Hayley Gans, MD

Kathleen Gutierrez, MD
Roshni Mathew, MD
Last Updated: January, 2013
Resident Selective

Antibiotic Overview

MIC (Minimal Inhibitory Concentration): The lowest concentration of antimicrobial that inhibits the
growth of the organism after an 18-24 hour incubation period.

MBC (Minimal Bactericidal Concentration): The lowest concentration of antimicrobial that results in
99.9% kill of the organism (determined by sub-culturing the “no-growth” cells).

Tolerance: Ability of the organism to survive the killing action of the antimicrobial MBC > 32 times the
MIC.

Bactericidal: In vitro killing of the organism by the antimicrobial.

Basteriostatic: In vitro inhibition of the organism by the antimicrobial.

“Time above MIC”: Effectiveness of b-lactams, macrolides, clindamycin and linezolid is optimal when
concentration of antibiotics exceeds the MIC of the organism for a long time (40% of dosing interval or
more) at the site of infection.

“Concentration dependent killing”: Effectiveness of fluouoquinolones and aminoglycosides is greatest

when peak levels of the drug are high (Peak/MIC ratios of 8 or more). Lends support to qday
aminoglycoside dosing.

Factors to consider when choosing an antibiotic (examples of why careful consideration should be given
any time antibiotic therapy is initiated – NOT comprehensive):

Host Factors:

A. Age:

Gastric Acidity: pH of gastric secretions is higher in young children (< 3 years and in the elderly.
Absorption of penicillin drugs is enhanced by higher pH (less acidity).

Renal Function: Relatively diminished in newborn children (reason for extended dosing intervals)
– reaches adult levels between 2 and 12 months of age.

Hepatic Function: Is underdeveloped in neonate – When neonates are given chloramphenicol,

high levels of unconjugated chloramphenicol (due to insufficient levels of glucuronyl transferase
in the neonate) accumulate and are toxic, leading to so-called gray baby syndrome. Some drugs
(e.g., isoniazid) are tolerated better in younger patients.
 B. Genetic or Metabolic Abnormalities:

Isoniazid acetylation in the liver is determined genetically. Asians are more often rapid
acetylators and U.S. and northern European patients are more often slow acetylators. Isoniazid
polyneuritis may be seen more frequently in slow acetylators compared to rapid acetylators.

C. Renal Function:

Patients with renal failure who develop excessive levels of penicillin G or imipnem may develop
significant CNS abnormalities, seizures, coma. Excessive serum levels of semisynthetic
penicillins or cephalothin may cause hemostatic defects in platelets. Tetracyclines may produce a
worsening of uremia because of their anti-anabolic effects. Aminoglycosides and vancomycin
are associated with eighth nerve damage. 5FC should be given with extreme caution in patients
with renal dysfunction and levels monitored carefully.

D. Hepatic Function:

Use the following drugs cautiously in patients with impaired liver function: erthomycin,
azithromycin, chloramphenicol, clindamycin, metroniadazole, tetracyclines, rifampin, isoniazid
and antifungals azoles.

E. Site of Infection: The concentration of the antimicrobial at the site of infection must be AT
LEAST equal to the MIC of the organism. In some cases, sub-inhibitory concentrations of drug
are enough to alter the characteristics of the infecting organism and enable bacterial killing by the
host immune system. Factors that determine efficacy include the ability of antibiotics to pass
through the lipid membranes, extent of protein binding (only unbound antibiotic is effective,
intra-cellular and tissue concentration. Except in neonates, none of the aminoglycosides produce
effective CSF levels when given parenterally. Third and fourth generation (cefepime)
cephalosporins penetrate the blood brain barrier reasonably well. Penicillins penetrate less well
and high parenteral doses must be given. First generation cephalosporins should not be used for
CNS infections. Penetration of antibiotics into clot (vegetations), necrotic and abscessed tissue is
poor. Abscesses must be drained, devitalized tissue debrided and foreign bodies removed.

F. Combination Therapy: Combinations of antibiotics may be either 1) indifferent 2) synergistic, or

3) antagonistic. Examples of theoretically antagonistic combinations of antibiotics include:
gentamicin plus chloramphenicol, P-lactam! P-lactam combinations.

Combinations are used to: 1) prevent resistance and are only clearly effective when resistance is
due to a chromosomal mutation 2) To treat polymicrobial infections 3) As initial empiric therapy
4) To decrease toxicity, and 5) for synergy (penicillin and aminoglycoside for treatment of
endocarditis).

G. Cost: Newer drugs (e.g., linezolid) are very expensive.

H. Adverse Effects

I. Route of Administration:
 
Good bioavailability: trimethoprim sulfamethoxazole, clindamycin, metronidazole,
fluoroquinolones, linezolid.
 Fair bioavailability: penicillins, and lactams, for serious infections dose can often be
increased substantially, with close monitoring for drug associated adverse effects (bone
marrow suppression, hepatitis)
Bad bioavailability: vancomycin, aminoglycosides, amphotericin

J. Drug Interactions: ALWAYS check.

I. Cell Wall Inhibitors

A. -lactams:

General:

Bactericidal
Inhibit synthesis of the mucopeptides in the cell wall (terminal step) of
multiplying bacteria. Cell wall defects cause lysis and killing of the bacteria.
Activity dependent on binding to PBP
Dose dependent: Effective cure if concentration at target is 10x above the
MIC for 40% of the dosing interval
50-90% bioavailable

Resistance

-lactamase production deactivates the -lactam ring of the antibiotic by

splitting the amide bond of the lactam ring
- Encoded by chromosomal or transferable (plasmids, transposons) genes
- 4 evolutionarily distinct molecular classes
1. Class A (Bush groups 2a-2f, >100 enzymes)
Preferentially hydrolyze penicillins
e.g. TEM 1
ESBLs are in this category, confer R to ceph 3 and
aztreonam
2. Class B (Bush group 3, 15 enzymes)
Metalloenzymes, zinc binding thiol group
3. Class C (Bush group 1, 57 enzymes)
Determined by chromosomal amp C gene
Mainly cephalosporinase activity
May have evolved from PBPs
4. Class D (Bush group 2d, approximately 20 enzymes)
Oxacillin hydrolyzing
-lactamases are further divided into BUSH Functional Groups 1, 2a-2f, 3 and 4.

Methicillin resistance of S. aureus and S. pneumoniae resistance is through

decreased affinity to the penicillin binding protein (PBP).
Tolerance: Bacteria suppress enzymes used for the autolysis when the cell
wall is defective. Inhibited growth but no death of the bacteria.
 SPACE organisms (Serratia sp, Pseudomonas sp, Acinetobacter sp,
Citrobacter sp., Enterobacter sp.) inducible B-lactamase production while on
treatment, double cover (beta lactam/AG) for serious infections. It is not clear
if “double coverage” is needed when carbapenem or cefepime is used.

1. Penicillins:
Natural:
Penicillin: Spectrum of Activity
Streptococci: Lancefield groups A, group B, C and G, viridans streptococci,
pneumococcus, enterococcus, Neisseria sp., respiratory anaerobes (except
Bacteroides fragilis), Bacillus anthracis, Pasturella multocida, Streptobacillus
moniliformis (rat bit fever), Actinomyces israeli, leptospira, Clostridium sp.,
penicillin susceptible S. aureus (drug of choice for this organism)
Aminopenicillins: ampicillin, amoxicillin
More active against gram negatives, E. coli, Proteus sp, Salmonella sp, Shigella
sp, H. influenzae
Carboxypenicillins: Ticarcillin
Less gram positive, but increased gram negative coverage, including
Pseudomonas sp, E.coli, Proteus mirabilis and vulgaris, Enterobacter sp., Serratia
sp, Salmonella sp, Shigella sp.
Ureidopenicillin: Piperacillin:
Good gram positive and gram negative coverage, including Pseudomonas sp, and
all of the same as carboxypenicillin group as will Citobacter sp.

Semisynthetic:
Naficillin, oxicillin, dicloxicillin, methicillin
Resistant to penicillinases ( -lactamases) with improved activity against
Staphlococcus aureus. No activity against gram negative bacteria since drug
cannot reach PBP target sites. Less active against the streptococcus. group than
penicillin.

2. Cephalosporins
General

As generation increases penetration into CSF increases.

First generation:
Mostly gram positive activity against Staphlococcus aureus and streptococcus. Some
activity against gram negative bacteria, such as Neisseria sp, E. coli, Klebsiella sp.,
Proteus sp., Kingella kingae.
 Second generation:
Higher MIC to gram positive bacteria and more activity against gram negative organisms.
Third generation:
Greater B-lactamase stability and increased activity against gram negative bacteria.
Fourth generation:
Cefepime more resistant to beta lactamases activity compared to ceph 3rd. Has better S.
aureus coverage that ceph 3rd. No anaerobic or enterococcus coverage.

*Table 1:
1st Generation 2nd Generation 3rd Generation 4th Generation
_____________________________________________________________________________
_
Oral Cefadroxil Cefaclor Cefdinir
Duracef Ceclor Omnicef
Cephalexin Cefprozil Cefpodoxime
Keflex Cefzil Vantin
Cephradine Cefuroxime axetil
Anspor Ceftin
Loracarbef
Lorabid
_____________________________________________________________________________
_
Parenteral Cefazolin Cefamandole Cefoperazone Cefepime
Ancef Mandol Cefobid Maxipime
Cephalothin Cefuroxime Cefotaxime
Keflin Zinacef Claforan
Cephapirin Ceftizoxime
Cefadryl Cefizox
Cephamycins Ceftriaxone
Cefotetan Rocephin
Cefotan Ceftazidime
Cefoxitin Fortaz
Mefoxin

______________________________________________________________________________
* The brand name of each drug is listed below it in italics.
B. Vancomycin

General
Glycopeptide antibiotic

Bactericidal against multiplying gram positive bacteria except enterococcus where

MBCs are >32x the MIC
 NOT THE DRUG OF CHOICE to treat MSSA- delayed sterilization of blood
compared to nafcillin or oxacillin
Inhibition of second step of cell wall synthesis of gram positive organisms
Inhibition of the cell membrane
Also inhibits RNA synthesis
Renal excretion unaltered
Poor CSF penetration
Ototoxicity: poor association, if it exists, it is dose dependent
Nephrotoxicity: poor association with decrease in reports since increased purity,
dose dependent
“Red man syndrome”: dose related with rapid infusions, systemic release of
histamine
Neutropenia has been reported in up to 13% of patients receiving drug for more
than 2 weeks.

Resistance
Abnormal pentapeptide production encoded by Van A gene or transposon

Activity
Gram positive bacteria, including susceptible S. aureus, coagulase negative
staphylococcus, Enterococcus sp., streptococci, listeria (but strains with high
MBCs are reported-not drug of choice), Corynebacterium spp, Rhodococcus sp.,
most Clostridium spp.

C. Carbapenems
General
 Inhibition of cell wall synthesis
 Activity dependent on binding to PBP-2
 Meropenem penetrates into CSF

Resistance
 Production of carbapenemase enzymes
 Alteration in PBP binding for gram positive bacteria

Imipenem, Meropenem
Activity
Broad gram positive and gram negative coverage, marginal enterococcus
coverage, listeria (not drug of choice), anaerobes. Imipenem and meropenem
susceptibilities are not always equivalent.

II. Protein synthesis inhibitors

A. Aminoglycosides
 General
Bactericidal by binding irreversibly to 30S RNA ribosomal subunit and disrupting
protein synthesis,
Concentration dependent due to active transport for uptake: total dose is important
Post-antibiotic effect
Does not penetrate blood brain barrier or cardiac tissue well
Renal excretion and uptake in the proximal tubules may cause nephrotoxicity
Ototoxicity secondary to cochlear damage
Narrow therapeutic and safety range: need for drug monitoring
Resistance
Decreased affinity at the RNA binding site
Some organisms (such as anaerobic organisms) do not have active transport
mechanisms (most important for amikacin)
Catalyzing enzymes that adenylate, phosphorylate, and acetylate (gentamicin least
stable, amikacin most stable against these enzymes)
Streptomycin, gentamicin, tobramycin, amikacin
Active against gram negative organisms, and some synergy when used with B-lactams
for gram positive bacteria. Amikacin and streptomycin have activity against
Mycobacterium sp.

B. Macrolides
General
Bind 50s ribosomal subunit: inhibits peptide bond formation
Metabolized by P450 cytochrome system in liver: drug interactions
(azithromycin less likely to have cytochrome P450 mediated drug
interactions)
Excreted in bile/stool
Do not penetrate blood brain barrier well

Resistance
Altered binding at ribsomal subunit
Active drug efflux
Bacterial esterases may hydrolyze the ring

Erythromycin, clarithomycin, azithromycin)

Gm. pos. (group A, B strep.) including B-lactamase producing S. aureus,
some gm. neg. H.influ/Neisseria, Bordetella pertussis, h. ducreyi,
oropharynx anaerobes, camplobacter jejuni, mycoplasma, chlaymdia,
legionella, ureaplasma, atypical mycobacterium,

C. Tetracyclines

General
 Bacteriostatic
Inhibit protein synthesis by binding the 30s subunit of the bacterial ribosome
Dental and skeletal abnormalities

Resistance
Decreased uptake, increased efflux
Chromosomally or plasmid derived, inducible

Tetracycline, doxycycline, minocycline

Gram positive cocci and bacilli, gram neg. diplococci, and some bacilli,
Mycoplasma sp, Chlamydia sp, spirochetes (Rickettsia, tularemia, Borrelia),
atypical mycobacteria, Borrelia,

D. Lincosamides
General:
Bind 50s ribosomal subunit
Very bioavailable with good tissue penetration (lungs, bones, abscess)
Poor CNS penetration (i.e. can’t use to treat meningitis/brain absess)
Liver elimination with renal excretion
Resistance
Similar to the macrolides, resistance to erythromycin predicts subsequent
resistance to clindamycin
Clindamycin
Gram positive (staph./strep.) some non-penicillin sensitive streptococcus ,
anaerobes, toxoplasmosis

III. Miscellaneous
A. Sulfonamides

General
Bacteriostatic
Inhibit bacterial folic acid synthesis by competitively inhibiting PABA
bacterial synthesis into folic acid.
Bioavailable Good penetration into body fluids including CSF
Metabolized in liver, and excreted by kidney
Resistance
Alterations in enzymatic processes of the cell wall to develop alternate
pathways for the synthesis of folic acid
Trimethoprim-sulamethoxazole
Drugs combined to have synergy for bactericidal effects for most susceptible
organisms by inhibiting subsequent steps in the in bacterial folate synthesis
 Gram positive and enteric gram negative bacteria, Shigella sp, Vibrio cholera,
Isospora belli, Cyclospora, Pneumocystis sp, Serratia sp, Nocardia sp, Brucella sp.
NO activity against some S. pyogenes (GABHS), Pseudomonas sp., enterococci,
Bacteroides sp., Mycoplasa sp, Treponema pallidum
B. Quinolones
General
Inhibit topoisomerase (DNA-gyrase) resulting in altered DNA supercoiling
and unraveling and thus increased DNA replication
Concentration dependent killing
Bioavailable
Good tissue penetration
Arthropathy due to cartilage toxicities, may be used judiciously in pediatric
patients, usually with ID service involvement.
Resistance
Mutation in DNA gyrase
Decreased uptake in OMPs
Ciprofloxicin, levofloxicin
Gram negative enterics, including Pseudomonas sp, Chlamydia sp, Mycoplasma
sp, Legionella sp, Neisseria sp, Bartonella, atypical mycobacterium
New fluoroquinolones have increased gram positive activity

C. Oxazolidindones
General
-Inhibit protein synthesis by binding to 50S ribosome at its interface with the 30S
subunit preventing the formation of the 70S initiation complex.
-Bacteriostatic against most bacteria (bacteriocidal against streptococci when used
with gentamicin)
-Excellent oral absorption (100% bioavailability)
-Adverse effects: GI, myelosuppression especially with therapy greater than 2
weeks, monamine oxidase inhibition resulting in serotonin syndrome, lactic
acidosis (mitochondrial toxicity), retinopathy, peripheral neuropathy
-Expensive, bitter taste of oral suspension

Linezolid
Broad gram positive coverage including MSSA, MRSA, coagulase negative
staphylococci, Enterococcus sp,
VRE, penicillin susceptible S. pneumoniae, Norcardia sp. No significant
anaerobic or gram negative coverage. Resistant strains of VRE/MRSA have
already been reported

D. Lipopeptides (Daptomycin)
General
 -Exact mechanism of action unclear, binds to cell membrane of gram positive
organisms and disrupts the bacterial cell membrane potential.
-Prolonged post-antibiotic effect
-Long half-life (q day dosing IV)
-Not yet approved for use in children
-Poor penetration into lungs
-May be associated with muscle weakness and myalgia
Daptomycin
Antimicrobial coverage: Similar to glycopeptides but retains (so far) activity against
vancomycin intermediate S. aureus, VRE.

D. Glycylcylines:
General:
• Structurally related to tetracyclines
• Bacteriostatic
• Inhibits protein synthesis in the bacteria by reversibly binding to 30S ribosomal subunit (binding
five times more effectively than tetracyclines thus helping overcome ribosome-based tetracycline
resistance)
• Only available as intravenous preparation
• Has broad spectrum of activity and used in intra-abdominal and skin-soft tissue infections due to
multi-drug resistant organisms.

Resistance:
• Can be a substrate for multi-drug efflux systems

Tigecycline:
• Gram positives including methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin
resistant Enterococcus (VRE), Enterobacteriaceae including multi-drug resistant gram-negative
organisms, including E coli and Klebsiella spp isolates expressing extended-spectrum b-lactamases and
carbapenemase-producing strains of Enterobacteriaceae. Of note, tigecycline has limited activity against
Pseudomonas.

Doripenem:
Similar spectrum as meropenem but may still retain activity against strains of P aeruginosa that are
resistant to other carbapenems.