1. Antibiotic Therapy in the Critically Ill Surgical and Trauma Patient Part I: Penicillins, Cephalosporins, Troleandomicins Justin Chandler, MD 1/5/11

2. Pharmacokinetics Quantifies the course of the drug through the body Goal is effective response with no toxicity –Must understand drug absorption, distribution, and elimination Influence plasma drug concentration Bioavailability - percentage of an administered dose that reaches the circulation Half-life – time required for halving of blood concentration –Function of clearance and volume of distribution Volume of distribution – proportion of drug in plasma compared to body –Derived factor, may be altered by 3 rd space volume, fluid overload, or hypoalbuminemia potentially altering dosing Clearance – refers to volume of liquid from which the drug is removed per unit time (distribution to tissues, metabolism, or elimination)

3. Pharmacodynamics Attempts to quantify the heterogenous responses to drug administration –Drug-patient, drug-microbe, and microbe-patient interactions are found when dealing with antibiotics –Knowledge of how patient characteristics influence absorption, distribution and elimination, along with how the antibiotic interact with the microbe can improve intended response –Microbial pathology, inoculum size, groth phase, resistance, pt milieu (pH, site of infection, immune response) are important factors Pharmacodynamics is a laboratory analysis, and can be difficult to translate to actual pt care In vitro studies include minimal inhibatory concentration (MIC) –Provides useful information about drug levels needed for inhibition of bacterial growth –May miss “subpopulations” of resistance –“Postantibiotic effect” is inhibition of bacterial growth despite non- theraputic blood levels seen with aminoglycosides and β-lactams

4. Penicillin Prototype drug –Discovered by Alexander Fleming in 1928 Group of antibiotics derived from Penicillium fungi –Florey, Chain, and associates made possible the commercial production of penicillin G (by the end of the 1940s) initiating the modern antibiotic era –Classified as β-lactam antibiotics –Are bacteriocidal, and act by inhibiting the synthesis of the peptidoglycan layer of cell walls An important for cell wall structural integrity (esp G+) The final transpeptidation step in the synthesis is facilitated by transpeptidases known as penicillin-binding proteins (PBPs)

5. β-lactams Divided into five classes on the basis of antibacterial activity (considerable overlap) –Natural penicillins Penicillin G and penicillin –Penicillinase-resistant penicillins Methicillin, nafcillin, and isoxazolyl penicillins –Aminopenicillins Ampicillin and amoxicillin –Carboxypenicillins Carbenicillin and ticarcillin –Acyl ureidopenicillins Azlocillin, mezlocillin, and piperacillin Carboxypenicillins and ureidopenicillins are also referred to as antipseudomonal penicillins

6. β-lactams Natural Penicillins –Do not have G- activity –Mostly used for aerobic and anaerobic streptococci, Enterococcus faecalis (but not E faecium), Corynebacterium, Listeria, Neisseria m, Proteus m, Pasturella m, Bacteroides (not B fragilis) and Clostridium (not C diff) Penicillinase-Resistant Penicillins –Useful for strep, C diphtheriae, some staphylococci (resistance: S aureus 60%, S epi 90%, and almost all enterococci) Aminopenicillins –Addition of amino group –Retain G+ and antistreptococcal activity, poor against staph –Effective against E faecalis (including VRE but not E faecium), Neisseria, Moraxella, some E coli and Klebsiella, Salmonella, Shigella, & Proteus and some H influenza Extended-Spectrum Penicillins (carboxypenicillins, acyl ureidopenicillins) –Enhances activity against G- and P aeruginosa –Ureidopenicillins have increased intrinsic activity against Pseudomonas –Effective against S aureus, Listeria m, Salmonella, Proteus, Providentia spp, P multocida, many anerobes (cocci, B fragilis, Bacteroides, Prevotella and Clostridium spp (not C diff) –Pip/taz widest coverage (esp P aeruginosa), Amp/sul poor againt nosocomial pathogens β-lactamase inhibitors (clavulanate, sulbactam, tazobactam) –Have marginilized use of ureidopenicillins

7. Cephalosporins Consist of >40 drugs with a wide variety of activities Split into 5 generations G+ coverage best with 1 st gen and decreases with 2 nd to 4 th gen G- coverage best with 3 rd gen, poor with 1 st gen 4 th gen has antipseudomonal activity and better G+ than 2 nd or 3 rd gen, but poor MRSA coverage 5 th gen has increased MRSA coverage

8. First Generation Strong G+ coverage –Some G- coverage with parenteral route –Used orally as outpt tx –Major role in surgical prophylaxis –Strong action against methacillin sensitive staph (MSSA) and strep Poor at anerobes Some activity againt E Coli, Klebsiella, H influenza, P miriabilis Cefadroxil (Duricef) –Oral (peak serum concentrations 16 and 28 mcg/mL ) Cefazolin (Ancef) –Parenteral Cephalexin (Keflex) –Oral Cephalothin (Keflin) –IV Cephapirin (Cefadyl) –IV Cephradine (Velosef) –Oral & IV

9. Second Generation Of interest to the abdominal surgeon Stronger G- Coverage, still retain some G+ coverage (between 1 st and 3 rd gen) –Retain activity against aerobic and anaerobic strep, lose some effectiveness against MSSA –Effective against N gonorrhea, cefuroxime for N meningitidis –Activity against Enterobacteriaceae except Enterobacter –No activity against Acinetobacer, Pseudomonas, or Stenotrophomonas –All are strong against E Coli & K pneumoniae –Cepamycins and Carbacephems have activity against G- anerobics, including B fragilis Cefaclor (Ceclor, Distaclor, Keflor, Raniclor) –Oral Cefamandole Cefminox –IV Cefonicid –IV Ceforanide –IM, IV Cefotiam –IV,IM Cefprozil (Cefzil) –Oral Cefbuperazone Cefuroxime (Ceftin) –Oral, IV, IM Cefuzonam Cephamycin (Cefoxitin [Mefox], Cefotetan, Cefmetazole) –IV ; IV Carbacephem (Loracarbef) –Oral

10. Third Generation Extremely popular choices for parenteral abx Are relatively resistant to β-lactamases –Have extended spectrum against GNR –Lack activity against G+ (except ceftriaxone) and anaerobes –Effective againt Enterbacteriaceae, (Enterobacter, Citrobacter, Providencia, Morganella), Aeromonas –Variable against Acinetobacter, Pseudomonads, –No activity against S maltophilia –Cefoperazone and ceftazidime useful againt B burgdorferi Have a role in induction of ESBL organisms (esp Enterbacteriaceae) and along with vancomycin, VRE –Because resistance can be transmitted to staphyloccci, GISA and VRSA are emerging Oral –Cefixime (Suprax) –Cefapene –Cefdinir (Omnicef) –Cefditoren (Meiact) –Cefpodoxime –Cefetamet –Cefteram –Ceftibuten (Cedax) Parenteral –Cefotaxime –Ceftazidime (Cefzim, Fortum, Fortaz) –Ceftriaxone (Rocephin) –Cefmenoxime –Cefpiramide –Cefodizime (Cefazone) –Cefoperazone (Kefotex, CEfoTaX, Claforan) –Cefsulodin –Ceftizoxime Oxacephem (Flomoxef, Latamoxef) Cefdaloxime Cefpimizole Ceftiolene

11. Fourth Generation Excellent penetration (brain) Broadest spectrum of activity of any cephalosporins –G- is broader than 3 rd gen with good activity againt Pseudomonads –G+ coverage comparable to 1 st generation –More resistant to hydrolysis by β- lactamase Also less risk of ESBL induction –Little activity for Enterococci or enteric anerobes Cefepime –IV, IM Cefozopran Cefpirome (Cefrom, Keiten, Broact, Cefir)

12. “Fifth” Generation Combines the activity of the 3 rd and 4 th generation cephalosporins Best in vitro activity of any β- lactam agent against CA- MRSA –Designed to bind to and inactivate PBP2a, which confers resistance in MRSA to β-lactam agents Ceftobiprole may be FDA approved, however Ceftaroline is already approved Ceftobiprole –Active against MRSA, penicillin-resistant S pneumoniae, P aeruginosa, and Enterococci –Non-inferior to the combination of vancomycin and ceftazidime for skin and soft tissue infections Ceftaroline –Activity against MRSA and G+ –Retains broad spectrum activity against G- –Being investigated for CAP and complicated skin and soft tissue infection

13. β-lactam Allergy Less common than generally believed (~7-40/1000) 4 distinct types –Immediate hypersenitivity due to preformed IgE Results in uticaria, angioedema, and anaphylaxis –Cytotoxic reactions occur when β-lactam-specific IgG or IgM bind to RBCs or renal intersitiail cells Results in complement dependent cell lysis (hemolysis, purpura) –Immune complex (Arthus) reaction occurs when IgG or IgM complexes fix complement Can lodge in tissue resulting in serum-sickness-like reactions or drug fever Typically occur 1-2 weeks after exposure –Cell-mediated hypersenitivity results from β-lactam specific T-cells causing cytokine release and lymphocyte proliferation Contact dermatitis is the usual manifestation as well as exanthematous reactions and photosenitivity Other reactions include pruritis, maculopapular reactions, erythema multiforme, erythema nodosum, photosenitivity, and exfoliative dermatitis Mechanism involves PCN binding to tissue proteins forming hapten-protein complex –Most common is penicilloyl derivative or major determinant Results in accelerated and late reactions –Minor determinant responsible for anaphylactic reaction Cephalosporins share a 5-10% cross reactivity, with 1 st generation being higher Anaphylaxis will occur in approximately 0.01% of patients

14. Question? What the hell are Troleandomicins? Troleandomycin is a macrolide antibiotic only sold in Italy and Turkey

15. Macrolides, Ketolides Macrolides –FDA approved: Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Ketolides –FDA approved: Telithromycin, Cethromycin Are all characterized by the macrolide ring Mechanism is protein synthesis inhibition by prevention of peptidyltransferase from adding the peptidyl attached to tRNA –Bind reversibly to the P site on the subunit 50S of the bacterial ribosome –Action is mainly bacteriostatic, but can also be bactericidal in high concentrations

16. Macrolides, Ketolides Commonly used in outpt settings for upper respiratory and simple skin infections Used to treat infections caused by G+ bacteria, S pneumoniae, and H influenzae –Does not cover coag (-) staph or MRSA Spectrum is slightly wider than penicillin –Are a common substitute for patients with a penicillin allergy –Also effective against mycoplasma, mycobacteria, some rickettsia, and chlamydia –Clarithryomycin esp useful for H pylori Ketolides have increase activity against resistant organisms Erythromtycin is effectively replaced by the newer generations because of its numerous side-effects, only advantage is cost

17. Non-antibiotic Macrolides Tacrolimus, pimecrolimus and sirolimus –Are used as immunosuppressants or immunomodulators –Have similar activity to cyclosporin

18. Side-effects A combination of macrolides and statins can lead to debilitating myopathy. –Macrolides are potent inhibitors of the cytochrome P450 system, particularly of CYP3A4 Class effect of QT prolongation –Can cause torsade de pointes. Macrolides exhibit enterohepatic recycling –Can lead to a build-up of the drugs

19. Lincosamides Clindamycin only agent that remains in the class Mechanism: binds the 50S ribosome unit Has good G+ and antianaerobic coverage (B fragilis resistance is increasing), but poor G- coverage Used for surgical prophylaxis in PCN allergic pts Has an association with C Diff colitis

20. Streptogramins Seperate class from the other MLS drugs Most contain a macrolide in a binary formulation Of the three, Quinupristin/dalfopristin is the most widely used –While each is only bacteriostatic, the combination is bactericidal activity –Dalfopristin binds to the 23S portion of the 50S ribosomal subunit, and enhances the binding of quinupristin by a factor of about 100 Also inhibits peptidyl transfer –Quinupristin binds nearby on the 50S subunit, preventing elongation polypeptides and causing incomplete chains to be released –Used to treat staphylococci and by vancomycin-resistant Enterococcus faecium (VRE) Pristinamycin –Oral Quinupristin/dalfopristin (Synercid) –IV Virginiamycin –Used for herbivores and to prevent bacterial contamination of fuel

21. Resistance Mechanisms PCNs –Destruction of antibiotic by β-lactamase most common mechanism of resistance (G+) β-Lactamases covalently react with the β-lactam ring, rapidly hydrolyze it, and destroy its activity –Failure of antibiotic to penetrate the outer membrane of G- bacteria to reach PBP targets –Efflux of drug across the outer membrane Most common in G- and P aeruginosa in particular –Reduced or low-affinity binding of antibiotic to target PBPs Result of mutations in PBP genes that lower binding affinity (penicillin-resistant pneumococci or Neisseria spp) Or presence of an extra, low-affinity PBP –PBP 5 produced by Enterococcus faecium –PBP 2a produced by methicillin-resistant staphylococci

22. Resistance Mechanisms Macrolides –The primary means is by a post- transcriptional methylation of the 23S bacterial ribosomal RNA Can be either plasmid-mediated or chromosomal –Two other types of acquired resistance Drug-inactivating enzymes (esterases or kinases) Active ATP-dependent efflux proteins

23. References Long: Principles and Practice of Pediatric Infectious Diseases, 3rd ed., 2008. Asensio: Current Therapy of Trauma and Surgical Critical Care, 2008. Drug Eruptions (http://emedicine.medscape.com/article /1049474-overview)