THER 202: Pharmacotherapeutics
1
Lec 8: Understanding and Optimizing the Use of Antibiotics
August 20, 2014
Cecilia Maramba-Lazarte, MD
TOPIC OUTLINE
I. Common Antibiotics
A. Penicillin
G. Tetracyclines
B. Cephalosporins
H. Macrolides
C. Carbapenems
I. Chloramphenicol
D. VancomycinJ. Clindamycin
E. Anti-folate K. Quinolones
F. Aminoglycosides
II. Patterns of Activity
A. Parameters
B. Type 1
ADVERSE EFFECT
 hypersensitivity
PIPERACILLIN
INDICATIONS
 gram (+), penicillin-sensitive anaerobes
 Pseudomonas, Enterobacteriacae
 beta-lactamase negative Moraxella, Neisseria, haemophilis
C. Type 2
I. COMMON ANTIBIOTICS
DOSING
 mild to moderate non-pseudomonal/streptococcal: 3g IV q 6 hrs
 moderate to severe pseudomonal: 3g IV q 4 hrs
AMPICILLIN
INDICATIONS
 gram (+)
 enteric gram (-)
o typhoid fever: Salmonella (<5% resistance)
o UTI: E. coli (70% resistance), Proteus
o dysentery: Shigella (70-90% resistance)
 respiratory tract gram (-)
o H. influenza: respiratory tract infection, pneumonia, meningitis
o Moraxella morganii (30-45% resistance in US)
 Pasteurella moltocida
 Listeria monocytogenes
 Enterococcus
o only bacteriostatic due to weak affinity to penicillin-binding
proteins
o needs aminoglycoside (gentamicin) to become bacteriacidal
o E. faecalis: sensitive
o E. faecium: resistant
 penicillin-sensitive
alpha-streptococcal
subacute
bacterial
endocarditis
FIGURE 1. Mechanism of action of common antibiotics
A. PENICILLIN
MECHANISM
 resisted by beta-lactamase and altered penicillin-binding proteins
 renally excreted
DOSING
 mild infection (cystitis, pharyngitis): amoxicillin 500mg PO TID
 moderate infection (pyelonephritis, cellulitis, osteomyelitis):
 ampicillin 2g IV Q4 hours
 severe infections (meningitis, endocarditis): 2g IV q 4 hrs
 adjust for renal failure
INDICATIONS
 Pneumococcus (15-30% resistant outside Phil)
 Neisseria (91% resistant in Phil due to beta-lactamase in gonorrhea)
 Streptococcus, Staphylococcus, syphilis
AMOXICILLIN
DOSAGE
 Mild (cellulitis, pharyngitis)
o Penicillin V 500mg PO QID
o Penicillin G 1-2M units IV q 4hrs
 Serious (meningitis, endocarditis)
o Penicillin G 4M unitis IV q 4 hrs
 Syphilis
o Latent: Benzathine Penicillin 2.4M units IM every week for 3
weeks
o Neuro: Penicillin 4M units IV q 4 hrs for 10 days
ADVERSE EFFECT
 nausea
ADVERSE EFFECT
 Hypersensitivity
OXACILLIN
INDICATIONS
 oxacillin-sensitive S. aureus and coagulase (-) Staphylococcus
 most potent anti-staphylococcus
 penetrates CNS
DOSING
 no adjustment for renal failure
ADVERSE EFFECT
 leukopenia, thrombocytopenia, interstitial nephritis
INDICATIONS
 respiratory tract infection, typhoid
Penicillin with narrowest spectrum? Anti-staphylococcus penicillin
Penicillin with broadest spectrum? Piperacillin
Penicillin for typhoid? Ampicillins and Extended-spectrum Penicillin
Penicillin
Route
Spectrum of Activity
Gram (+)
Gram (-)
Others
Natural Penicillins
Penicillin
G, K, or Na
Benzathine
Penicillin
(Depository
preparation,
therapeutic
levels up to
3-4 wks)
IV, IM
IM
Streptococci
Pneumococci
Neisseria
Corynebacterium
meningitides
Listeria
H.influenza
Enterococcus
(high doses)
Clostridium
Oral Anaerobes
Treponema
Leptospira
CLOXACILLIN
INDICATIONS
 skin infection
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Understanding and Optimizing the Use of Antibiotics
Penicillin VK to
poor gram (-)


PO
Anti-staphylococcus
penicillins
Streptococci
Staphylococci
none
none
gram (-) UTI in hospitalized patients
combined with beta-lactams or anti-anaerobes:
o empiric therapy for serious infections
o (neonatal sepsis, febrile neutropenia, nosocomial infections)
o mixed aerobic/anaerobic infection (peritonitis from ruptured
viscus)
o infective bacterial endocarditis, systemic Pseudomonas
aeruginosa
ADVERSE EFFECTS
 ototoxicity, nephrotoxicity, neuromuscular blockade
Oxacillin
IM, IV
Cloxacillin
PO
Aminopenicillin
Ampicillin
IV, IM
G(+)
G(-)
Others
Anaerobes
Amoxicillin
PO
THER 202
Streptococci
Pneumococci
Neisseria
Corynebacterium meningitides
Listeria
H. influenza
Enterococcus Salmonella
Clostridium
E. Coli
Oral Anaerobes
TABLE 1. Penicillin
B. ANTI-FOLATE
MECHANISM
 sulfonamide: structurally similar to para-aminobenzoic acid, inhibits
pteridinesynthetase
 trimethoprim: diaminopyrimidine inhibiting dihydrofolatereductase
and folic acid synthesis
D. TETRACYCLINES
MECHANISM
 reversibly bind tO 30S ribosome and inhibit binding of aminoacyl-tRNA to the 50S ribosome’s A site
 not for pregnant women and children <8 years old
 chelated by metals and calcium
INDICATIONS
 Chlamydia (urethritis, PID, lymphogranuloma venereum, psittacosis)
 Mycoplasma pneumonia, cholera, leptospirosis, acne
 alternative for actinomycosis, rat bite fever, syphillis, gonorrhea,
tularemia, shigellosis, and Yersinia enterocolitica enteritis
ADVERSE EFFECTS
 nausea and vomiting, vaginal or oral candidiasis, enterocolitis
 teeth discoloration, enamel hypoplasia, bone deformity
 hepatotoxicity (especially in pregnancy)
 nephrotoxicity (renal tubular acidosis)
 photosensitization, SLE, allergy, dizziness, vertigo
INDICATIONS
 treatment and prophylaxis of pneumocystis carinii pneumonia
 treatment and prophylaxis of UTI due to susceptible E. coli (not 1st
line because 70% resistant in Phil)
 1st line for typhoid fever
 respiratory, bone, and joint infections with susceptible H. influenzae
or S. pneumoniae
 acute and chronic bacterial prostatitis
ADVERSE EFFECTS
 75% involve skin: urticarial rash (common), Steven-Johnsons
Syndrome, exfoliative dermatitis, and toxic epidermal necrolysis
 allergic cholestatic hepatitis
 irreversible renal failure if with renal disease
 reversible creatinine clearance drop if with normal renal function
G(+)
S. aureus, S. pyogenes, S. pneumoniae
E.coli (high resistance in the Phils.), Proteus mirabilis, H.
influnzae, Shigella spp., Salmonella spp., Burkolderi
G(-)
acepacia, Malleomyces pseudomallei, Yersinia,
Stenotrophomonas maltophila, M. catarrhalis, Listeria
monocytogenes
Pneumocystis jirovecii (carinii), atypical mycobacteria,
Others
Toxolasma gondii
TABLE 2. Cotrimoxazoles (Trimethoprim, Sulfamethoxazole)
Which is broader: Vancomycin or Cotrimoxazole? Cotrimoxazole
Why should Vancomycin be reserved for MRSA? to prevent resistance
C. AMINOGLYCOSIDES
MECHANISM
 beta-lactams inhibit cell wall synthesis and increase permeability of
aminoglycosides
 combined with beta-lactams and not a monotherapy except for UTI
 different mechanisms of action and binding sites
 absorption: oral has poor bioavailability, so given IV or IM
 distribution: poor penetration to blood-brain barrier unless intrathecal
 excretion: 94-98% unchanged in urine
S. aureus, S. viridans
E.coli, Klebsiella, Proteus, Pseudomonas,
Enterobacter, Acinetobacter etc.
Mycobacteria-streptomycin, amikacin
No activity; O2 required for uptake of antibiotic
TABLE 3. Aminoglycosides
Classification
DRUGS
T1/2
Chlortetracycline
SHORT-ACTING
Tetracycline
6-8 hrs
Oxyttracycline
INTERMEDIATE- Democlocycline
12 hrs
ACTING
Methacycline
LONG-ACTING
Doxycycline
16-118 hrs
TABLE 4. Tetracycline Classification
G (+)
G(-)
Atypical
Anaerobes
Parasites
Streptococcus, Staphylococcus, Actinomycetes,
Bacillus anthracis
H. influenzae, E.coli, Vibrio cholerae, N. gonorrhea,
Shigella, Yersinia, N. meningitides, Treponema
pallidum, Leptospira, Spirillium
Chlamydia, Mycoplasma, Legionella
Bacteroides fragilis, Prevotella
Plasmodium, Filaria
TABLE 5. Tetracycline Spectrum
E. MACROLIDES
MECHANISM
 bacteriostatic but bactericidal in high concentrations
 inhibits protein synthesis by inhibiting tRNA translocation from A to P
INDICATIONS
 Chlamydia trachomatis, Mycoplasma pneumoniae, Legionella
pneumophillia, Campylobacter jejuni, diphtheria, syphilis
 Bordetella pertussis (whooping cough) therapy and prophylaxis
 penicillin alternative for streptococcal/pneumococcal infections
outside CNS
 bacterial endocarditis prevention after dental procedures
 rheumatic fever prophylaxis
INTERACTIONS
 as CYP1A2 and CYP3A3/4 inhibitors: decreased hepatic
metabolism of other drugs (Dicumarol, Ergot, Digoxin,
Carbamazepine, Theophylline, Cyclosporin,Triazolam) increases
and toxicities
 with Terfenadine and Astemizole (H-blockers with no sedating
effect): cardiac arrhythmias.
 with statins (except azithromycin): myopathy
INDICATIONS
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Understanding and Optimizing the Use of Antibiotics
ADVERSE EFFECTS
 GI (frequent for Erythromycin): abdominal pain, nausea, vomiting,
cramping, diarrhea, stomatitis
 liver: cholestatic hepatitis, jaundice
 CVS: ventricular arrhythmias, QT interval prolongation, bradycardia,
hypotension after IV
 CNS: fever, dizziness
 rash, eosinophilia, thrombophlebitis, ototoxicity, allergy
Gram Positive
ERYTHROMYCIN
S. pneumoniae
S. pyogenes
Clostridium
S. aureus
C. diphtheriae
L. monocytogenes
CLARITHROMYCIN
S. pneumoniae
S. pyogenes
Clostridium
S. aureus
C. diphtheriae
L. monocytogenes
AZITHROMYCIN
S. pneumoniae
S. pyogenes
Clostridium
S. aureus
C. diphtheriae
L. monocytogenes
Gram Negative
Others
N. gonorrhea
B. pertussis
M. pneumoniae
C. pneumoniae
C. trachomatis
Legionella
N. gonorrhea
B. pertussis
H. influenzae
M. catarrhalis
M. pneumoniae
C. pneumoniae
C. trachomatis
Legionella
M. pneumoniae
C. pneumoniae
C. trachomatis
Legionella
TABLE 6. Macrolides
F. CHLORAMPHENICOL
MECHANISM
 non-beta lactam
 palmitate if oral (better bioavailability), succinate if IV
 binds to 50S ribosome and inhibits transpeptidation (peptide chain
on tRNA on P transfers to tRNA on A) by inhibiting peptidyl
transferase
 good CNS penetration
DOSING
 250 mg capsules or 125mg/5ml liquid palmitate
 chloramphenicol palmitate ester
o inactive but same bioavailability as chloramphenicol
o hydrolysed to active chloramphenicol in the small intestines
 succinate ester
o IV chloramphenicol (pure chloramphenicol is not water-soluble)
o inactive and must hydrolysed to chloramphenicol
o 30% is lost unchanged in urine
o 70% bioavailability of IV compared to oral (oral is preferred)
INDICATIONS
 H. influenzae (meningitis, acute epiglotittis, pneumonia)
 Meningococcus, Pneumococcus, salmonella
 typhoid fever, brain abscess, severe anaerobic infections
ADVERSE EFFECTS
 dose-dependent bone marrow aplasia (>50mg/kg/day after a week)
 irreversible idiosyncratic aplastic anemia
 gray baby syndrome due to lack of conjugation mechanism
(abdominal distension, vomiting, flaccidity, cyanosis, circulatory
collapse, death)
 optic neuritis, hypersensitivity (rare)
G(+)
G(-)
Anaerobes
Others
MECHANISM
 chlorine substituted derivative of lincomycin
 same binding sites as macrolides
 inhibits translocation
 hepatic metabolism
 oral or IV
INDICATIONS
 anaerobic (including B.fragilis) infections outside CNS
 alternative for actinomycosis, Gardnerella vaginalis vaginosis,
toxoplasmosis, P. carinii pneumonia, staphylococcus, and
streptococcus (except enterococcal) if allergic to beta-lactams
ADVERSE EFFECTS
 diarrhea (20%), pseudomembranous colitis (0.01-10%)
 hepatotoxicity and hematologic abnormalities (rare)
G(+)
G(-)
Anaerobes
Others
N. gonorrhea
H. influenzae
M. catarrhalis
Salmonella
S. pneumoniae, S. pyogenes, S. aureus,
Enterococci, Bacillus anthracis
H. influenzae, Shigella, Salmonella, E.coli,
N.gonorrheae, N. meningitidis, B. pertussis, M.
catarrhalis,
Klebsiella,
Vibrio,
Yersinia,
Pseudomonas (not aeruginosa)
Bacteroides (including fragilis), Prevotella,
Clostridium, Peptostreptococcus, Actinomycetes
Rickettsia, Mycoplasma, Chlamydia
TABLE 7. Chloramphenicol
Which
is for meningitis: macrolides
or chloramphenicol?
Chloramphenicol due to good CNS penetration.
Which is safer: macrolides or chloramphenicol? Macrolides
THER 202
S. pneumoniae, S. pyogenes, S. aureus, S. viridans (no
activity against Enterococci)
Caopnocytophaga canimorsus ( all others are resistant)
Bacteroides (including fragilis), Fusobacterium,
Prevotella, Clostridium perfringens, Peptostreptococcus
Toxoplasma gondii, Plasmodium, Pneumocystis jerovocii
(carinii)
TABLE 8. Clindamycin
H. QUINOLONES
MECHANISM
 inhibits DNA synthesis by binding to DNA gyrase (topoisomerase II)
and preventing supercoiling of DNA
 inhibits topoisomerase IV and interferes with separation of replicated
chromosomal DNA
ADVERSE EFFECTS
 nausea, vomiting, diarrhea (3-17%), prolonged QT interval (rare)
 delirium, headache, hallucinations, seizures (0.9-11%)
 allergy (0.4-2.8%) arthropathy (0-14% frequency)
CIPROFLOXACIN




GU/GI infections: Campylobacter, Shigella, and Salmonella
STD, and non-gonococcal (chlamydial) urethritis
susceptible gram (-), multi-drug resistant typhoid fever
meningococcus and anthrax prophylaxis
LEVOFLOXACIN



gram (-) (less active than Ciprofloxacin for P. aeruginosa)
MDR/mycobacteria TB, community-acquired pneumonia
meningococcus and anthrax prophylaxis
Generation
1st
2nd
3rd
Drugs
Nalidixic Acid
Cinoxin
Ciprofloxacin
Ofloxacin
Spectrum of Activity
G (-) except Pseudomonas
G (-) (Salmonella, Shigella, E. coli
including
Pseudomonas,
H.
influenza), few G (+), Mycoplasma,
Chlamydia,
Legionella,
mycobacteria
Levofloxacin
H. influenza, Salmonella, Shigella,
Gatifloxacin
E. coli, other Enterobacteriaceae,
Moxifloxacin
Mycoplasma,
Chlamydia,
Legionella,
S.
pneumoniae,
Methicillin-sensitive
S.
aureus,
mycobacteria
TABLE 9. Quinolones
Which is broader: quinolones or clindamycin? Quinolones
Which has activity for Mycobacterium tuberculosis?
Levofloxacin (3rd gen quinolones)
I. VANCOMYCIN
MECHANISM
 glycopeptide inhibiting cell wall synthesis & transglycosylase,
preventing peptidoglycan elongation
 very poor oral and erratic IM, so given IV
 very narrow spectrum
 histamine-releaser, hence unviable for skin test
G. CLINDAMYCIN
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Understanding and Optimizing the Use of Antibiotics
THER 202
INDICATIONS
 oral: antibiotic-associated diarrhea, pseudomembranous colitis
 IV: serious MRSA infections
 gram (+) but allergic to penicillin and cephalosporin
ADVERSE EFFECTS
 phlebitis, chills and fever, ototoxicity, nephrotoxicity
 red man syndrome - erythema multiforme-like reaction with intense
pruritus, tachycardia, hypotension, rash, flushing due to rapid
infusion
G (+)
G (-)
Others
S. pneumoniae, S. pyogenes, S. aureus including MRSA,
S. viridans, S. epidermidis, Enterococcus
None
None
TABLE 10. Vancomycin
II. PATTERNS OF ACTIVITY
PHARMACOKINETICS
 pharmakon – Greek for “drug”
 kineticos – Greek for “put into motion”
 absorption, distribution, metabolism, excretion
 only factor considered in traditional dosing (but drugs have been
classified according to PK/PD for the last 20 years)
FIGURE 4. PK/PD Index
Pattern of Activity
Antibiotics
Type I
Concentration
dependent killing
and prolonged
persistent effects
Type II
Time dependent
killing and Minimal
persistent effects
Aminoglycosides
Daptomycin
Fluoroquinolones
Ketolides
PK/PD
Parameter
24hAUC/MIC
Peak/MIC
Maximize
duration of
exposure
T>MIC
Type III
Maximize
Time dependent
amount of drug
killing and
Moderate to
prolonged
persistent effects
TABLE 11. Types based on patterns of activity
A. PARAMETERS


Carbapenems
Cephalosporins
Erythromycin
Linezolid
Penicillins
Azithromycin
Clindamycin
Oxazolidinones
Tetracyclines
Vancomycin
Goal of
Therapy
Maximize
concentrations
Cmax – maximum concentration of drug in blood
AUC (Area under the Curve) – total drug bioavailability
24hAUC/MIC
B. TYPE 1 (CONCENTRATION-DEPENDENT)


FIGURE 2. Cmax and AUC

MIC (Minimum Inhibitory Concentration) – lowest
concentration inhibiting microorganism growth
antibiotic
greater concentration (higher Cmax/MIC and AUC/MIC) has
more extensive and faster effect
ex. aminoglycosides, quinolones, daptomycin, ketolides
POST-ANTIBIOTIC EFFECT
 Persistent bacterial growth suppression after concentration falls
below MIC
 Species and drug specific (ex. gram (-) with aminoglycosides)
 Mechanisms:
o prolonged microorganism recovery
o drug persistence at binding site
o organism needs to synthesize new enzymes
AMINOGLYCOSIDE ONCE DAILY DOSING
FIGURE 5. Aminoglycoside ODD vs Multiple Daily Dosing
FIGURE 3. MIC


PK/PD Index (Pharmacokinetic-Pharmacodynamic)
o Cmax:MIC, AUC:MIC
o T>MIC (time above MIC)
cumulative % of time over a 24 hr period that the drug
concentration exceeds the MIC (must be 90-100% if severe)
o ex. 12 hrs: (12/24) x 100% = 50%








Ferrer, Flores, Fontanilla
25% less nephrotoxic & just as effective as conventional regime
did not affect ototoxicity, febrile neutropenia, and pedia cases
benefits increased with Pseudomonas isolates
more convenient (omitted measurement of peak antibiotic
concentration) and less costly
higher Cmax and AUC
Cmax/MIC ≥10 means better rate and extent of clinical response
maximizes efficacy and minimizes potential drug accumulation
and toxicity – standard of care for adult patients
prohibited in:
o ascites (drug goes to ascites), pregnancy, endocarditis
o burns>20% body surface area (loss of fluids through burns)
o pregnancy
o dialysis (excreted through dialysate)
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Understanding and Optimizing the Use of Antibiotics
o staphylococcal and enterococcal
therapy is used for synergy
when
aminoglycoside
PRACTICAL IMPLICATIONS

For concentration-dependent antibiotics:
o Higher concentrations results in increase killing and faster
killing of bacteria
o Post antibiotic effect accounts for killing of bacteria when
concentration is low
o Appropriate dosing is a high dose, once or twice daily
C. TYPE 2 (TIME-DEPENDENT)






effective as long as concentration at site is higher than MIC
maximal effect at 4x MIC (higher dose has no significant effect)
extent of killing is dependent on time of exposure (T>MIC)
no post‐antibiotic effect
T>MIC
ex. penicillins, cephalosporins, carbapenems, macrolides, linezolid
T>MIC
 The cumulative % of time over a 24-hr period that the drug
concentration exceeds the MIC
 If concentration of the drug is above the MIC for 12 hrs
12/24 x 100% = 50%
50% T>MIC
WAYS TO MAXIMIZE T>MIC



THER 202
Improve pharmacokinetic profile within class (half‐life)
o drugs with longer half‐lives can be administered less frequently
Increase dosing frequency
o entails more working hours, materials, and cost
o ex. penicillin G every 4 hrs instead of every 8 hrs
Continuous infusion
o ensures steady‐state concentration using the same daily dosage
o minimizes serum concentration fluctuation and cost
o must consider:

drug stability and consequent frequent infusion bag changes

ex. most beta lactams are only stable for 4-8 hrs in 25˚C

necessity of a dedicated IV line to prevent interaction
Optimal amoxicillin dosing (40 mg/kg/day) for 4-yo 20kg boy with
pneumonia?
daily dose = 40 x 20 = 800
Type 2: 250mg/5ml q 8 hrs
Optimal gentamicin (5 mg/kg/day) and ampicillin (200 mg/kg/day)
dosing for 3-mo 4kg baby with sepsis?
GENTAMICIN
daily dose = 5 x 4 = 20mg
Type 1: 20mg IV once a day
AMPICILLIN
daily dose = 200 x 4 = 800mg
Type 2: 200mg IV q 6 hrs
D. SUMMARY
Optimize the use of our antibiotics depending on their PK/PD
classification
1. Concentration-dependent antibiotics
 Cmax/MIC, AUC/MIC – pk/pd parameter which determines efficacy
 Once daily therapy – entire dose given once for aminoglycosides
 1-2x/day for fluoroquinolones
 Daptomycin, once daily dose
2. Time-dependent antibiotics
 Maximize T>MIC
 Options include:
o Increase dosing frequency
o Continuous infusion
o Extended infusion
END OF TRANSCRIPTION
FIGURE 6. Intermittent vs Continuous Infusion

Extend duration of infusion
o lower Cmax but still high T>MIC
o more practical because less stability issue
o may infuse other drugs between dosing times
Class
Cephalosporins
Penicillins
Carbapenems
Organism
G(-) rods,
Pneumo
Staph
G(-) rods,
Pneumo
Staph
G(-) rods,
Pneumo
Staph
Stasis
Maximum
Killing
40-50
70-80
20-30
40-50
30-40
60-70
20-30
40-50
20-30
40-50
10-20
25-40
* T>MIC of 90-100% = For severe infections, decrease development
of resistance
TABLE 12. Pharmacodynamic Goals (T>MIC as percent of interval)
with B-lactams
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