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Outline. Principals of Antibiotic Pharmacology Classifications of Antibiotics Mechanisms of Action Mechanisms of Resistance Spectrum of Activity Adverse effects (most common, very serious or unique) Drug interactions.

Antimicrobial Mechanism of Action. Cell Wall Synthesis Inhibitors.

Selection of Antimicrobial Drugs. Host Factors Antimicrobial Activity Pharmacokinetic Properties Adverse Effect Profile Cost.

Selection of Antimicrobial Drugs Host Factors. Pregnancy Drug allergies Age Immune Status Renal impairment Hepatic insufficiency Site of Infection: Abscesses Indwelling catheters.

Selection of Antimicrobial Drugs How We Use Antibiotics.

AGENTS AFFECTING THE CELL WALL. ß- LACTAMASE INHIBITORS Clavulanic acid Sulbactam Tazobactam Avibactam Relebactam Vaborbactam.

Antimicrobial Mechanism of Action. Cell Wall Synthesis Inhibitors.

 - Lactams: Mechanism. Interfere with cell wall synthesis binding to penicillin- binding proteins (PBPs) located in bacterial cell walls leads to inhibition of final transpeptidation step of peptidoglycan synthesis Number and type of PBPs vary between different bacteria.

β- Lactams:Resistance. Inactivation of the drug by β lactamase enzymes Reduced affinity of penicillin binding proteins for the drug (MRSA, PRSP) Decreased entry of the drug into bacteria through membrane porins Decreased penetration Efflux pumps Removal of drug from cell.

β-Lactams: Spectrum. Primary determinant of its clinical use NARROW spectrum if active against single species or limited group of pathogens (ex: gram +) BROAD spectrum active against wide range of pathogens EXTENDED spectrum intermediate range of activity.

 - Lactamase Enzyme Inhibitors. Inhibit  -lactamase enzymes Clavulanate Sulbactam Tazobactam Avibactam Relebactam vaborbactam.

 - Lactamase Inhibitors. Combo drugs Amoxicillin/Clavulanate (Augmentin ® ): PO Ampicillin/Sulbactam (Unasyn ® ): IV Piperacillin/Tazobactam ( Tazocin ® ): IV Ceftolozane /Tazobactam ( Zerbaxa ® ): IV Ceftazidime/Avibactam ( Zavicefta ® ): IV The inhibitors have no antimicrobial activity themselves…only used as surrogate substrate for the  - lactamase enzymes.

 - Lactamase Enzymes. Only certain bacteria make and secrete  - lactamase enzymes Staphylococci Neiserria gonorrheae H. influenzae E. coli Klebsiella pneumoniae Multiple other gram negative bacteria Bacteroides spp. (anaerobe).

Agents Affecting the Cell Wall: β-lactams: Penicillins.

Natural Penicillins. (Penicillin G, Penicillin VK).

Penicillinase-Resistant Penicillins. (Nafcillin, Dicloxacillin, Oxacillin, Methicillin) Developed to overcome penicillinase production in S. aureus Spectrum Methicillin- susceptible S. aureus Groups A, B, C, G Streptococci Viridans group Streptococci.

Aminopenicillins (Ampicillin, Amoxicillin). Developed to increase activity against gram- negative aerobes Spectrum Gram Positive As with natural penicillins Gram Negative Salmonella spp. Shigella spp. Some E. coli Haemophilus influenzae Proteus mirabilis.

Anti- Pseudomonal Penicillins. Developed to further increase activity against oft- resistant gram-negative aerobes Spectrum Gram Positive As with natural penicillins Gram Negative Salmonella spp., Shigella spp. E. coli, Haemophilus influenzae Enterobacter spp., Pseudomonas aeruginosa Serratia marcescens Klebsiella pneumoniae.

 -Lactamase Inhibitor Combinations. Developed to gain or enhance activity against  - lactamase producing organisms Spectrum Gram Positive S. aureus (similar activity to penicillase-resistant penicillins). NOT MRSA Gram Negative Bacteroides spp. E. coli Klebsiella spp. Proteus spp..

AGENTS AFFECTING THE CELL WALL. ß- LACTAMASE INHIBITORS Clavulanic acid Sulbactam Tazobactam.

Classification and Spectrum of Activity of Cephalosporins.

First Generation Cephalosporins. Best activity against gram-positive aerobes Limited activity against a few gram-negative aerobes No anaerobic activity Gram Positive MSSA PCN-susceptible S. pneumoniae Groups A, B, C, G Streptococci Viridans group Streptococci Gram Negative E. coli Klebsiella pneumoniae Proteus mirabilis.

Second Generation Cephalosporins. In general, slightly less active against gram- positive aerobes, but more active against gram-negative aerobes Several second generation agents have activity against anaerobes.

Second Generation Cephalosporins:. Cefuroxime and Cefoxitin (others) Spectrum Gram Positive MSSA Penicillin-susceptible S. pneumoniae Groups A, B, C, G Streptococci Viridans group Streptococci Gram Negative E. coli Proteus mirabilis Haemophilusinfluenzae Neisseria spp. Moraxella catarrhalis Anaerobes Some activity (cefotetan, cefoxitin) Bacteroides spp. Clostridium spp. (not C. difficile ).

Third Generation Cephalosporins. Spectrum Gram Positive Somewhat disparate coverage Ceftazidime has poor gram-positive coverage Ceftriaxone and cefotaxime are potent against S. pneumoniae Gram Negative As with second generation PLUS Citrobacter, Enterobacter, Acinetobacter, Serratia Pseudomonas Ceftazidime (NOT ceftriaxone or cefotaxime).

Fourth Generation Cephalosporin:. Cefepime 4th generation cephalosporins for 2 reasons: Extended spectrum of activity Gram-positives similar to ceftriaxone Gram-negatives similar to ceftazidime, including Pseudomonas aeruginosa beta-lactamase producing Enterobacter spp. Stability against  - lactamases Weak inducer of extended- spectrum  - lactamases.

Advanced Generation Cephalosporin:. Ceftaroline Ceftobiprole Approved for treatment of acute bacterial skin and soft structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP). Modified 4th generation cephalosporin or New 5th generation cephalosporin , yielding broad activity against gram positives and gram negatives, including those clinically important for CABP pathogens ( S.pneumoniae,S.aureus,S . pyogenes, Haemophilus influenzae, Moraxella catarrhalis) and ABSSSI (S. aureus, S. pyogenes) The first generation with activity against Methicillin-resistant S. aureus (MRSA) Ceftolozane.

Carbapenems Imipenem/cilastin, Meropenem, Ertapenem, and Doripenem.

Agents Affecting the Cell Wall: β- lactams. ß-LACTAM ANTIBIOTICS.

Monobactam: Aztreonam. Aztreonam binds to PBP3 of gram- negative aerobes little to no activity against gram-positives or anaerobes Gram- negative E. coli , K. pneumoniae , P. mirabilis , S. marcescens H. influenzae , M. catarrhalis Enterobacter , Citrobacter , Providencia , Morganella, Salmonella , Shigella Pseudomonas aeruginosa.

AGENTS AFFECTING THE CELL WALL. ß- LACTAMASE INHIBITORS Clavulanic acid Sulbactam Tazobactam.

Vancomycin: Mechanism. Inhibits bacterial cell wall synthesis at a site different than β- lactams Inhibits synthesis and assembly of the second stage of peptidoglycan polymers Binds firmly to D-alanine-D-alanine portion of cell wall precursors – Inhibits addition of peptidoglycan units to growing cell wall Bactericidal (except for Enterococcus).

Vancomycin: Resistance. Modification of D-alanine-D-alanine binding site of peptidoglycan Terminal D-alanine replaced by D- lactate Loss of binding and antibacterial activity 3 phenotypes - vanA, vanB, vanC Primarily been characterized in Enterococcus spp . (VRE).

Vancomycin: Spectrum. Methicillin-Susceptible AND Methicillin- Resistant S. aureus and coagulase-negative staphylococci Streptococcus pneumoniae (including PRSP) Viridans group Streptococci Groups A and B Streptococci Enterococcus spp. Corynebacterium, Bacillus. Listeria, Actinomyces Clostridium sp. (including C. difficile ), Peptococcus,Peptostreptococcus No activity against gram- negative aerobes or anaerobes.

Vancomycin: Pharmacokinetics. Absorption Absorption from GI tract is negligible after oral administration except in patients with intense colitis Use IV therapy for treatment of systemic infection Distribution Widely distributed into body tissues and fluids, including adipose tissue; use TBW for dosing Variable penetration into CSF, even with inflamed meninges Elimination Primarily renal elimination Elimination half- life depends on renal function.

Vancomycin: Adverse Effects. Red- Man Syndrome Flushing, pruritus, erythematous rash on face and upper torso Related to RATE of intravenous infusion; should be infused over at least 60 minutes Resolves spontaneously after discontinuation May lengthen infusion (over 2 to 3 hours) or pretreat with antihistamines in some cases.

Vancomycin. Adverse Effects Nephrotoxicity and Ototoxicity Rare with monotherapy, more common when administered with other nephro- or ototoxins Risk factors include renal impairment, prolonged therapy, high doses, ? high serum concentrations, other toxic meds Dermatologic - rash Hematologic - neutropenia and thrombocytopenia with prolonged therapy Thrombophlebitis.

Telavancin.

Telavancin. Mechanism of Action Like vancomycin (D-ala, D-ala) plus depolarizes bacterial cell membrane Bactericidal Spectrum of Activity Great gram + coverage (including MRSA) NO gram – Concentration Dependent Killing.

Telavancin. Adverse Effects Metallic taste GI Foamy urine Once daily administration BLACK BOX warning Pregnancy- abnormal fetal development.

Daptomycin.

Daptomycin. Daptomycin is a cyclic lipopeptide antibiotic Developed in response to need for agents with activity against resistant gram- positives (MRSA, VRE).

Daptomycin: Mechanism. Causes rapid depolarization of the membrane potential, which causes inhibition of protein, DNA, and RNA synthesis Concentration-dependent bactericidal activity.

Daptomycin: Spectrum. Gram-Positive Bacteria Methicillin- Resistant S. aureus (MRSA) Vancomycin resistant Enterococcus faecium Enterococcus faecalis Gram-Negative Aerobes – relatively inactive.

Daptomycin: Pharmacokinetics. Only available parenterally Distribution: readily distributes into well perfused tissue Protein binding = 90% Elimination: excreted primarily by the kidneys; Half life: 9 hrs (CrCl >80mL/min) 15 hrs (CrCl 30-50 mL/min) 30 hours (CrCl <30 mL/min).

Daptomycin: Adverse Effects. Myopathy and creatine phosphokinase (CPK) elevations Monitor CPK weekly Consider suspending HMG-CoA reductase inhibitor (statins) when receiving daptomycin.

Reviving an old drug COLISTIN.

Colistin. Commercial formulations Colistin sulfate (only used topically due to toxicity) Colistimethate sodium (less toxic, used parenterally) Coly- Mycin M Colomycin.