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 Neisseria spp.
Penicillin-susc S. pneumoniae
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 Gram-negative
MSSA H. influenzae
E. coli
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 Generation 2nd Generation 3rd Generation 4th Generation

Cefadroxil 1 Cefaclor1 Cefdinir 1 Cefepime2

Cefprozil1 Cefixime1
Cephalexin1
Cefuroxime axetil1 Cefpodoxime1
Cefazolin
Cefotetan3 Ceftibuten1
Cefoxitin3 Ceftazidime2
Cefuroxime sodium Cefotaxime
Ceftriaxone

1Oral dosage form available 3Anaerobe coverage

2Antipseudomonal activity notable
 1st Generation Cephalosporins
Best activity against gram-positive aerobes,
with limited activity against gram-negative
aerobes

Gram-positive Gram-negative
MSSA E. coli
Pen-Susp S. pneumoniae K. pneumoniae
Group Streptococci P. mirabilis
Viridans Streptococci
 2nd Generation Cephalosporins

Slightly less active against gram-positive aerobes,

but more active against gram-negative aerobes
Several have activity against anaerobes
Gram-positive Gram-negative
MSSA E. coli
Pen-susp S. pneumoniae K. pneumoniae
Group Streptococci P. mirabilis
Viridans Streptococci H. influenzae
M. catarrhalis
Neisseria spp.
 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 cross-reactivity 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 gram-positives
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
Trimethoprim-Sulfamethoxazole
(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