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Antibiotics 101 Puja Van Epps 1/20/14

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Beta-lactams Core PCN structure Core Cephalosporin structure

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Beta-lactams Beta-lactamases are enzymes produced by some bacteria that provide resistance against beta lactams through hydrolysis of the -lactam ring

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Natural Penicillins Bicillin L-A (Penicillin G benzathine) IM only Penicillin G (IV) Penicillin V = PO

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Natural Penicillins- Spectra GroupsImportant Organisms Gram Positive Group A/B/C/G strep S. pneumoniae* viridans streptococci gr.*, Strep milleri* Enterococcus (feacalis>faecium) Gram Negative Neisseria meningitidis* Pasteuralla multocida Haemophilus ducreyi Anaerobes Actinomyces Clostridial sp. Peptostreptococcus Fusobacterium OtherTreponema pallidum

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Natural Penicillins Bicillin: Primary, secondary, latent and late latent syphillis PCN G: Neurosyphillis; systemic infection due to susceptible bacteria (Streptococci) PCN V: Group A strep pharyngitis

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Anti-staphylococcal Penicillins Nafcillin, oxacillin, methicillin, dicloxacillin (PO) Penicillinase is a specific type of -lactamase, showing specificity for Penicillins First -lactamase to be identified; PCN R in S. aureus Major Uses: Methicillin-susceptible S. aureus or Coagulase Negative Staph; PCN-susceptible strains of Streptococci No gram negative activity

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Aminopenicillins Ampicillin/amoxicillin; Augmentin (Amox- Clav); Unasyn (Amp-Sulbactam) Amp/amox Great for susceptible streps and enterococcus; very limited GN activity; cover anaerobes Addition of Clavulanate or Sulbactam enhances Gram negative activity No activity against MSSA without the beta- lactamase inhibitor.

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Aminopenicillins Important holes in coverage Pseudomonas sp. Atypical gram negatives mycoplasma pneumoniae, chlamydia pneumoniae, legionella sp. Enterobacter sp. If susceptible Ampicillin is the DOC for Enterococcus and Listeria

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Anti-Pseudomonal Penicillins Ticarcillin, Ticar-Clav, Piperacillin, Pip-Tazo Generally good gram positive, gram negative and anaerobic coverage Ticarcillin and Piperacillin without their beta-lactamase inhibitor DO NOT cover MSSA Important holes in coverage: MRSA (ESBL+, KPC+, or other resistant GN) Stenotrophomonas maltophilia Ticar-Clav is second line, Pip/Tazo does not cover.

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Cephalosporins 5 generations, increasing gram negative coverage with each generation

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First Generation Cephalosporins Cefadroxil, Cephalexin (PO) Cefazolin (IV) Gram Positive Group A, B, C, G Strep Strep pneumo Viridans strep MSSA Gram Negative E. coli, Klebsiella sp., Proteus mirabilis AnaerobesNo activity

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First Generation Cephalosporins Important holes in coverage MRSA, Enterococcus, Pseudomonas, anerobes

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Second Generation Cephalosporins Cefuroxime (IV, PO), Cefotetan (IV), Cefoxitin (IV) In addition to the coverage of 1 st generation - H. influenzae, M. catarrhalis, Neisseria sp., and anearobic coverage (variable) Important holes in coverage: - MRSA, Enterococcus, Pseudomonas

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Third Generation Cephalosporins Ceftriaxone, Cefotaxime, Ceftazadime (IV) Cefixime, Cefdinir (PO) In general less active against gram-positive aerobes than previous generations, but have greater activity against gram- negatives Cefotaxime and Ceftriaxone have the best gram + coverage in the group Only Ceftazadime covers Pseudomonas

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Third Generation Cephalosporins Major holes in coverage - Enterococcus, MRSA, Pseudomonas (except Ceftazidime), +/- Acinetobacter, Listeria Ceftazidime crosses BBB, Ceftriaxone in inflamed meninges

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Fourth Generation Cephalosporins Cefepime (IV) gram-positives: similar to first generation gram-negatives: broad, including Pseudomonas Major holes: MRSA, poor anaerobic coverage, listeria Crosses BBB

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Fifth Generation Cephalosporin Ceftaroline (IV) Major advantage: - MRSA Major holes in coverage: - Pseudomonas, enterococcus and anaerobes CAP, SSTI

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Cephalosporin Review Antipseudomonal Ceftazadime and Cefepime Anti-MRSA Ceftaroline Anti-Enterococcal None (Ceftaroline has in-vitro activity against E. faecalis) Enterobacter sp. can develop resistance to cephalosporins during treatment, therefore not the treatment of choice

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Carbapenems Ertapenem, Doripenem, Imipenem, Meropenem Broadest spectrum of activity Have activity against gram-positive and gram- negative aerobes and anaerobes Bacteria not covered by carbapenems include MRSA, VRE, MR coagulase-negative staph Additional ertapenem exceptions: Pseudomonas, Acinetobacter, Enterococcus

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Carbapenems Major holes in coverage: - Atypicals (Legionella, Mycoplasma), MRSA, VRE, Stenotrophomonas maltophilia, KPC+ Ertapenem does not cover: - Pseudomonas, Acinetobacter, Enterococcus

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Monobactam Aztreonam: binds preferentially to PBP 3 of gram-negative aerobes No gram positive or anaerobic activity Major uses Hospital acquired infections in patients with anaphylaxis to any beta lactams (does not have cross reactivity) Important gram neg holes: Acinetobacter, ESBL+, KPC+

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Fluoroquinolones Ciprofloxacin, Levofloxacin, Moxifloxacin Broad spectrum of activity, excellent bioavailability, tissue penetration Cipro has poor gram + coverage Disadvantages: resistance, expense, C diff Advantages: Atypical coverage, Antipseudomonal (Cipro, Levo)

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Aminoglycosides Gentamicin, Tobramycin, Amikacin inhibit protein synthesis by irreversibly binding to 30S ribosome, bactericidal For gram + use in combination with cell wall agents Broad spectrum gram neg coverage including Pseudomonas and Acinetobacter Also have mycobacterial coverage

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Aminoglycosides adverse effects Nephrotoxicity Nonoligouric renal failure from damage to the proximal tubules Underlying CKD, Age, other nephrotixins, duration, high troughs Ototoxicity 8th cranial nerve damage - vestibular and auditory toxicity; irreversible Related to duration of therapy (>2wks)

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Macrolides Clarithromycin, Erythromycin, Azithromycin Inhibit protein synthesis by reversibly binding to the 50s ribosomal unit

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Macrolides Gram-Positive Aerobes Clarithro>Erythro>Azithro Gram-Negative Aerobes Azithro>Clarithro>Erythro No activity against any Enterobacteriaceae or Pseudomonas Anaerobes activity against upper airway anaerobes Atypical Bacteria Excellent Also cover Mycobacterium avium complex, Campylobacter, Borrelia, Bordetella, Brucella.

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Anti-MRSA drugs

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Vancomycin Inhibits synthesis and assembly of the second stage of peptidoglycan polymers Gram-positive bacteria: excellent coverage Major uses: MRSA, MSSA (in PCN all), PCN R streptococci No activity against gram-negatives or anaerobes If MIC to Vancomycin in MRSA is 2, Do not use

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Vancomycin Red-Man Syndrome flushing, pruritus, rash related to rate of infusion resolves spontaneously may lengthen infusion NOT AN ALLERGY

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Daptomycin Lipopeptide; binds to components of the cell membrane and causes rapid depolarization, inhibiting intracellular synthesis of DNA, RNA, and protein Major uses - SAB, Right-sided IE caused by S. aureus, VRE Indicated for SSTI, R sided IE Do not use for lung infections including MRSA PNA pulmonary surfactant inhibits Daptomycin

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Linezolid Binds to the 50S ribosomal subunit near the surface interface of 30S subunit causes inhibition of 70S initiation complex which inhibits protein synthesis Active against wide range of Gram + bacteria, limited to no Gram negative or anearobic activity Major uses MRSA, VRE. Major problem thrombocytopenia with prolonged use (>2wks), bacteriostatic (cidal against Enterococcus)

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Tigecyline Binds to the 30S ribosomal subunit of susceptible bacteria, inhibiting protein synthesis. Broad spectrum of activity including - MRSA, VRE, gram negatives (including resistant GN) Major holes- The 3 Ps Pseudomonas, Proteus and doesnt get in the urine Indicated for complicated SSTI, intra-abdominal infections, CAP Major problems: GI issues, and shown to have increased mortality in serious infections monotherapy only as a last resort.

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Clindamycin Inhibits protein synthesis by binding exclusively to the 50S ribosomal subunit Major uses - MRSA (some isolates), anaerobic coverage

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Clindamycin A positive D test indicates the presence of macrolide-inducible resistance to clindamycin produced by an inducible methylase that alters the common ribosomal binding site for macrolides, clindamycin

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Tetracylines Doxycyline, Minocyline Good gram pos, neg and anaerobic coverage Major uses MRSA, anti-malarial prophylaxis, rickettsial infections, Borrelia bu