ANTIBIOTICS LauraLe Dyner MD Pediatric Infectious Disease Fellow March 2009

PREP Question A 14-year-old boy with a h/o CF is admitted with a pulmonary exacerbation. His sputum grows Pseudomonas. What is the most appropriate therapy (+ an aminoglycoside)?  A. Ampicillin  B. Ceftriaxone  C. Cefuroxime  D. Pipericillin  E. Vancomycin

PREP Question A 10-year-old boy with a h/o short gut syndrome has coagulase-negative Staph bacteremia. What is the most appropriate antibiotic therapy?  A. Cephalothin  B. Clindamycin  C. Nafcillin  D. Penicillin G  E. Vancomycin

PREP Question Of the following, the greatest advantage of using a 3 rd generation cephalosporin over an aminoglycoside, is a lower rate of:  A. Hypersensitivity reactions  B. Nephrotoxicity  C. Pseudomembraneous colitis  D. Thrombocytopenia  E. Thrombophlebitis

PREP Question A 2-year-old girl develops meningococcal meningitis. Family members are prescribed rifampin. What medication may be less effective when taking rifampin?  A. Amoxicillin  B. Furosemide  C. Oral contraceptives  D. Ranitidine  E. Salicylates

History of Antibiotics Molds were used in ancient cultures 1880s: Search for antibiotics began after acceptance of the germ theory 1929: The mold penicillium was found to inhibit bacterial growth of Staph aureus 1935: Synthetic antimicrobial were discovered (sulfonamides) 1942: Penicillin G Procaine was manufactured & sold 1940s-1960s: Natural antibiotics (streptomycin, chloramphenicol, tetracycline, etc) were discovered

Classes of Antibiotics Spectrum of Activity  Gram-positives  Gram-negatives  Anaerobes  Atypicals  Mycobacteria Chemical structure Mechanism of Action

Choice of Antibiotics Identify the infecting organism Evaluate drug sensitivity  Antibiotogram  Specific sensitivities of the organism Target the site of infection Drug safety/side effect profile  Selective toxicity: drugs that kill microorganisms but do not affect the host  DRUG INTERACTIONS Patient factors  Age  Genetic or metabolic abnormalities  Renal or hepatic function

Mechanism of Action Bacteria have their own enzymes for:  Cell wall formation  Protein synthesis  DNA replication  RNA synthesis  Synthesis of essential metabolites Antibiotics target these sites

Minimal Inhibitory Concentration (MIC) Lowest concentration of antimicrobial that inhibits the growth of the organism after an 18 to 24 hour incubation period Interpreted in relation to the specific antibiotic and achievable drug levels Can not compare MICs between different antibiotics Discrepancies between in vitro and in vivo

MIC

Time Above MIC Effectiveness of beta-lactams, macrolides, clindamycin, & linezolid is optimal when the concentration of the antibiotics exceeds the MIC of the organism for > 40% of the dosing interval at the site of the infection

Concentration Dependent Killing Effectiveness of fluoroquinolones and aminoglycosides is greatest when peak levels of the drug are high  Peak/MIC ratios of > 8  Supports the idea of daily aminoglycoside dosing

Inhibitors of Cell Wall Synthesis Penicillins  Penicillin G  Aminopenicillins  Penicillinase-resistant  Anti-pseudomonal  Cephalosporins Monobactams Carbapenems Bacitracin Vancomycin Isoniazid Ethambutol

Beta-Lactams

Bactericidal Inhibits synthesis of the mucopeptides in the cell wall of multiplying bacteria Cell wall defects lead to lysis & death

Penicillins Derived from the fungus Penicillum Therapeutic concentrations in most tissues  Poor CSF penetration Renal excretion Side effects  Hypersensitivity (5% cross react with cephalosporins), nephritis, neurotoxicity, platelet dysfunction

Penicillins Structure

Natural Penicillins Active against Strep, some Staph, Enterococcus, Neisseria, Actinomyces, Listeria, Treponema Bacteriocidal Binds to & competitively inhibits the transpeptidase enzyme Cell wall synthesis is arrested Susceptible to penicillinase (beta-lactamase) Side effects: hypersensitivity/anaphylaxis

Aminopenicillins Ampicillin & amoxicillin Effective against Strep, Enterococcus Better penetration through the outer membranes of gram-negative bacteria & better binding to transpeptidase Offer better coverage of gram-negative bacteria  H. influenza, Moraxella, E.coli, Proteus, Salmonella First line therapy for otitis media/sinusitis Still inhibited by penicillinase, therefore less effective against Staph

Aminopenicillins Side effects: rash with mononucleosis infection

Semi-synthetic Penicillins Penicillinase-resistant penicillins Monobactams Carbapenems Extended-spectrum penicillins Penicillins + beta-lactamase inhibitors

Penicillinase-Resistant Penicillins Methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin Gram-positive bacteria, particularly Staph No activity against gram-negatives These are the drugs of choice for Staph aureus when it is resistant to penicillin  Natural penicillins are more efficacious if the organism is penicillin sensitive

Anti-Pseudomonal Penicillins Ureidopenicillins (piperacillin & mezlocillin)  Good gram-positive and gram-negative coverage  Including Pseudomonas & Citrobacter Carboxypenicillins (ticarcillin & carbenicillin)  Less gram-positive coverage & more gram- negative coverage  Pseudomonas, Proteus, E. coli, Enterobacter, Serratia, Salmonella, Shigella Often used with aminoglycosides

Beta-Lactamase Inhibitors Clavulanic acid, sulbactam, tazobactam Enzymes that inhibit beta-lactamase Clavulanic acid irreversibly binds beta-lactamase Given in combination with penicillins  Augmentin = amoxicillin + clavulanic acid  Timentin = timentin + clavulanic acid  Unasyn = ampicillin + sulbactam  Zosyn = piperacillin + tazobactam

Cephalosporins Semisynthetic beta-lactams Beta-lactam ring that is more resistant to beta-lactamase New R-group side chain: leads to drugs with different spectrums of activity  Cover a broad spectrum of gram-positive and negative organisms Cephalosporinases Enterococci and MRSA are resistant to cephalosporins As the generation increases, penetration into the CSF increases Side effects: 5-10% cross-reactivity with penicillins

Cephalosporins Cefazolin Cefuroxime Ceftriaxone Cefepime

Cephalosporin Generations 1 st generation Cefadroxil (Duricef) Cephalexin (Keflex) Cefazolin (Kefzol) 2 nd generation Cefaclor (Ceclor) Cefuroxime (Ceftin) Cefotetan Cefoxitin (Mefoxin) 3 rd Generation Ceftriaxone (Rocephin) Cefotaxime (Claforan) Cefdinir (Omnicef) Cefixime (Suprax) Ceftazidime (Fortaz) 4 th Generation Cefepime (Maxipime)

Cephalosporin Generations 1 st 2 nd 3 rd 4 th  Strep, Staph, E. coli, Klebsiella, Proteus  Surgical ppx  H. influenza, Moraxella, E. coli, Enterobacter, etc  Not as effective against S. aureus as 1 st gen.  Gram negative> gram positive  Ceftriaxone: useful against meningitis  Ceftazidime is active against Pseudomonas  Active against MSSA, Strep, aerobic gram negatives including Pseudomonas  No Enterococcus or anaerobic coverage

Monobactams Aztreonam Beta-lactamase resistant Has the beta-lactam ring with side groups attached to the ring. Narrow spectrum of activity: only binds to the transpeptidase of gram-negative bacteria  Pseudomonas, E.coli, Klebsiella, Proteus  Ineffective against gram-positives & anaerobes Can use in penicillin allergic patients

Carbapenems Meropenem Imipenem Ertapenem Broadest spectrum beta-lactam Activity against gram-negatives, gram-positives, anaerobes  MSSA, Strep, Pseudomonas, Proteus, Klebsiella, Bacteroides Resistance in MRSA, some Pseudomonas, Mycoplasma Imipenem lowers the seizure threshold Side effects: some PCN allergy cross-reactivity

Vancomycin Covers nearly all gram-positive organisms  MRSA, coagulase-negative Staph, Enterococcus, highly resistant Strep pneumo  Leuconostoc resistant Glycopeptide (Streptomyces orientalis) Inhibits synthesis of cell wall phospholipids & prevents cross-linking of peptidoglycans at an earlier step than beta-lactams Also inhibits RNA synthesis Synergy with aminoglycosides

Vancomycin Not absorbed orally! Poor CSF penetration Not the drug of choice for MSSA  Delayed sterilization of blood infections Drug levels  Peak = Toxicity (goal 25-40)  Trough = Efficacy (5-15)  Goal is to achieve drug levels above the MIC Side effects: “red man syndrome”, neutropenia, renal and ototoxicity, phlebitis, fever, chills

Vancomycin

Protein Synthesis Inhibitors Chloramphenicol, clindamycin, macrolides, aminoglycosides, tetracyclines Bacterial cells depend on the continued production of proteins for growth and survival Targets the bacterial ribosome  Bacterial – 70S (50S/30S)  Human – 80S (60S/40S)

Bacterial Ribosome 70S Particle 50S subunit (large)  Chloramphenicol  Lincosamides (Clindamycin)  Oxazolidindones (Linezolid)  Macrolides 30S subunit (small)  Tetracycline  Aminoglycosides

Lincosamides Clindamycin Gram-positive organisms & anaerobes Inhibits protein synthesis by irreversibly binding to the 50S subunit Poor CSF penetration Good PO bioavailability Side effects: C. difficile (pseudomembraneous colitis)

Oxazolidinones Linezolid Broad gram-positive coverage (MRSA & VRE) Prevents the formation of the 70S initiation complex of bacterial protein synthesis by binding to the 50S subunit at the interface with 30S subunit. Bacteriostatic Treatment of gram-positives including VRE & MRSA Good PO bioavailability Side effects: bone marrow suppression, lactic acidosis, headache, GI upset

Macrolides Irreversibly bind the 50S subunit Inhibits peptide bond formation Erythromycin  Gram positives: MSSA, Strep, Bordetella, Treponema  Atypicals: Mycoplasma, Chlamydia, Ureaplasma Clarithromycin  Similar to Erythromycin  Increased activity against gram negatives (H. influenza, Moraxella) Azithromycin  Decreased activity against gram positives  Increased activity against H. influenza & Moraxella

Macrolides Azithromycin structure Side Effects  Oxidized by cytochrome P450 Leads to increased serum concentrations of theophylline, coumadin, digoxin, cyclosporin, etc.  Erythromycin GI symptoms

Tetracyclines Tetracycline, doxycycline Bacteriostatic; Binds the 30S subunit Spirochetes, Mycoplasma, Chlamydia, some gram- positives & gram-negatives Can chelate with milk products, Ca, & Mg Side effects: phototoxic dermatitis, discolored teeth, renal & hepatic toxicity

Aminoglycosides Streptomycin, gentamicin, tobramycin, amikacin Binds to the 30S subunit, disrupting protein synthesis Active against aerobic gram-negative organisms  E. coli, Proteus, Serratia, Klebsiella, Pseudomonas Synergism for gram positive organisms with cell wall inhibitors because it leads to increased permeability of the cell Side effects: CN VIII toxicity (hearing loss, vertigo), renal toxicity, neuromuscular blockade  Patients also on vancomycin are at higher risk of ototoxicity and nephrotoxicity

Aminoglycosides

Concentration dependent due to active transport for uptake Significant post-antibiotic effect Drug levels  Peak = efficacy  Trough = toxicity (<2)

Inhibitors of Metabolism Septra/Bactrim Bacteria must synthesize folate to form cofactors for purines, pyrimidines, and amino acid synthesis Gram-positives (including some MRSA), enteric gram negatives, Pneumocystis jiroveci, H. influenza, Strep pneumo, Stenotrophomonas, Nocardia Sulfomethoxazole & TMP act synergistically Side effects: bone marrow suppression, anemia in those with G6PD deficiency, rashes (photodermatitis; can lead to TEN)

Trimethoprim (TMP) Dihydrofolate reductase inhibitor Mimics dihydrofolate reductase of bacteria & competitively inhibits the reduction of folate into its active form, tetrahydrofolate (TH4) Inhibiting bacterial DNA formation

Sulfonamides Sulfamethoxazole, sulfasoxazole Bacteriostatic Inhibit bacterial folic acid synthesis by competitively inhibiting para amino benzoic acid (PABA) Good penetration including CSF

Inhibitors of Nucleic Acid Synthesis & Function Fluoroquinolones Rifampin

Fluoroquinolones Ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin Synthetic derivative of nalidixic acid Effective against gram positives and negatives, atypicals, Pseudomonas (cipro)  Decreased activity against anaerobes Inhibit DNA gyrase, resulting in permanent DNA cleavage (bacteriocidal) Concentration dependent killing Great PO bioavailability Wide distribution: CSF, saliva, bone/cartilage Side effects: headache, nausea; damage cartilage in animals, Achilles tendonitis & rupture

Fluoroquinolones Ciprofloxacin  Pseudomonas, H. influenza, Moraxella  Resistance in MRSA, Strep pneumo & pyogenes  Ciprofloxacin can inhibit GABA and cause seizures Levofloxacin (Respiratory)  Strep, S. aureus (MRSA), H. influenza, atypicals  Levofloxacin & moxifloxacin have increased Staph coverage, including ciprofloxacin resistant strains  Used for otitis media, sinusitis, & pneumonia

Rifampin Interacts with the bacterial DNA-dependent RNA polymerase, inhibiting RNA synthesis Mycobacterium, gram positives & negatives Treats the carrier state in H. influenza and meningococcus Resistance develops rapidly May induce the cytochrome P450 system

Conclusion Target antibiotic use for the patient and the organism you are treating Know side effect profiles Always check your antibiotic dosing and drug interactions

Questions & Comments

Resources Hayley Gans MD & Kathleen Gutierrez, “Antibiotics Overview” 2006 Prober, Long, & Pickering. Principles & Practice of Pediatric Infectious Disease, 3 rd Edition Centers for Disease Control UpToDate 2007 The 2006 American Academy of Pediatrics Redbook PREP American Academy of Pediatrics Questions