Lecture 31 Beta-Lactam and Other Cell Wall- and Membrane- Antibiotics (Chapter 43) Katzung, B. G., Masters, S. B.

, & Trevor, A. J. (2009). Basic & clinical pharmacology . (11th ed.). United States: McGraw-Hill Companies.
Selected Prototype Drugs Beta-Lactam Compounds: Penicillins a. Penicillins (penicillin G) b. Antistaphylococcal penicillins (Nafcillin, Methicillin, Isoxazolyl Penicillins oxacillin, cloxacillin, dicloxacillin) c. Extended-spectrum penicillins(ampicillin, antipseudomonal penicillins, aminoampicillins, carboxypenicillins, ureidopenicillins) Pharmacodynamics (Mechanism of Action) *Inhibits bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis: -lactam antibiotics bind to active sites of Penicillin-binding proteins (PBPs) cell death Pharmacokinetics Clinical Application (Therapeutics) * Penicillins: against Gm(+) organisms, Gm() cocci, and non-lactamase producing anaerobes; little activity with Gm(-) rods; PenG DOC; PenV minor infections; Benzathine penicillin, Procaine penG treat/prevent hemolytic streptococcal infection (syphilis, pneumococcal pneumonia/gonorrhea respectively) prolonged blood conc. with IM administration * Antistaphylococcal penicillins: against lactamase-producing staphylococci, streptococci, pneumococci; Isoxazolyl penicillins mild to moderate localized staphylococcal infections, 0.25-0.5g oral every 4-6hrs; Oxacillin or Naficillin serious systemic infections, 8-12g/d intermittently (IV,1-2g every 4-6hrs) * Extended-spectrum penicillins: Gm(-) organisms; amoxicillin better as oral UTI, sinusitis, otitis, lower respiratory tract infection; ampicillin shigellosis; ampicillin and amoxicillin most active against penicillin resistant pneumococci; ampicillin serious infections caused by penicillin-susceptible organisms at IV, 412g/d; carbenicillin indanyl sodium UTI, oral; Ticarcillin (a Adverse Effects Contraindications Drug-Drug Interactions *Blood levels of penicillin with simultaneous administration of Probenecid (0.5g adult, 10mg/kg children) every 6hrs orally *Antipseudomonal penicillins with aminoglycoside or fluoroquinolone against P. aeruginosa infection outside urinary tract, effective against resistance *Ampicillin, amoxicillin, ticarcillin, piperacillin with -lactamase inhibitors: clavulanic acid, sulbactam, tazobactam (which extends the activity of penicillins against S. aureus and -lactamase producing Gm(-) bacteria)

*Contains a thiazolide ring attached to a lactam ring (6aminopenicillanic acid nucleus) *Dicloxacillin, Ampicillin, Amoxicillin Oral, serum conc. of 48mcg/mL after 500-mg oral dose; most oral penicillins should be taken at least 1-2hrs before/after a meal *Complete and rapid absorption for Parentaral penicillins *IV, serum conc. 2050mcg/mL from 1g after 30mins of *Benzathine, Procaine penicillins IM delayed absorption prolonged blood and tissue concentration *Most tissue conc. is equal with serum conc.; excreted into sputum, milk, eye, prostrate, CNS *Rapid excretion via kidneys (10% glomerular, 90% tubular); normal halflife of PenG 30mins, with renal failure 10hrs; of Ampicillin 1hr *Naficillin biliary excretion *Oxacillin, Dicloxacillin, Cloxacillin both renal and biliary excretion

*Resistance : 1. Inactivation of antibiotic by lactamase 2. Modification of target PBPs 3. impaired penetration of drug to target PBPs ( porins) 4. Efflux *Generally nontoxic *hypersensitivity allergic reactions include: 1. anaphylactic shock, 2. serum sicknesstype reaction (urticaria, fever, joint swelling, angioneurotic edema, intense pruritis, respiratory embarrassment) 3. skin rashes *other reactions include: 1. oral lesions 2. fever 3. intestinal nephritis 4. eosinophilia 5. hemolytic anemia 6.vasculitis *Penicillin in large doses: 1. if with renal failure seizures 2. orally GI upset (nausea, vomiting, diarrhea) *Naficillin neutropenia *Oxacillin hepatitis *Methicillin intestinal nephritis *Ampicillin skin rashes, pseudomembranous colitis secondary infections such as vaginal candidiasis *Amoxicillin skin rash

*Most oral pencillins (except amoxicillin) is impaired by food *IM irritation and local pain with large doses *Newborn: less efficient clearance of penicillins higher systemic concentration for longer periods than in adult * Penicillins: susceptible to lactamase * Antistaphylococcal penicillins: resistant to staphylococcal lactamase, but rates of methicillin-resistance in staphylococci * Extended-spectrum penicillins: susceptible to lactamase

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carboxypenicillin) for UTI; piperacillin, mezlocillin, azlocillin (are ureidopenicillins) Gm(-) bacilli Cephalosporins and Cephamycin SAME AS ABOVE *(7-aminopenicillanic acid) *Allergy: 1. anaphylaxis 2. fever 3. skin rash 4. nephritis 5. granulocytopenia 6. hemolytic anemia *Toxicity: 1. local irritation severe pain after IM or thrombophlebitis after IV 2. renal toxicity (interstitial nephritis, tubular necrosis) 3. Cephalosporins containing methylthiotetrazole group cause hypoprothrombinemia and bleeding disorders; with methylthiotetrazole ring cause severe disulfiram-like reactions *very active against Gm(+) cocci; rarely as DOC; oral maybe used against UTI, staphylococcal or streptococcal infections (cellulitis or soft tissue abscess) *cefazolin DOC for surgical prophylaxis; infections (as it is the least toxic drug); for patients with staphy or sterp infections and has hx of penicillin allergy other than immediate hypersensitivity *against anaerobes, Gm(+)and Gm(-) bacteria, not for enterobacter infections with lactamase *oral lactamaseproducing H. influenzae or Moraxella catarrhalis; treat sinusitis, otitis, lower respiratory tract infections *cefoxitin, cefotetan, *Pts with hx of anaphylaxis to penicillin *Alcohol and alcoholcontaining medications should be avoided when taking cephalosporins containing methylthiotetrazole ring

a. 1st Gen. Cephalosporins: cefazoline, cefadroxil, cephalexin, cephalothin, cephapirin, cephradine

*Oral cefadroxil, cephalexin, cephradine, serum conc. at 1520mcg/mL after 500mg dose; excretion by glomerular filtration and tubular secretion *Parenteral cefazolin, serum conc. at 90120mcg/mL after 1g; excretion via kidneys

*1st Gen. Cephalosporins: if with probenecid, may serum level

b, 2nd Gen. Cephalosporins: cefaclor, cefamandole, cefonicid, cefuroxime, cefprozil, loracarbef, ceforanide; Cephamycins: cefoxitin, cefmetazole, cefotetan

*Oral cefaclor, cefuroxime axetil, cefprozil, loracarbef (1015mg/kg/d in 2-4 divided doses) *Parenteral serum conc. at 75-125mcg/mL after 1g IV

*cefaclor more susceptible to lactamase hydrolysis *IM painful, should be avoided

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c. 3rd Gen. Cephalosporins: cefoperazone, cefotaxime, ceftazidime, ceftizoxime, ceftriaxone, cefixime, cefpodoxime proxetil, cefdinir, cefditoren pivoxil, ceftibuten, moxalactam

*Prenteral serum conc. 60-140mcg/mL after 1g IV *Ceftriaxone half-life 7-8hrs; Cefoperazone half-life 2hrs; other drugs half-life 11.7hrs *cefoperazone, ceftriaxone excreted via biliary tract, other drugs via kidney

d. 4th Gen. Cephalosporins: cefepime Monobactams: aztreonam SAME AS ABOVE

*half-life of 2hrs, cleared by kidney

*Monocyclic -lactam ring *Penetrates well into cerebrospinal fluid *Azetronam IV, serum conc. 100mcg/mL after 1-2g dose every 8hrs; half-life is 1-2hrs; excreted via kidneys

Beta-Lactamase inhibitors: clavulanic acid, sulbactam, tazobactam

SAME AS ABOVE

cefmetazole treat mixed aerobic infections such as peritonitis, diverticulitis *cefuroxime community-acquired pneumonia *expanded Gm(-) coverage; some can cross blood-brain barrier; against lactamase-producing strains of haemophilus and neisseria *ceftazidime, cefoperazone against P. aeruginosa *ceftizoxime, moxalectam against B. fragilis *ceftriaxone, cefotaxime against meningitis, penicillin-resistant strains of pneumococci, for empirical therapy *cephalosporin least toxic drug for sepsis in both immunocompetent & immunocompromised pt. *against P. aeruginosa, Enterobacteriaceae, S. aureus, S. penumoniae, haemophilus, neisseria, *Against aerobic Gm(-) rods, including pseudomonas *For penicillin-allergic patients; especially to those with pneumonia, meningitis, sepsis caused by susceptible Gm(-) pathogens *Against Ambler class A lactamases , inhibit chromosomal lactamases of bacterodes and moraxella *For empirical therapy fr infections caused by wide range of pathogens in both immunocompetent and immunocompromised *Treatment of mixed aerobic and anaerobic infections

*not for treating enterobacter infections emerging resistance

*3rd gen cephalosporins with vancomycin effective against highly penicillin-resistant strains of pneumococci *3rd gen cephalosporins with aminoglycoside for neturopinic, febrile, immunocompromised patients

1. skin rashes 2. aminotransferases

*Available only in fixed combination, spectrum depends on companion penicillin provided that the inactivity of penicillin is due to destruction by lactamase and that the inhibitor is active against the lactamase produced

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Carbapenems: doripenem, ertapenem, imipenem, meropenem

SAME AS ABOVE

*Penetrate body tissues and fluid, CSF; cleared renally *Imepenem IV, 0.250.5g every 6-8hrs, halflife 1hr *Meropenem IV, 0.51g every 8hrs *Doripenem 4hr infusion, 0.5g every 8hrs *Ertapenem IV or IM, 1g, once daily (longest half-life)

*Imipenem wide spectrum, against many Gm(-) rods, Gm(+) organisms, and anaerobes *Doripenem, Meropenem same with imipenem but with greater activity for Gm() aerobes *Ertapenem least active *DOC for enterobacter infections and infections by extended-spectrum -lactamases-producing Gm(-)s *Imipenem and Meropenem w/ or w/o aminoglycoside for febrile, neutropenic pts. *Against Gm(+)s, particularly staphylococci *Main indication: sepsis or endocarditis caused by methicillin-resistant staphylococci *For meningeal inflammation

*Ertapenem IM irritating *Common; 1. Nausea, vomiting 2. diarrhea 3. skin rashes 4. reactions at infusion site *Large dose of imipenem seizure *Allergic reactions if pt is allergic to penicillin

*Imipenem not resistant to metallo-lactamases; inactivated by dehydropeptidases in renal tubules

*Imipenem with cilastatin to inhibit renal dehydropeptidase *Ertapenem with 1% lidocane for IM administration to avoid irritations

Glycopeptide Antibiotics Vancomycin *Inhibits cell wall synthesis by binding firmly to D-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide, thus inhibiting the transglycosylase, preventing further elongation of peptidoglycan and cross-linking susceptible to lysis

Teicoplanin

SAME AS ABOVE

Dalbavancin

SAME AS ABOVE

*Poorly absorbed in the intestinal tract, oral only for enterocolitis by C. difficile *Parenteral serum conc. 15-30mcg/mL after 1g within 1hr IV infusion *90% excreted via glomerular filtration; directly proportional with creatinine clearance *Oral 0.125-0.25g every 6hrs for enterocolitis caused by C. difficile *IM or IV *Long half-life: 4570hrs, once daily dosing *Long half-life: 611days, once weekly IV

*Irritating to tissue phlebitis at site of injection, with chills and fever *If given with aminoglycoside risk of ototoxicity (minimized by maintaining serum conc. below 60mcg/mL)/ nephrotoxicity *Red man or Red neck syndrome: infusionrelated flush caused by release of histamine

*Resistance: D-Ala-DAla is replaced by Dlactate

*Vancomycin with gentamicin as alternative regimen for enterococcal endocarditis in pts with serious penicillin allergy

Telavancin

SAME AS ABOVE *In addition, it targets bacterial cell membrane and causes disruption of membrane potential and membrane permeability *Bind to cell membrane via calcium-dependent

*Half-life: 8hrs, once daily IV dosing

*Improved against Gm(+) bacteria, including methicillinresistant and vancomycinintermediate S. aureus *Against Gm(+) bacteria, including strains with reduced susceptibility to vancomycin

Other Drugs Daptomycin

*Cleared renally *4mg/kg/dose for skin

*Effective alternative for vancomycin

*Myopathy (creatine phosphokinase should

*Pulmonary surfactant antagonizes, therefore

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insertion of its lipid tail depolarization of the cell membrane with potassium efflux and rapid cell death

Fosfomycin Trometamol

Bacitracin

*Inhibits early stage of bacterial cell wall synthesis by inhibiting cytoplasmic enzyme enolpyruvate transferase by covalently bonding to the cysteine residue of the active site and blocking the addition of phosphoenolpyruvate to UDP-Nacetylglucosamine *Inhibits cell wall formation by interfering with dephosphorylation in cycling of lipid carrier that transfers peptidoglycan unit to the growing cell wall

and soft tissue infections; 6mg/kg/dose for bacteremia and endocarditis once daily in pts with normal renal function, and every other day in pts with creatinine clearance less than 30mL/min *Oral serum conc. 10mcg/mL and 30mcg/mL after 2g or 4g oral dose, respectively; half-life 4hrs *Excreted via kidneys *Available parenter dose

be monitored)

not used for pneumonia

*Active against both Gm(+) and Gm(-) organisms *For uncomplicated UTI *Safe for pregnancy

*Resistance: inadequate transport of drug into cell (glucose 6phosphate transfer system)

*In vitro synergism with -latam antibiotics, aminoglycosides, and fluoroquinolones

*Poorly absorbed *Topical applications for local antibacterial activity without systemic toxicity

Cycloserine

*Inhibits incorporation of D-Alanine into peptidoglycan pentapeptide by inhibiting alanine racemase

*Oral serum conc. 2030mcg/mL after ingestion of 0.25g *Widely distributed in tissues *Most are excreted as active form in urine *For TB: 0.5-1g/d in two or three divided doses Decrease

*Against Gm(+) organisms *For mixed bacterial flora in surface lesion of the skin, in wounds, or on mucous membranes *Can be used for irrigation of joints, wounds, of pleural cavity *Most useful against tuberculosis

*Highly nephrotoxic when administered systemically

*Serious dose related CNS toxicity, with headaches, tremors, acute psychosis, convulsions

Resulting to,

Due to,

Increase,

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