Dept.

Pharmacology & Therapeutic

School of Medicine

Universitas Sumatera Utara

-Lactams

-Lactam Characteristics

MOA: All inhibit cell wall synthesis

Bactericidal (exception: Enterococcus)
Time-dependent killers
Short t1/2
Primarily renally eliminated
(exceptions: nafcillin, oxacillin,
ceftriaxone)
Resistance: -lactamase degradation
PBP alteration
Decreased penetration

Chemical Structure:
Allergenicity

Natural Penicillins

(Penicillin G, Penicillin VK)

Gram-positive

Gram-negative

Penicillin-susc S. aureus
Penicillin-susc S. pneumoniae

Neisseria spp.

Group streptococci
Anaerobes
Viridans streptococci Above the diaphragm
Enterococcus
Clostridium spp.
(not difficile)

Other

Treponema pallidum (syphilis)

Penicillinase-Resistant
Penicillins
(Nafcillin, Oxacillin, Dicloxacillin)
Developed to overcome inactivation ability
of penicillinase enzyme to S. aureus

Gram-positive
Methicillin Susceptible S. aureus (MSSA)
Group streptococci
Viridans streptococci

Aminopenicillins
(Ampicillin, Amoxicillin)
Developed to increase activity against
Gram-Negative aerobes
Gram-positive

Gram-negative

PCN-Susp S. aureus
Proteus mirabilis
PCN-Susp S. pneumoniae Listeria
monocytogenes
Group streptococci
Salmonella
Viridans streptococci
Shigella
Enterococcus
H. influenzae
S. pyogenes
E. coli

Antipsuedomonal Penicillins:
Carboxypenicillin
(Ticarcillin)

Developed to further increase activity

against resistant gram-negative aerobes
Gram-positive

Gram-negative

marginal
Proteus mirabilis
Salmonella, Shigella
E. coli
H. influenzae
Enterobacter sp.
*Pseudomonas aeruginosa*

Antipsuedomonal Penicillins:
Ureidopenicillins
(Piperacillin)

Developed to further increase activity against

resistant gram-negative aerobes

Gram-positive

Gram-negative

Viridans Strep Proteus mirabilis

Group Strep. Salmonella, Shigella
Enterococcus
E. coli
L-H. influenzae
Anaerobes
Enterobacter spp.
Fairly good activity *Pseudomonas aeruginosa*
including Bacteroides spp.
Klebsiella spp.

-Lactamase Inhibitor
Combos
(Unasyn, Augmentin, Zosyn)

Developed to gain or enhance activity

against -lactamase producing organisms
Gram-positive
MSSA
E. coli

Gram-negative

H. influenzae

Anaerobes Proteus sp.

Bacteroides sp.
Klebsiella sp.
Neisseria gonorrhoeae
Moraxella catarrhalis
Only ZOSYN covers Pseudomonas aeruginosa

IV conversion to PO
Penicillin to Penicillin
Ampicillin to Amoxicillin
Oxacillin to Dicloxacillin
Anti-Staphlococcal penicillin dosed QID
Liquid not tolerated well & no longer available
Recommend cephalexin for PO Staphylococcal
treatment if can not swallow capsules

Unasyn

to Augmentin

Cephalosporins

Cephalosporins by
Generation
1st
2nd
Generation Generation

Cefadroxil

Cephalexin
Cefazolin

3rd
Generation

4th
Generation

Cefaclor1

Cefdinir

Cefepime2

Cefprozil1

Cefixime1

Cefuroxime axetil1

Cefpodoxime1

Cefotetan3

Ceftibuten1

Cefoxitin3

Ceftazidime2

Cefuroxime sodium

Cefotaxime

Ceftriaxone

Oral dosage form available

Antipseudomonal activity notable

Anaerobe coverage

1st Generation
Cephalosporins
Best activity against gram-positive
aerobes, with limited activity against
gram-negative aerobes
Gram-positive
negative
MSSA
Pen-Susp S. pneumoniae
Group Streptococci
Viridans Streptococci

GramE. coli
K. pneumoniae
P. mirabilis

2nd Generation Cephalosporins

Slightly less active against gram-positive
aerobes, but more active against gramnegative aerobes
Several have activity against anaerobes

Gram-positive
MSSA
E. coli
Pen-susp S. pneumoniae
Group Streptococci
Viridans Streptococci
M. catarrhalis
Neisseria spp.

Gram-negative
K. pneumoniae
P. mirabilis
H. influenzae

3rd Generation Cephalosporins

Spectrum of Activity

Less active against gram-positive

aerobes, but have greater activity
against gram-negative aerobes
Ceftriaxone and cefotaxime have the
best activity against gram-positive
aerobes, including PCN-resistant S.
pneumoniae
Strong inducers of ESBL production

3rd Generation Cephalosporins

Spectrum of Activity

Gram-negative aerobes
E. coli
K. pneumoniae
P. mirabilis
H. influenzae
M. catarrhalis N. gonorrhoeae
N. meningitidis
Citrobacter spp.
Enterobacter spp.
Acinetobacter sp.
Morganella morganii
Serratia marcescens Providential
Ceftazidime only: Pseudomonas aeruginosa

4th Generation Cephalosporins

Extended spectrum of activity
Gram-positives: similar to ceftriaxone
Gram-negatives: similar to ceftazidime
(including Pseudomonas aeruginosa),
also covers beta-lactamase producing
Enterobacter spp.

Stable against -lactamases

Poor inducer of ESBLs

IV to PO - Cephalosporins
Cefazolin to Cephalexin
Cheapest price & good palatability but QID dosing may
compromise compliance

Cefoxitin to Cefuroxime axetil + Metronidazole

Ceftriaxone or Cefotaxime to Cefdinir or Cefixime
Ceftazidime or Cefepime to: Treating
Pseudomonas?
Yes- ciprofloxacin
No- cefdinir

Carbapenems

Carbapenems
(Imipenem, Meropenem, Ertapenem)
Most broad spectrum activity amongst all
antimicrobials: gram-positive & gram-negative
aerobes & anaerobes
Meropenem and Imipenem cover P. aeruginosa
Ertapenem does NOT cover P. aeruginosa
Bacteria not covered by carbapenems:
MRSA Staph. epidermidis
VRE
C. difficile

Monobactams

Monobactams
(Aztreonam)

Gram-negatives
E. coli
K. pneumoniae
P. mirabilis
S. marcescens
H. influenzae
M. catarrhalis
Enterobacter
Citrobacter
Providencia
Morganella
Salmonella
Shigella
Pseudomonas aeruginosa

No activity against gram-positives or

anaerobes

-Lactams
ADME

Absorption
PO forms have variable absorption
Food can delay rate and extent of absorption

Distribution

Widely to tissues & fluids

CSF penetration:
Parenteral PCNs limited unless inflamed meninges
Parenteral 3rd & 4th gen cephalosporins, meropenem,
&
aztreonam penetrate well

Metabolism & Excretion

Primarily renal elminiation

Nafcillin, oxacillin, ceftriaxone, cefoperazone: via liver
ALL -lactams have short elimination half-lives

-Lactams

Adverse Effects

Hypersensitivity 0.4% to 10 %
Mild to severe: rash to anaphylaxis &
death
Cross-reactivity exists among all
penicillins and even other -lactams (5 to
10%)
Desensitization is possible
Aztreonam does not display crossreactivity with penicillins and can be
used in penicillin-allergic patients

-Lactams

Adverse Effects

Neurologic: notably high dose PCN &

carbapenems
Increased incidence w/ high doses &/or renal
insufficiency
Irritability, jerking, confusion, seizures

Hematologic
Leukopenia, neutropenia, thrombocytopenia with
prolonged therapy (> 2 weeks)

Gastrointestinal
Increased LFTs, nausea, vomiting, diarrhea,
pseudomembranous colitis

Interstitial Nephritis (Type IV hypersensitivity reaction)

Especially with nafcillin

Fluoroquinolones

Fluoroquinolones
(Ciprofloxacin, Levofloxacin,
Moxifloxacin)

Novel synthetic antibiotics developed

in response to growing resistance
Concentration-dependent bactericidal
activity
Broad spectrum of activity
Improved PK properties excellent
bioavailability, tissue penetration,
prolonged half-lives

Disadvantages: emergence of
resistance

Fluoroquinolones
Mechanism of Action
Inhibit bacterial topoisomerases which are

necessary for DNA synthesis

DNA gyrase Primary target for gram-negatives
Topoisomerase IV Primary target for grampositives

Resistance

Altered target sites: Most important and most

common
Altered cell wall permeability
Efflux pumps
Cross-resistance occurs between FQs

Fluoroquinolones
Spectrum of Activity

Gram-positive: moxi>levo>>cipro
MSSA
Streptococcus pneumoniae

Gram-Negative: cipro=levo>moxi
Enterobacteriaceae
H. influenzae, M. catarrhalis, Neisseria sp.
Pseudomonas aeruginosa ciprofloxacin &
levofloxacin

Atypical bacteria: all have excellent activity

Fluoroquinolones
ADME

Absorption: good bioavailability

Food delays peak concentration

Distribution: extensive tissue distribution

Lung, skin/soft tissue, bone, urinary tract (not
moxifloxacin)
Minimal CSF penetration

Metabolism & Elimination renal and

hepatic
Exception: Moxifloxacin is NOT reanally
eliminated

Fluoroquinolones
Adverse Effects

Gastrointestinal: nausea, vomiting, diarrhea

CNS: headache, agitation, insomnia,
dizziness, rarely, hallucinations
Cardiac: prolongation QTc interval

Assumed to be class effect

Led to withdrawal of grepafloxacin, sparfloxacin

Articular Damage: cartilage damage,

arthralgia
Dysglycemias
Led to withdrawal of gatifloxacin

Hepatotoxicity

Led to withdrawal of trovafloxacin

Fluoroquinolones
Drug Interactions

Divalent and trivalent cations

Zinc, Iron, Calcium, Aluminum,
Magnesium
Antacids, Sucralfate, enteral feeds
Administer doses 2 to 4 hours apart; FQ
first

Macrolides

Macrolides
Mechanism of Action

Inhibits protein synthesis by

reversibly binding to the 50S
ribosomal subunit
Bacteriostatic
Time-dependent activity

Resistance
Efflux pumps
Altered target sites
Cross-resistance occurs between all
macrolides

Macrolides
(Erythromycin, Azithromycin,
Clarithromycin)

Erythromycin: narrow spectrum of

activity, short t1/2, not acid labile, GI
intolerance
Clarithromycin & azithromycin:

Broader spectrum of activity

Improved PK properties:

Better bioavailability
Better tissue penetration
Prolonged half-lives

Improved tolerability

Macrolides

Spectrum of Activity
Gram-Positive Aerobes: Clarithr>Erythr>Azithr
MSSA
S. pneumoniae: resistance is emerging
Group and viridans streptococci

Gram-Negative Aerobes:
Azithr>Clarithr>Erythr
H. influenzae, M. catarrhalis, Neisseria sp.
NO activity against any Enterobacteriaceae

Anaerobes: upper airway anaerobes

Atypical Bacteria
Other Bacteria: Mycobacterium avium complex

Macrolides
ADME

Absorption
Erythromycin: variable absorption of 15% - 45%
Clarithromycin: 55%
Azithromycin: 38%

Distribution
Clarithromycin & azithromycin extensive tissue
penetration with minimal CSF penetration

Metabolism & Elimination

Clarithromycin partially eliminated by the kidney
ALL hepatic elimination
t1/2: erythro 1.4 hr, clarithro 3-7 hr, azithr 68 hr

Macrolides
Adverse Effects

Gastrointestinal: up to 33 %
Nausea, vomiting, diarrhea, dyspepsia
Erythro > > clarithro, azithro

Thrombophlebitis: IV Erythro & Azithro

QTc prolongation, ventricular
arrhythmias
Other: ototoxicity (high dose erythro
in patients with RI)

Macrolides
Drug Interactions

Erythromycin and Clarithromycin are

STRONG INHIBITORS of cytochrome

p450 system (3A4):

Digoxin SSRIs
Carbamazepine
Valproic acid
Benzodiazepines
Methylprednisolone
Phenytoin
Warfarin
Ergot alkaloids
Azole antifungals
Tacrolimus
Cyclosporine
Sirolimus Calcium Channel Blockers

Aminoglycosides

Aminoglycosides
Mechanism of Action
Inhibition of protein synthesis by
irreversibly bind to 30S ribosomes resulting
in a defective bacterial cell membrane
Bactericidal
Concentration-dependent killer

Resistance
Alteration of ribosomal binding site
Decreased intracellular penetration

Aminoglycosides
Spectrum of Activity

Gram-Negative Aerobes
E. coli, K. pneumoniae, Proteus sp.
Acinetobacter, Citrobacter, Enterobacter sp.
Morganella, Providencia, Serratia, Salmonella,
Shigella
Pseudomonas aeruginosa (amik>tobra>gent)

Gram-Positive Aerobes (in combination w/

cell wall inhibitor)

S. aureus and coagulase-negative staph

viridans streptococci
Enterococcus sp. (gentamicin)

Aminoglycosides
Pharmacology

Absorption: negligible
Distribution
Hydrophilic: widely distributes into body
fluids but NOT the CSF
Distribute poorly into adipose tissue

Elimination
85-95% eliminated unchanged via
kidney
t1/2 dependent on renal function

Aminoglycosides
Adverse Effects
Nephrotoxicity
Direct proximal tubular damage - reversible if
caught early
Risk factors: High troughs, prolonged duration of
therapy, underlying renal dysfunction,
concomitant nephrotoxins

Ototoxicity
8th cranial nerve damage irreversible
vestibular and auditory toxicity
Vestibular: dizziness, vertigo, ataxia
Auditory: tinnitus, decreased hearing

Risk factors: same as for nephrotoxicity

Vancomycin

Vancomycin
Mechanism of Action

Inhibits bacterial cell wall synthesis

at final stage of peptidoglycan
polymers
Bactericidal (except for Enterococcus)
Time dependent killer

Resistance
Modification of D-alanyl-D-alanine
binding site of peptidoglycan

Vancomycin
Spectrum of Activity

Gram-positive bacteria
MSSA, MRSA and S. epidermidis
Streptococcus pneumoniae (including PRSP),
viridans streptococcus, Group streptococcus
Enterococcus
Corynebacterium, Bacillus, Listeria, Actinomyces

Anaerobes
Clostridium sp. (including C. difficile),
Peptostreptococcus, Peptococcus

No activity against gram-negative

aerobes

Vancomycin
ADME
Absorption
oral is negligible
IV required therapy for systemic infections

Distribution
Distributes widely into body tissues and fluids,
including adipose tissue
Variable penetration into CSF, even with
inflamed meninges

Elimination
Primarily eliminated unchanged by the kidney

Vancomycin
Adverse Effects

Red-Man Syndrome
Erythema multiforme-like reaction with
intense pruritus, tachycardia,
hypotension, rash involving face, neck,
upper trunk, back and upper arms
Related to infusion rate
Resolves spontaneously after discontinuation
Lengthen infusion (over 2 - 3 hr) and/or
pretreat with antihistamines

Hematologic: neutropenia, eosinophilia

Vancomycin
Clinical Uses

Serious gram-positive
infections (MRSA) in lactam allergic patients

Oxazolidinone

Linezolid
Mechanism of Action

Inhibits bacterial protein synthesis

by binding to bacterial 23S
ribosomal RNA of the 50S subunit
Time dependent killer
Bacteriostatic against enterococci &
staphylococcus
Bacteriocidal against streptococci

Resistance: RARE
Alterations in ribosomal binding sites

Linezolid
Spectrum of Activity

Gram-Positive Bacteria
MSSA, MRSA and S. epidermidis
Streptococcus pneumoniae (including
PRSP), viridans streptococcus, Group
streptococcus
Enterococcus faecium & faecalis
(including VRE)
Bacillus, Listeria, Clostridium sp. (NOT
C. difficile), Peptostreptococcus, P.
acnes

Linezolid
ADME

Absorption: 100% bioavailable

Distribution: readily distributes into
well-perfused tissue; CSF 30%
Metabolism & Elimination: primarily
metabolized via liver; 30% parent
drug excreted via kidney

Linezolid
Adverse Effects

Gastrointestinal: nausea, vomiting,

diarrhea (11%)
Headache: 10%
Thrombocytopenia: 3 to 10%

Overall myelosuppression often with

treatment durations of >2 weeks
Therapy should be discontinued and
hematologic counts will return to normal

Linezolid
(Drug-Drug & Drug-Food Interactions)
Linezolid is a reversible, nonselective
monoamine oxidase inhibitor
Serotonin syndrome possible with
concomitant use of:
Tyramine rich foods
Serotonergic medications (SSRIs, MAOIs)

Foods high in tyramine:

Aged, fermented, pickled, smoked
Cheese, pepperoni, soy sauce, red wines, beer,
sauerkraut

Serotonin Syndrome
Presence of three or more of the following:
Agitation (34%)
Abdominal pain (4%)
Ataxia/incoordination (40%)
Diaphoresis (45%)
Diarrhea (8%)
Hyperpyrexia (45%)
Hypertension/hypotension (35%)
Hyperthermia
Hyper-reflexia (52%)
Mental status change

Daptomycin

Daptomycin
Mechanism of Action
Binds to bacterial membranes and
causes rapid depolarization of the
membrane potential, inhibiting
synthesis of protein, DNA, RNA and
protein
Concentration-dependent
Bactericidal activity

Mechanism of Resistance
Currently, no mechanisms of resistance
have been identified

Daptomycin
Spectrum of Activity
Gram-Positive Bacteria
MSSA, MRSA and Staph. epidermidis
Streptococcus pneumoniae (including
PRSP), viridans streptococcus, Group
streptococcus
Enterococcus faecium AND faecalis
(including VRE)

Gram-Negative Aerobes: inactive

Daptomycin
ADME
Absorption: minimal
Distribution: protein binding = 95%,
small volume of distribution
NOT indicated for TREATMENT of
PNEUMONIA

Metabolism & Elimination: possible renal

metabolism and 80% parent drug
excreted via the kidneys

Daptomycin
Adverse Effects
Gastrointestinal: nausea, diarrhea,
constipation
Headache, insomnia
Injection site reactions
Rash
Myopathy and CPK elevations

Drug Interactions
HMG-CoA reductase Inhibitors
(statins)

Clindamycin

Clindamycin
Mechanism of Action

Reversibly binds to 50S ribosomal

subunits inhibiting bacterial protein
synthesis
Bacteriostatic or bactericidal depending on
drug concentration, infection site, and
organism
Binds in close proximity to macrolides
competitive inhibition

Resistance
Altered binding site: confers resistance to
clindamycin & macrolides

Clindamycin
Spectrum of Activity

Gram-Positive Aerobes

MSSA
CA MRSA
Streptococcus pneumoniae (only PSSP) resistance is developing
Group and viridans streptococci

Anaerobes

Bacteroides sp
Peptostreptococcus
Actinomyces
Propionibacterium
Clostridium sp. (not C. difficile)

Clindamycin
ADME

Absorption: Rapidly & completely

absorbed (90%); food with minimal effect
on absorption
Distribution
High concentrations in bone and urine
NO significant levels in CSF
Metabolism & Elimination
Clindamycin primarily metabolized by the liver
10% of an oral dose excreted in urine

Clindamycin
Adverse Effects

Gastrointestinal: >10%
Nausea, vomiting, diarrhea, dyspepsia
Esophagitis
Pseudomembranous colitis
Mild to severe diarrhea
Requires treatment with metronidazole

Hepatotoxicity: rare
Elevated transaminases

Allergy: rare

Metronidazole

Metronidazole
Mechanism of Action

After complex reduction reactions,

causes DNA to lose helical structure
and results in inhibition of protein
synthesis
Concentration-dependent killer
Bactericidal activity
Resistance: relatively uncommon
Impaired oxygen scavenging ability
Altered ferredoxin levels

Metronidazole
Spectrum of Activity

Gram positive and negative anaerobes

Bacteroides sp.
Fusobacterium
Prevotella sp.
Helicobacter pylori
Clostridium sp.
(Drug of choice: C. difficile pseudomembranous colitis)

Anaerobic Protozoa
Trichomonas vaginalis
Giardia lamblia
Gardnerella vaginalis

Metronidazole
ADME

Absorption: Rapidly and completely

(90%)

Distribution
Saliva, bile, seminal fluid, bone, liver,
abscesses, lung and vaginal secretions
Penetrates CSF

Metabolism & Elimination

30% - 60% metabolized by the liver
Kidney excretes up to 77% as unchanged drug
Urine may be dark or reddish-brown

Metronidazole
Adverse Effects

Gastrointestinal: Nausea, vomiting,

stomatitis, metallic taste
CNS: seizures, encephalopathy,
confusion, headache
Requires discontinuation of
metronidazole

Neuromuscular & skeletal:

Peripheral neuropathy

Metronidazole
Drug Interactions

Drug

Interaction

Warfarin anticoagulant effect

Alcohol
Disulfiram-like reaction
Phenytoin phenytoin concentrations
Lithium
lithium concentrations
Phenobarbital metronidazole
concentrations
Rifampin metronidazole concentrations

TrimethoprimSulfamethoxazole
(Bactrim)

Bactrim
(Mechanism of Action)
Provide sequential inhibition of folinic acid
synthesis; necessary for microbial DNA
production

SMX: Inhibits dihydropteroate synthase inhibits

incorporation of p-aminobenzoic acid (PABA) into
dihydrofolic acid
TMP: Inhibits dihydrofolate reductase prevents
reduction of dihydrofolate to tetrahydrofolate
Each agent is bacteriostatic, however, combination
displays bactericidal activity

Resistance
Mediated by point mutations in dihydro-pteroate
synthase and/or altered production or sensitivity of
dihydrofolate reductase

Bactrim
(Spectrum of Activity)
Gram-Positives:

Some S. pneumoniae
CA MRSA
Staph aureus
S. pyogenes
Nocardia

Gram-Negatives:

Other:

E. coli
Pneumocystis jiroveci (carinii)
K. pneumoniae
Salmonella, Shigella
M. catarrhalis
Haemophilus sp.
N. gonorrhoeae
Stenotrophomonas maltophilia

Bactrim
ADME

Absorption: Rapidly & completely

absorbed (> 90%)
Peaks are higher and more predictable with
IV administration

Distribution: urine, joints, sputum, middle

ear fluid, bile and CSF
Metabolism & Elimination:
SMX- extensive metabolized in liver and 10%30% parent drug excreted in urine
TMP- metabolized by liver and up to 75%
parent drug excreted in urine

Bactrim
Adverse Effects

Gastrointestinal: Nausea, vomiting, diarrhea

Hematologic
Leukopenia, thrombocytopenia, eosinophilia
Hemolysis (with G-6-PD deficiency)

Dermatologic: Rash, urticaria, epidermal

necrolysis, Stevens-Johnson, drug fever
CNS: Headache, seizures, KENICTERUS in
neonates
Other: phlebitis