ANTIBIOTICSLauraLe Dyner MD

Pediatric Infectious Disease FellowMarch 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 3rd 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

Microbial Sources

of Antibiotics

Classes of Antibiotics

Spectrum of Activity Gram-positives Gram-negatives Anaerobes Atypicals Mycobacteria

Chemical structure Mechanism of Action

1944

1948

1947

1950

1955

1955

1959

1962

1962

1963

20001985

19901940

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

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

1st generation Cefadroxil (Duricef) Cephalexin (Keflex) Cefazolin (Kefzol)

2nd generation Cefaclor (Ceclor) Cefuroxime (Ceftin)

Cefotetan Cefoxitin (Mefoxin)

3rd Generation Ceftriaxone (Rocephin) Cefotaxime (Claforan) Cefdinir (Omnicef) Cefixime (Suprax)

Ceftazidime (Fortaz)

4th Generation Cefepime (Maxipime)

Cephalosporin Generations 1st

2nd

3rd

4th

Strep, Staph, E. coli, Klebsiella, Proteus Surgical ppx

H. influenza, Moraxella, E. coli, Enterobacter, etc Not as effective against S. aureus as 1st 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

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, 3rd Edition

Centers for Disease Control UpToDate 2007 The 2006 American Academy of Pediatrics Redbook PREP American Academy of Pediatrics Questions

1999-2006