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ANTIBIOTICS
LauraLe Dyner MD
Pediatric Infectious Disease Fellow
March 2009
PREP Question
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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
B. Ceftriaxone
C. Cefuroxime
D. Pipericillin
E. Vancomycin
PREP Question
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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
B. Clindamycin
C. Nafcillin
D. Penicillin G
E. Vancomycin
PREP Question
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Of the following, the greatest advantage of
using a 3rd generation cephalosporin over an
aminoglycoside, is a lower rate of:
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A. Hypersensitivity reactions
B. Nephrotoxicity
C. Pseudomembraneous colitis
D. Thrombocytopenia
E. Thrombophlebitis
PREP Question
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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
C. Oral contraceptives
D. Ranitidine
E. Salicylates
History of Antibiotics
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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
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Spectrum of Activity
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Gram-positives
Gram-negatives
Anaerobes
Atypicals
Mycobacteria
Chemical structure
Mechanism of Action
1955
1962
1985
1940
1990
2000
1959
1950
1962
1955
1948
1944
1947
1963
Choice of Antibiotics
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Identify the infecting organism
Evaluate drug sensitivity
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Target the site of infection
Drug safety/side effect profile
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Antibiotogram
Specific sensitivities of the organism
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
Renal or hepatic function
Mechanism of Action
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Bacteria have their own enzymes for:
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Cell wall formation
Protein synthesis
DNA replication
RNA synthesis
Synthesis of essential metabolites
Antibiotics target these sites
Minimal Inhibitory Concentration
(MIC)
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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
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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
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Effectiveness of fluoroquinolones and
aminoglycosides is greatest when peak levels
of the drug are high
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Peak/MIC ratios of > 8
Supports the idea of daily aminoglycoside dosing
Inhibitors of Cell Wall Synthesis
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Penicillins
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Penicillin G
Aminopenicillins
Penicillinase-resistant
Anti-pseudomonal
Cephalosporins
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Monobactams
Carbapenems
Bacitracin
Vancomycin
Isoniazid
Ethambutol
Beta-Lactams
Beta-Lactams
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Bactericidal
Inhibits synthesis of
the mucopeptides
in the cell wall of
multiplying bacteria
Cell wall defects
lead to lysis &
death
Penicillins
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Derived from the fungus Penicillum
Therapeutic concentrations in most tissues
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Poor CSF penetration
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Renal excretion
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Side effects
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Hypersensitivity (5% cross react with
cephalosporins), nephritis, neurotoxicity, platelet
dysfunction
Penicillins
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Structure
Natural Penicillins
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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
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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
First line therapy for otitis media/sinusitis
Still inhibited by penicillinase, therefore less effective
against Staph
Aminopenicillins
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Side effects: rash with mononucleosis
infection
Semi-synthetic Penicillins
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Penicillinase-resistant penicillins
Monobactams
Carbapenems
Extended-spectrum penicillins
Penicillins + beta-lactamase inhibitors
Penicillinase-Resistant Penicillins
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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
Anti-Pseudomonal Penicillins
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Ureidopenicillins (piperacillin & mezlocillin)
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Carboxypenicillins (ticarcillin & carbenicillin)
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Good gram-positive and gram-negative coverage
Including Pseudomonas & Citrobacter
Less gram-positive coverage & more gramnegative coverage
Pseudomonas, Proteus, E. coli, Enterobacter,
Serratia, Salmonella, Shigella
Often used with aminoglycosides
Beta-Lactamase Inhibitors
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Clavulanic acid, sulbactam, tazobactam
Enzymes that inhibit beta-lactamase
Clavulanic acid irreversibly binds beta-lactamase
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Given in combination with penicillins
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Augmentin = amoxicillin + clavulanic acid
Timentin = timentin + clavulanic acid
Unasyn = ampicillin + sulbactam
Zosyn = piperacillin + tazobactam
Cephalosporins
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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
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
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Cefazolin
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Ceftriaxone
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Cefuroxime
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Cefepime
Cephalosporin Generations
1st generation
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Cefadroxil (Duricef)
Cephalexin (Keflex)
Cefazolin (Kefzol)
2nd generation
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3rd Generation
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Ceftriaxone (Rocephin)
Cefotaxime (Claforan)
Cefdinir (Omnicef)
Cefixime (Suprax)
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Ceftazidime (Fortaz)
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Cefaclor (Ceclor)
Cefuroxime (Ceftin)
Cefotetan
Cefoxitin (Mefoxin)
4th Generation
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Cefepime (Maxipime)
Cephalosporin Generations
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1st
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2nd 
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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
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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
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Pseudomonas, E.coli, Klebsiella, Proteus
Ineffective against gram-positives & anaerobes
Can use in penicillin allergic patients
Carbapenems
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Meropenem
Imipenem
Ertapenem
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
Vancomycin
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Covers nearly all gram-positive organisms
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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
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Not absorbed orally!
Poor CSF penetration
Not the drug of choice for MSSA
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Drug levels
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Delayed sterilization of blood infections
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
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Chloramphenicol, clindamycin, macrolides,
aminoglycosides, tetracyclines
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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)
Bacterial Ribosome 70S Particle
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50S subunit (large)
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Chloramphenicol
Lincosamides
(Clindamycin)
Oxazolidindones
(Linezolid)
Macrolides
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30S subunit (small)
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Tetracycline
Aminoglycosides
Lincosamides
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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
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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
Macrolides
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Irreversibly bind the 50S subunit
Inhibits peptide bond formation
Erythromycin
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Clarithromycin
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Gram positives: MSSA, Strep, Bordetella, Treponema
Atypicals: Mycoplasma, Chlamydia, Ureaplasma
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
Macrolides
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Azithromycin structure
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Side Effects
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Oxidized by cytochrome P450
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Leads to increased serum concentrations of
theophylline, coumadin, digoxin, cyclosporin, etc.
Erythromycin
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GI symptoms
Tetracyclines
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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
Aminoglycosides
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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
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Synergism for gram positive organisms with cell wall
inhibitors because it leads to increased permeability
of the cell
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Side effects: CN VIII toxicity (hearing loss, vertigo),
renal toxicity, neuromuscular blockade
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Patients also on vancomycin are at higher risk of ototoxicity
and nephrotoxicity
Aminoglycosides
Aminoglycosides
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Concentration dependent due to active
transport for uptake
Significant post-antibiotic effect
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Drug levels
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Peak = efficacy
Trough = toxicity (<2)
Inhibitors of Metabolism
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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
Sulfomethoxazole & TMP act synergistically
Side effects: bone marrow suppression, anemia in
those with G6PD deficiency, rashes
(photodermatitis; can lead to TEN)
Trimethoprim (TMP)
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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
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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
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Fluoroquinolones
Rifampin
Fluoroquinolones
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Ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin
Synthetic derivative of nalidixic acid
Effective against gram positives and negatives,
atypicals, Pseudomonas (cipro)
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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
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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
Rifampin
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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
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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
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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