CHAPTER 43: BETA-LACTAM & MEMBRANE-ACTIVE ANTIBIOTICS

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BETA-LACTAM COMPOUNDS Beta-lactam compounds: have a 4-membered lactam ring o Penicillins o Cephalosporins o Monobactams o Carbapanems o Beta-lactamase inhibitors PENICILLINS Chemistry Thiazolidine ring attached to a beta-lactam ring that carries a secondary amino group Substituents can be attached to the amino group 6-aminopenicillanic acid nucleus essential for biologic activity Hydrolysis of beta-lactam ring by beta-lactamase penicilloic acid (lacks antibacterial activity) A. Classification Substituents of the 6-aminopenicilloic acid moiety determine the essential pharmacologic and antibacterial properties of the resulting molecules Within each of these groups are compounds that are relatively stable to gastric acid and suitable for oral administration (eg. Penicillin V, dicloxacillin, amoxicillin) 1. Penicillins (eg. penicillin G) Greatest activity: o Gram (+) o Gram (-) cocci o Non-beta-lactamase producing anaerobes Little activity: o Gram (-) rods Susceptible to hydrolysis by beta-lactamases Antistaphylococcal penicillins (eg. Nafcillin) Resistant to staphylococcal beta-lactamase Active against staphylococci and streptococci Inactive against enterococci, anaerobes, gram (-) cocci and rods Extended-spectrum penicillins (ampicillin, antipseudomonal penicillins) Retain the antibacterial spectrum of penicillin Improved activity against gram (-) Relatively susceptible to hydrolysis by beta-lactamase

A 5-amino acid peptide is linked to N-acetylmuramic acid, terminates in D-alanyl-D-alanine Penicillin-binding protein (PBP) removes the terminal alanine in the process of forming a cross-link with a nearby peptide Cross-links structural rigidity Beta-lactam antibiotics o Structural analogs of the natural D-Ala-D-Ala substrate o Covalently bind to the active site of PBPs inhibits the transpeptidase reaction halt peptidoglycan synthesis cell dies o Autolysins, disruption of cell well morphogenesis involved o Kill bacterial cells only when they are actively growing and synthesizing cell wall

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Resistance 4 general mechanisms: 1. Inactivation of antibiotic by beta-lactamase most common 2. Modification of target PBPs basis of methicillin resistance in staphylococci and penicillin resistance in pneumococci and enterococci Produce PBPs that have low affinity for binding lactam antibiotics Inhibited only at high, often clinically unachievable, drug concentrations 3. Impaired penetration of drug to target PBPs occur only in gram (-) species (impermeable outer cell membrane) Beta-lactam antibiotics cross the outer membrane and enter gram (-) organisms via porins. Absence of the proper channel or production downregulation impair drug entry Poor penetration alone not sufficient to confer resistance; presence of -lactamase important 4. Efflux gram (-) Cytoplasmic and periplasmic protein components transport some -lactam antibiotics from the periplasm back across the outer membrane Beta-lactamases produced by S. aureus, H. influenzae, and E. coli are relatively narrow in substrate specificity, preferring penicillins to cephalosporins AmpC beta-lactamase (P. aeruginosa, Enterobacter), extendedspectrum beta-lactamases (ESBLs) hydrolyze both cephalosporins and penicillins Carbapanems o Highly resistant to hydrolysis by penicillinases and cephalosporinases o Hydrolyzed by metallo--lactamase and carbapanemases Pharmacokinetics Absorption differ depending in part on acid stability and protein binding GI absorption of nafcillin is erratic not suitable for oral administration Dicloxacillin, ampicillin, amoxicillin acid-stable, well absorbed o Serum concentrations = 4 8 mcg/mL after a 500mg oral dose Absorption impaired by food (except amoxicillin) Should be administered 1-2 hours before or after a meal IV route of pen G preferred to IM (irritation, local pain from large doses) Serum concentrations 30 minutes after an IV injection of 1 g (1.6 million units of pen G) of a penicillin = 20 50 mcg/mL Only a small amount is present as free drug, concentration of which is determined by protein binding o Highly protein bound (eg nafcillin) lower free drug concentrations in serum than less protein-bound (eg pen G, ampicillin) Widely distributed in body tissues and fluids with a few exceptions Polar molecules intracellular concentrations below those in ECF

B. Penicillin Units and Formulations Crystalline sodium penicillin G = 1600 units per mg (1 unit = 0.6 mcg; 1 million units of penicillin = 0.6 g) Semisynthetic penicillin prescribed by weight rather than units Minimum inhibitory concentration (MIC) given in mcg/mL Formulated as the sodium or potassium salt of the free acid Potassium penicillin G = 1.7 meq of K per million units of penicillin (2.8 mEq/g) Nafcillin = Na 2.8 mEq/g Procaine salts, benzathine salts of penicillin G provide repository forms for IM injection Salts are stable for 4 years at 4C in dry crystalline form Solutions lose activity rapidly (24 hours at 20C); must be prepared fresh for administration Mechanism of Action Inhibit bacterial growth by interfering with the transpeptidation reaction of bacterial cell wall synthesis Cell wall o Completely surrounds the cytoplasmic membrane o Maintains cell shape and integrity o Prevents cell lysis from high osmotic pressure o Composed of a complex, cross-linked polymer of polysaccharides and polypeptides, peptidoglycan (murein or mucopeptide) o Polysaccharide contains alternating amino sugars: N-acetylglucosamine N-acetylmuramic acid

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Benzathine, procaine penicillins formulated to delay absorption prolonged blood and tissue concentrations o Single IM injection of 1.2 million units of benzathine penicillin maintains serum levels of above 0.02 mcg/mL for 10 days sufficient to treat -hemolytic strep infection o After 3 weeks, levels still exceed 0.003 mcg/mL o 600,000 U dose of procaine penicillin yields peak concentrations of 1-2 mcg/mL and clinically useful concentrations for 12-24 hours Concentrations in most tissues are equal to those in serum o Excreted into sputum and milk to levels 3-15% of those in the serum o Poor penetration into the eye, prostate, and CNS o Bacterial meningitis 1-5 mcg/mL achieved with a daily parenteral dose of 18-24 million units kill susceptible pneumococci and meningococci Rapidly excreted by the kidneys o 10% glomerular filtration, 90%tubular secretion Half-life of pen G: 30 minutes o 10 hours in renal failure Ampicillin, extended-spectrum secreted more slowly; half-life: 1 hour Dose must be adjusted according to renal function o to 1/3 the normal dose if creatinine clearance is 10 mL/min or less Nafcillin cleared by biliary excretion Oxacillin, dicloxacillin, cloxacillin both kidney and biliary excretion; no dosage adjustment for renal failure\ Clearance is less efficient in newborns

B. Penicillins Resistant to Staphylococcal Beta Lactamase o Methicillin o Nafcillin o Isoxazolyl penicillins Oxacillin Cloxacillin Dicloxacillin Indicated for infection by -lactamase-producing staphylococci, susceptible strains of streptocci and pneumococci Resistant: o Listeria monocytogenes o Enterococci o Methicillin-resistant staphylococci strains DOC for infections caused by methicillin-susceptible and penicillin-resistant strains of staphylococci Isoxazoyl penicillins 0.25 0.5 g orally every 4 6 hours o Treatment of mild to moderate localized staphylococcal infections o Relatively acid-stable o Have reasonable bioavailability o Absorption interfered by food Oxacillin or nafcillin 8-12 g/d given by intermittent IV infusion of 1 2 g every 4 6 hours for serious systemic staph infections C. Extended-Spectrum Penicillins o Aminopenicillins Ampicillin Amoxicillin o Carboxypenicillins Carbenicillin Ticarcillin o Ureidopenicillins Piperacillin Mezlocillin Azlocillin Have greater activity than penicillin against gram (-) bacteria because of their enhanced ability to penetrate the outer membrane Inactivated by many -lactamases Aminopenicillins have nearly identical spectrums of activity o Amoxicillin Better absorbed orally 250-500 mg 3x/day = same amount of ampicillin given 4x/day UTI, sinusitis, otitis, LRTI o Most active of the oral -lactams against pneumococci with elevated MICs to penicillin o Ampicillin Shigellosis Its use to treat incomplicated salmonella gastroenteritis is controversial because it may prolong the carrier state 4-12 g/d IV anaerobes, enterococci, Listeria monocytogenes, -lactamase-negative strains of gram (-) cocci and bacilli (E. coli, Salmonella) Resistant strains of H. influenzae because of altered PBPs are emerging Use for empiric therapy of UTI, meningitis, and typhoid fever precluded Not active against Klebsiella, Enterobacter, P. aeruginosa, Citrobacter, Serratia marcescens, indole-positive Proteus, and other hospital-acquired gram (-) aerobes Carbenicillin o First antipseudomonal carboxypenicillin o No longer used in the USA Ticarcillin o Less active than ampicillin against enterococci Ureidopenicillins o Antipseudomonal o Active against selected gram (-) bacilli (eg. Klebsiella pneumoniae) Antipseudomonal penicllins are usually used in combination with an aminoglycoside or fluoroquinolone for pseudomonal infections outside the urinary tract

Clinical Uses Given 1-2 hours before or after a meal to minimize binding to food proteins and acid inactivation o Except oral amoxicillin Blood levels raised by simultaneous administration of probenecid (0.5 g q6h) due to impaired renal tubular secretion of weak acids Should never be used for viral infections Should be prescribed only when there is reasonable suspicion of, or documented infection with, susceptible organisms A. Penicillin Penicillin G o Drug of choice for infections caused by: Streptococci Meningococci Some enterococci Penicillin-susceptible pneumococci Non--lactamase producing staphylococci Treponema pallidum, other spirochetes Clostridium Actinomyces, certain gram (+) rods Non--lactamase-producing gram (-) anaerobes o Effective doses: between 4 and 24 million units per day IV in 4 6 divided doses o High-dose given as a continuous IV infusion Penicillin V o Oral form of penicillin o Indicated only in minor infections Poor bioavailability 4x/day dosing Narrow antibacterial spectrum Amoxicillin used instead Benzathine penicillin & procaine penicillin IM o Yield low but prolonged drug levels o -hemolytic streptococcal pharyngitis (once every 3-4 weeks prevents reinfection) o Benzathine penicillin G syphilis, 2.4 M units once a week for 1-3 weeks o Procaine penicillin G formerly used for uncomplicated pneumococcal pneumonia or gonorrhea

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Ampicillin, amoxicillin, ticarcillin, and piperacillin are available in combination with one of several -lactamase inhibitors, which extends the activity of these penicillins to include -lactamase producing S. aureus and gram (-) bacteria o Clavulanic acid o Sulbactam o Tazobactam

Poor activity: P. aeruginosa, indole-positive Proteus, enterobacter, S. marcescens, Citrobacter, Acinetobacter, Bacteroides fragilis

Adverse Reactions Generally well-tolerated encourages misuse and inappropriate suse Most of the serious AEs are due to hypersensitivity Cross-sensitizing and cross-reacting Antigenic determinants are degradation products of penicillins; o Penicilloic acid o Products of alkaline hydrolysis bound to host protein Should be administered with caution or a substitute drug if a person has a history of serious penicillin allergy Incidence of allergic reactions in young children is negligible Allergic reactions; o Anaphylactic shock very rare, 0.05% o Serum sickness-type reactions rare Urticaria Fever Joint swelling Angioneurotic edema Intense pruritus Respiratory compromise 7-12 days after exposure o Skin rashes Oral lesions, fever, eosinophilia, hemolytic anemia, other hematologic disturbances, vasculitis Interstitial nephritis autoimmune reaction to a penicillin-protein complex Desensitization can be accomplished with gradually increasing doses of penicillin High doses in patients with renal failure seizures Nafcillin neutropenia Oxacillin hepatitis Methicillin interstitial nephritis Large oral doses GI upset: nausea, vomiting, diarrhea Ampicillin pseudomembranous colitis Secondary infections such as vaginal candidiasis Ampicillin, amoxicillin skin rashes not allergic in nature o Occur when inappropriately prescribed for a viral illness CEPHALOSPORINS & CEPHAMYCINS Similar to penicillins but more stable to many bacterial -lactamases Have a broader spectrum of activity Strains of E. coli and Klebsiella expressing extendedspectrum -lactamases that can hydrolyze most cephalosporins are a growing clinical concern Not active against enterococci and L. monocytogenes Chemistry 7-aminocephalosporanic acid nucleus o Bears a close resemblance to 6-aminopenicillanic acid Intrinsic antimicrobial activity is low, but the attachment of various R1 and R2 has yielded hundreds of potent compounds of low toxicity FIRST-GENERATION CEPHALOSPORINS o Cefazolin o Cefadroxil o Cephalexin o Cephalothin o Cephapirin o Cephradine Very active against gram (+) cocci (pneumococci, streptococci, staphylococci) Not active against methicillin-resistant staphylococci Sensitive: E. coli, K. pneumoniae, Proteus mirabilis, anaerobic cocci (peptococci, peptostreptococci)

Pharmacokinetics & Dosage A. Oral Cephalexin, cephadrine, cefadroxil o Absorbed from the gut to a variable extent o Oral doses of 500 mg - serum levels are 15-20 mcg/mL o Urine concentration is usually very high o Tissue levels are variable and generally lower than in serum Cephalexin and cephadrine 0.25 to 0.5 4x daily Cefadroxil 0.5 to 1 g 2x daily Excretion mainly by glomerular filtration and tubular secretion Drugs that block tubular secretion (probenecid) increase serum levels substantially Dosage must be reduced with impaired renal function B. Parenteral Cefazolin only first-generation parenteral cephalosporin still in general use; can also be administered IM o IV infusion of 1 g peak level = 90 120 mcg/mL o Usual dosage IV: 0.5 2 g q8h o Excretion via the kidney o Dose adjustments with impaired renal function Clinical Uses Oral o UTI, staphylococcal or streptococcal infections; cellulitis, or soft tissue abscess o Should not be relied on in serious systemic infections Cefazolin o Penetrates well into most tissues o DOC for surgical prophylaxis o May also be a choice in infections for which it is the least toxic drug (eg penicillinase-producing E. coli or K. pneumoniae) and in individuals with staph or strep infections who have a history of penicillin allergy o Does not penetrate CNS; cannot be used for meningitis o Alternative to an antistaphylococcal penicillin for allergics SECOND-GENERATION CEPHALOSPORINS o Cefaclor o Cefamandole o Cefonicid o Cefuroxime o Cefprozil o Loracarbef o Ceforanide o Cephamycins have activity against anaerobes Cefoxitin Cefmetazole Cefotetan Active against organisms inhibited by first-gen drugs Have extended gram (-) coverage Sensitive against Klebsiella including those resistant to cephalothin Cefamandole, cefuroxime, cefonicid, ceforanide, cefaclor o Active against H. influenzae but not against Serratia or B. fragilis Cefoxitin, cefmetazole, cefotetan o Active against B. fragilis and some Serratia strains but are less active against H. influenza May exhibit in vitro activity against Enterobacter; resistant mutants express beta-lactamase should not be used to treat enterobacter infections Pharmacokinetics & Dosage A. Oral Cefaclor, cefuroxime axetil, cefprozil, loracarbef o can be given orally o usual dose: 10-15 mg/kg/d in 2 to 4 divided doses o maximum for children 1 g/d

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Except for cefuroxime axetil, not active against penicillin-non-susceptible pneumococci and should be used cautiously to treat suspected or proved pneumococcal infections Cefaclor more susceptible to -lactamase hydrolysis

B. Parenteral After 1 g IV infusion serum levels are 75 125 mcg/mL IM administration is painful and should be avoided Marked differences in half-life, protein binding, and interval between doses Renally cleared Dosage adjustment in renal failure Clinical Uses Oral o Active against -lactamase-producing H. influenzae or Moraxella catarrhalis o Sinusitis, otitis, LRTI Cefoxitin, cefotetan, cefmetazole o Mixed anaerobic infections: peritonitis, diverticulitis, PID Cefuroxime o Community-acquired pneumonia o Active against -lactamase-producing H. influenzae or K. pneumoniae and some penicillin-non-susceptible pneumococci o Crosses the BBB, but less effective in meningitis than ceftriaxone or cefotaxime and should not be used THIRD-GENERATION CEPHALOSPORINS o Cefoperazone o Cefotaxime o Ceftazidime o Ceftizoxime o Ceftriaxone o Cefixime o Cefpodoxime proxetil o Cefdinir o Cefditoren pivoxil o Ceftibuten o Moxalactam Antimicrobial Activity Have expanded gram(-) coverage Some are able to cross the BBB Active against Citrobacter, S. marcescens, Providencia (resistance can emerge - cephalosporinase) Effective against -lactamase-producing strains of Haemophilus and Neisseria Ceftazidime, cefoperazone o Only 2 drugs with useful activity against P. aeruginosa Hydrolyzed by constituvely produced AmpC -lactamase Not reliably active against Enterobacter Ceftizoxime, moxalactam o Active against B. fragilis Cefixime, cefdinir, ceftibuten, cefpodoxime proxetil o Oral agents possessing similar activity o Cefixime, ceftibuten much less active against pneumococci and have poor acitivity against S. aureus Pharmacokinetics & Dosage 1 g IV infusion serum levels 60-140 mcg/mL Penetrate body fluids and tissues well Achieve levels in the CSF sufficient to inhibit most susceptible pathogens (except cefoperazone and oral cephalosporins) Ceftriaxone: o Half-life: 7-8 hours o Injected once q24h, 15-50 mg/kg/d o Single daily 1 g dose for most serious infections o 2 g every 12 hours for meningitis Cefoperazone o Half-life: 2 hours o Infused every 8 12 hours, 25 100 mg/kg/day

Remaining drugs o Half-life: 1 1.7 hours o Infused every 6 8 hours in dosages between 2 and 12 g/d Cefixime o Can be given orally 200mg twice daily or 400mg once daily UTI o Single 400 mg dose uncomplicated gonococcal urethritis and cervicitis Cefpodoxime proxetil, cefditoren pivoxil o 200 400 mg twice daily Ceftibuten 400 mg once daily Cefdinir 300 mg/12 hours Excretion of cefoperazone and ceftriaxone biliary; no dosage adjustment for renal insufficiency Others are excreted by kidney; dosage adjustment for renal insufficiency

Clinical Uses Strains expressing extended-spectrum beta-lactamases are not susceptible. Avoided in treatment of enterobacter infections because of emergence of resistance. Ceftriaxone, cefotaxime o Meningitis (pneumococci, meningococci, H. influenzae, enteric gram (-) rods, except L. monocytogenes) o Most active cephalosporins against penicillin-nonsusceptible strains of pneumococci o Recommended for empirical therapy o Meningitis caused by pneumococci with penicillin MICs > 1mcg/mL addition of vancomycin Ceftazidine in combination with other antibiotics for neutropenic, febrile immunocompromised patients FOURTH-GENERATION CEPHALOSPORINS o Cefepime o Cefpirome Cefepime o More resistant to hydrolysis by chromosomal lactamases (eg Enterobacter) o Hydrolyzed by extended-spectrum -lactamases (like 3rd gen) o Has good activity against P. aeruginosa, Enterobacteriaceae, S. aureus, and S. pneumoniae o Highly active against Haemophilus and Neisseria o Penetrates well into CSF o Cleared by the kidneys o Half-life: 2 hours o Pharmacokinetics similar to ceftazidime o Has good activity against most penicillin-nonsusceptible streptococci o Useful in the treatment of Enterobacter infections FIFTH GENERATION: Cephalosporins Active Against MethicillinResistant Staphylococci o Ceftaroline fosamil Ceftaroline fosamil o Prodrug of the active metabolite ceftaroline o First to be approved for clinical use o Has increased binding to PBP 2a, which mediates methicillin resistance o Bactericidal activity o Has some activity against enterococci and a broad gram (-) spectrum o Not active against extended-spectrum -lactamaseproducing strains ADVERSE EFFECTS OF CEPHALOSPORINS A. Allergy Sensitizing; may elicit hypersensitivity reactions identical to those of penicillin Anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, hemolytic anemia Some individuals with a history of penicillin allergy may tolerate cephalosporins

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Cross-allergenicity: 5 10% o More common with penicillins and early generation cephalosporins Patients with a history of anaphylaxis to penicillins should not receive cephalosporins

B. Toxicity IM injection: local irritation, pain IV: thrombophlebitis Renal toxicity: interstitial nephritis, tubular necrosis o Caused withdrawal of cephaloridine Cephalosporins that contain a methylthiotetrazole group (cefamandole, cefmetazole, cefotetan, cefoperazone) o Hypoprothrombinemia, bleeding disorders Prevent by oral vitamin K1, 10 mg twice weekly o Disulfiram-like reactions Avoid alcohol and alcohol-containing medications OTHER BETA-LACTAM DRUGS MONOBACTAMS o Aztreonam Drugs with a monocyclic -lactam ring Spectrum of activity limited to aerobic gram (-) rods (including P. aeruginosa) Have no activity against gram (+) bacteria or anaerobes Structurally similar to ceftazidime Gram (-) spectrum similar to that of 3rd generation cephalosporins Stable to many -lactamases except AmpC -lactamases and extended-spectrum -lactamases Penetrates well into CSF Given IV q8h, 1-2 g Serum peak levels 100 mcg/mL Half-life: 1 2 hours; greatly prolonged in renal failure Tolerated by penicillin-allergic patients AEs: Occasional skin rashes, elevations of serum aminotransferases; major toxicity uncommon May be used to treat serious infections (pneumonia, meningitis, sepsis) caused by susceptible gram (-) pathogens in patients with a history of penicillin anaphylaxis BETA-LACTAMASE INHIBITORS o Clavulanic acid o Sulbactam o Tazobactam Resemble -lactam molecules but have very weak antibacterial action Potent inhibitors of many bacterial -lactamases Can protect hydrolysable penicillins from inactivation Most active against Ambler class A -lactamases o Plasmid-encoded transposable element (TEM) o Produced by staph, H. influenzae, N. gonorrhea, salmonella, shigella, E. coli, and K. pneumoniae Not good inhibitors of class C -lactamases o Chromosomally encoded and inducible o Enterobacter, Citrobacter, S. marcescens, P. aeruginosa Inhibit chromosomal -lactamases of B. fragilis and M. catarrhalis Available only in fixed combination with specific penicillins Spectrum determined by the companion penicillin Extends the spectrum of a penicillin provided that the inactivity of the penicillin is due to destruction by -lactamase and that the inhibitor is active against the -lactamase that is produced Ampicillin-sulbactam o -lactamase-producing S. aureus and H. influenza, but not against Serratia Indications o Empirical therapy in both immunocompromised and immunocompetent patients o Mixed aerobic and anaerobic infections (eg intraabdominal infections) Doses same as single agents; except for piperacillin-tazobactam: 3-4 g piperacillin every 6 hours Adjustment for renal insufficiency based on penicillin component

CARBAPANEMS o Doripenem o Ertapenem o Imipenem o meropenem Imipenem o first drug of this class o wide spectrum; good activity against: Many gram (-) rods, including P. aeruginosa Gram Anaerobes o Not resistant to carbapenemases or metallo-lactamases o Enterococcus faecium, methicillin-resistant staph, Clostridium difficile, Burkholderia cepacia, Stenotrophomonas maltophilia resistant o Inactivated by dehydropeptidases in renal tubules low urinary concentrations o Administered together with an inhibitor of renal dehydropeptidases (cilastatin) o 0.25 0.5 g IV q6-8 hours o Half-life: 1 hour Doripenem, meropenem o Have slightly greater activity against gram (-) aerobes o Slightly less activity against gram (+) o Not degraded by renal dehydropeptidase; do not require an inhibitor o Doripenem: 0.5 g, 1- 4-hr infusion q8h o Meropenem: 0.5 1 g IV q8h Ertapenem o Less active than the other carbapenems against P. aeruginosa and Acinetobacter o Not degraded by renal dehydropeptidase o Longest hal-life: 4 hours o Administered as a once-daily dose of 1 g IV or IM o IM irritating; formulated with 1% lidocaine Penetrate body tissue and fluids well, CSF Renal clearance; dose reduced in renal insufficiency Indications: o Infections caused by susceptible organisms that are resistant to other available drugs, eg, P aeruginosa o Treatment of mixed aerobic and anaerobic infections. o Active against many penicillin-non-susceptible strains of pneumococci. o Highly active in the treatment of enterobacter infections because they are resistant to destruction by the lactamase produced by these organisms o Treatment of choice for infections caused by extendedspectrum -lactamase-producing gram-negative bacteria o Ertapenem should not be used to treat infections caused by P. aeruginosa o Imipenem, meropenem, or doripenem, with or without an aminoglycoside, may be effective treatment for febrile neutropenic patients Adverse Effects (more common in imipenem): o Nausea, vomiting, diarrhea, skin rashes, and reactions at the infusion sites o Excessive levels in renal failure seizures o Patients allergic to penicillins may be allergic to carbapenems as well GLYCOPEPTIDE ANTIBIOTICS VANCOMYCIN Produced by Streptococcus orientalis and Amycolatopsis orientalis Active only against gram (+) bacteria, except for Flavobacterium Molecular weight: 1500 Water stable, quite stable Mechanisms of Action and Basis of Resistance Inhibits cell wall synthesis by binding firmly to the d-Ala-D-Ala terminus of nascent peptidoglycan pentapeptide inhibits transglycosylase, preventing further elongation of peptidoglycan and cross-linking peptidoglycan is weakened cell lysis, cell membrane damage

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Resistance in enterococci modification of the D-Ala-D-Ala binding site o Terminal D-alanine is replaced by D-lactate loss of a critical hydrogen bond that facilitates high-affinity binding to its target loss of activity o Also in vancomycin-resistant S. aureus (MIC 16 mcg/mL) Vancomycin-intermediate S. aureus (MIC = 4 8 mcg/mL) altered cell wall metabolism thickened cell wall, increased DAla-D-Ala residues (dead-end vancomycin binding sites) vancomycin sequestered within the cell

TEICOPLANIN Glycopeptide with similar mechanism of action and antibacterial spectrum with vancomycin Can be given IM or IV Long half-life: 45 70 hours; once-daily dosing Available in Europe; not approved for use in the US TELAVANCIN Semisynthetic lipoglycopeptide derived from vancomycin Active against gram (+), including strains with susceptibility to vancomycin 2 mechanisms of action 1. Inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of peptidoglycan 2. Disrupts bacterial cell membrane potential and increases membrane permeability Half-life: 8 hours; once-daily IV dosing Treatment of complicated skin and soft-tissue infections (10 mg/kg IV daily) Monitoring of serum levels not required unlike vancomycin Potentially teratogenic DALBAVANCIN Semisynthetic lipoglycopeptide derived from teicoplanin Same mechanism of action as vancomycin and teicoplanin but with improved activity against gram (+) including MRSA and vancomycin-intermediate S. aureus Not active against most vancomycin-resistant enterococci Long half-life: 6 11 days; once-weekly IV administration OTHER CELL WALL- OR MEMBRANE-ACTIVE AGENTS DAPTOMYCIN Novel cyclic lipopeptide fermentation product of Streptomyces roseosporus Spectrum of activity similar to vancomycin, but more rapidly bactericidal May be active against vancomycin-resistant enterococci and S. aureus Known to bind to the cell membrane via calcium-dependent insertion of its lipid tail depolarization of cell membrane potassium efflux rapid cell death Cleared renally Skin and soft tissue infections 4 mg/kg/dose Bacteremia, endocarditis 6 mg/kg/dose once daily (normal renal function); every other day for patients with creatinine clearance <30 mL/min Higher than 6 mg/kg/dose for serious infections Can cause myopathy Creatine phosphokinase levels should be monitored weekly Antagonized by pulmonary surfactant not used for pneumonia Can cause allergic pneumonitis in patients receiving prolonged therapy (> 2 weeks) Effective alternative to vancomycin FOSFOMYCIN Fosfomycin trometamol o Stable salt of fosfomycin (phosphonomycin) o Inhibits a very early stage of bacterial cell wall synthesis o Analog of phosphoenolpyruvate o Structurally unrelated to any other antimicrobial agent Inhibits the cytoplasmic enzyme enolpyruvate transferase by covalently binding to the cysteine residue of the active site and blocking the addition of phosphoenolpyruvate to UDP-Nacetylglucosamine (first step in the formation of UDP-Nacetylmuramic acid) UDP-N-acetylmuramic acid precursor of N-acetylmuramic acid Transported into the bacterial cell by glycerophosphate or glucose-6-phosphate transport systems Resistance is due to the inadequate transport of drug into the cell Active against both gram (+) and gram (-) - 125 mcg/mL Susceptibility tests should be performed in growth medium supplemented with glucose-6-phosphate to minimize falsepositive indications of resistance Synergism with beta-lactam antibiotics, aminoglycosides, fluoroquinolones

Antibacterial Activity 0.5 10 mcg/mL: bactericidal for gram (+) 2 mcg/mL: bactericidal for most pathogenic staphylococci Kills staphylocci relatively slowly and only if cells are actively dividing Synergistic in vitro with gentamicin and streptomycin against Enterococcus faecium and E. faecalis that do not exhibit high levels of aminoglycoside resistance Pharmacokinetics Poorly absorbed from the intestinal tract Administered orally for antibiotic-associated colitis by Clostridium difficile 1 hour IV infusion of 1 g blood levels of 15 30 mcg/mL for 1 2 hours Widely distributed in the body CSF levels 7 30% with meningeal inflammation 90% excreted by glomerular filtration Accumulation with renal insufficiency Clinical Uses Parenteral o Bloodstream infections and endocarditis caused by methicillin-resistant staphylococcus o Not as effective as antistaphylococcal penicillin for treatment of serious infections by methicillin-susceptible strains Vancomycin + gentamicin o Alternative regimen for enterococcal endocarditis in patients with serious penicillin allergy Vancomycin + cefotaxime, ceftriaxone, or rifampin o Meningitis by penicillin-resistant pneumococcus Normal renal function = 30 60 mg/kg/d in 2 3 divided doses Serious infections = 45 60 mg/kg/d starting dose, titration to achieve trough levels of 15 20 mcg/mL Children: 40 mg/kg/d in 3 4 divided doses Clearance is directly proportional to creatinine clearance Dosage reduced with renal insufficiency Oral vancomycin 0.125 0.25 g q6h o Antibiotic-associated colitis by C. difficile o Metronidazole for vancomycin-resistant enterococci o First-line treatment for severe cases or for cases that fail to respond to metronidazole Adverse Reactions 10% of cases, minor Irritating to tissue phlebitis at injection site Chills, fever Ototoxicity rare o Administration with aminoglycoside increased risk o Minimized by maintaining serum concentrations below 60 mcg/mL Nephrotoxicity uncommon Red man or red neck syndrome o Infusion-related flushing caused by release of histamine o Prevented by prolonging the infusion period to 1 2 hours or pretreatment with antihistamine (diphenhydramine)

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Available in both oral and parenteral formulations Oral bioavailability: 40% Peak concentrations: 10 mcg/mL (2 g dose); 30 mcg/mL (4 g dose) Half-life: 4 hours Excreted by the kidney Single 3 g dose for uncomplicated lower UTI in women Safe for use in pregnancy

BACITRACIN Cyclic peptide mixture first obtained from the Tracy strain of Bacillus subtilis in 1943 Active against gram (+) Inhibits cell wall formation by interfering with dephosphorylation in cycling of the lipid carrier that transfers peptidoglycan subunits to the growing cell wall No cross-resistance between bacitracin and other antimicrobials Highly nephrotoxic Only used topicall local antibacterial activity Poorly absorbed 500 units/g ointment base, often combined with polymyxin or neomycin Suppression of mixed bacterial flora in surface lesions of skin, in wounds, or on mucous membranes 100 200 units/mL solutions in saline for irrigation of joints, wounds, or pleural cavity CYCLOSERINE Produced by Streptomyces orchidaceous Water soluble, very unstable at acid pH Used almost exclusively to treat TB caused by strains of M. tuberculosis resistant to first-line agents Structural analog of D-alanine Inhibits the incorporation of D-alanine into peptidoglycan pentapeptide by inhibiting alanine racemase, which converts Lalanine to D-alanine, and D-alanyl-D-alanine ligase 0.25 g blood levels = 20 30 mcg/mL Widely distributed in tissues Excreted in active form into the urine TB dosage: 0.5 to 1 g/d in 2 3 divided doses Causes serious dose-related CNS toxicity: Headaches Tremors Acute psychosis Convulsions o Avoided by maintaining dosages below 0.75 g/d

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