fragilis strains), they (cefoxitin, cefotetan, cefmetazole) are used to treat mixed anaerobic infections such as peritonitis, diverticulitis, and pelvic inflammatory diseasec. Cefuroxime community-acquired pneumonia because it is active against B-lactamase-producing H flu and K pneumoniae and some penicillin-non-susceptible pneumococcii. Can pass BBB but not as effective as ceftriaxone or cefotaxime for meningitis so dont use for meningitisv. Third Generation (Cefoperazone, Cefotaxime, Ceftazidime, Ceftizoxime, Ceftriaxone, Cefixime, Cefpodoxime proxetil, Cefdinir, Cefditoren pivoxil, Ceftibuten, Moxalactam)1. Expanded Gram neg coverage compared to 2nd gen, some are able to cross BBB2. Active against:a. Citrobacter, S marsescens, Providencia (resistance can emerge in Tx_b. Beta-lactamase-producing strains of haemophilus and Neisseriac. P aeruginosa (only ceftazidime and cefoperazone)d. B fragilis (Ceftizoxime, Moxalactam)3. Not fora. Enterobacter sp4. Hydrolyzed by constitutively produced AmpC beta lactamase (like 2nd gen)5. Serratia, Providencia, Citrobacter can produce a chromosomally encoded cephalosporinase that can confer resistance when constitutively expressed6. Ceftizoxime and moxolactam active against B fragilis.7. Cefixime, cefdinir, ceftibuten, cefpodoxime proxetil are oral agents with similar activity except cefixime and ceftibuten are much less active against pneumococci and have poor activity against S aureus.8. Penetrate body fluids and tissues well. Except for cefoperazone and all oral cephs, achieve levels in CSF sufficient to inhibit most pathogens including Gram-neg rods, except pseudomonas9. Strains with extended-spectrum B-lactamases are not susceptible.10. Avoid treatment of enterobacter even if susceptible in vitro because of emergence of resistance11. Ceftriaxone and cefotaxime for meningitis caused by pneumococci, meningococci, H flu, and susceptible enteric Gram-neg rods but not L monocytogenesa. These two are also for serious infections from penicillin resistant strains of pneumococcib. But vancomycin is added in meningitis caused by these strains (pneumococci with penicillin MICs > 1mcg/mL)12. Empirical therapy of sepsis of unknown cause in both immunocompetent and immunocompromised pt and treatment of infections where cephs are the least toxic drug available13. 3rd gen cephs used with aminoglycosides: pts who are neutropenic, febrile and immunocompromisedvi. Fourth Generation (Cefepime1. Resistant to hydrolysis by chromosomal B-lactamases (by enterobacter)2. Hydrolyzed by extended-spectrum beta-lactamases3. Good activity against P aeruginosa, enterobacteriaceae, S aureus, S pneumoniae4. Highly active against Neisseria and hemophilus5. Penetrates well to CSF6. Cleared renally half life of 2 hours7. Pharmacokinetic properties similar to ceftazidimea. Except cefepime has good activity against most penicillin resistant strains of streptococcib. May be useful against enterbactervii. Cephalosporins active against Methicillin-resistant staphylococci1. Under development2. Ceftaroline3. Fosamil4. Ceftobiprole medocaril5. Against enterococci and has broad Gram-neg coverage6. Neither is active against extended spectrum B lactamase-producing strainsviii. Adverse Effects of Cephs1. Allergy2. Toxicityc. Other Beta-Lactams