LauraLe Dyner MD
Pediatric Infectious Disease Fellow
March 2009

 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)?
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A. Ampicillin
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B. Ceftriaxone
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C. Cefuroxime
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D. Pipericillin
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E. Vancomycin

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

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

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

 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)
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1942: Penicillin G Procaine was manufactured & sold
1940s-1960s: Natural antibiotics (streptomycin, chloramphenicol, tetracycline, etc) were discovered

 Spectrum of Activity
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Gram-positives
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Gram-negatives
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Anaerobes
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Atypicals
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Mycobacteria
 Chemical structure
 Mechanism of Action

1955
1962
1985
1940
2000
1962
1947
1959
1990
1955
1950
1948
1944
1963

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

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

 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

 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

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

 Penicillins
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Penicillin G
Aminopenicillins
Penicillinase-resistant
Anti-pseudomonal
Cephalosporins
 Monobactams
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Carbapenems
Bacitracin
Vancomycin
Isoniazid
Ethambutol

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

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

 Structure

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

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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
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H. influenza, Moraxella, E.coli, Proteus, Salmonella
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First line therapy for otitis media/sinusitis
Still inhibited by penicillinase, therefore less effective against Staph

 Side effects: rash with mononucleosis infection

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

 Methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin
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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
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Natural penicillins are more efficacious if the organism is penicillin sensitive

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

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

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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
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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

 Cefazolin  Ceftriaxone
 Cefuroxime  Cefepime

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

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

 Aztreonam
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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
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Pseudomonas, E.coli, Klebsiella, Proteus
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Ineffective against gram-positives & anaerobes
Can use in penicillin allergic patients

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

 Covers nearly all gram-positive organisms
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MRSA , coagulase-negative Staph, Enterococcus, highly resistant Strep pneumo
Leuconostoc resistant
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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

 Not absorbed orally!
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Poor CSF penetration
Not the drug of choice for MSSA
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Delayed sterilization of blood infections
Drug levels
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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

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

 50S subunit (large)
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Chloramphenicol
Lincosamides
(Clindamycin)
Oxazolidindones
(Linezolid)
Macrolides
 30S subunit (small)
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Tetracycline
Aminoglycosides

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

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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

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

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

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

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Streptomycin, gentamicin, tobramycin, amikacin
Binds to the 30S subunit, disrupting protein synthesis
Active against aerobic gram-negative organisms
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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

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

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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
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Sulfomethoxazole & TMP act synergistically
Side effects: bone marrow suppression, anemia in those with G6PD deficiency, rashes
(photodermatitis; can lead to TEN)

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

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

 Fluoroquinolones
 Rifampin

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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

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

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

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

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Hayley Gans MD & Kathleen Gutierrez, “Antibiotics
Overview” 2006
Prober, Long, & Pickering. Principles & Practice of
Pediatric Infectious Disease, 3 rd Edition
Centers for Disease Control
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UpToDate 2007
The 2006 American Academy of Pediatrics Redbook
PREP American Academy of Pediatrics Questions
1999-2006