Anita Q.

Sangalang, MD, FPOGS

FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CHEMOTHERAPEUTIC AGENTS

CHEMOTHERAPEUTIC
MICROBIAL RESISTANCE
AGENTS 1. Production of antibiotic-inactivating enzymes
2. Changes in the structure of target receptors
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

1 2

CHEMOTHERAPEUTIC AGENTS CHEMOTHERAPEUTIC AGENTS

MICROBIAL RESISTANCE STRATEGIES

3. Increased efflux via drug transporters 1. Use of adjunctive agents that can protect against
4. Decreases in the permeability of microbes’ cellular antibiotic inactivation
membrane to antibiotics 2. Use of antibiotic combinations

3 4

CHEMOTHERAPEUTIC AGENTS CHEMOTHERAPEUTIC AGENTS

STRATEGIES MICROORGANISMS & ANTIMICROBIALS

3. Introduction of new (and often expensive) Bacteria - Antibacterial
chemical derivatives of established antibiotics
Viruses - Antiviral
4. Efforts to avoid indiscriminate use or misuse
Fungi - Antifungal
of antibiotics
Parasites - Antiparasitic

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL

WALL SYNTHESIS INHIBITORS

BETA-LACTAM ANTIBIOTICS AND • Major antibiotics that inhibit cell wall synthesis
OTHER CELL WALL SYNTHESIS – Penicillins
INHIBITORS – Cephalosporins
• Beta-lactams because of the unusual 4-member ring
that is common to all members

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL

BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS
WALL SYNTHESIS INHIBITORS

• Most effective
• Widely used
• Well-tolerated

Penicillin G (benzylpenicillin)

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

• Antibiotics that inhibit cell wall synthesis

• More than 50 drugs that act as cell wall
• Not as important as beta-lactam drugs
inhibitors are currently available
– Vancomycin
– Fosfomycin
– Bacitracin

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS
BACTERIAL CELL WALL SYNTHESIS INHIBITORS

PENICILLINS CEPHALOSPORINS MISCELLANEOUS

PENICILLINS
A. CLASSIFICATION
Narrow Wider Narrow Wider Carbenepems
spectrum spectrum spectrum spectrum • Derivatives of 6-aminopenicillanic acid
Astreonam • Contains a beta-lactam ring structure
Penicillinase 1st generation 2nd, 3rd, 4th
susceptible generations Vancomycin – Essential for antibacterial activity
Penicillinase
resistant

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS
A. CLASSIFICATION PENICILLINS
• Subclasses B. PHARMACOKINETICS
– Additional chemical substituents that confer • Vary in resistance to gastric acid
differences in • Vary in their oral bioavailability
• Antimicrobial activity • Polar compounds
• Susceptibility to acid and enzymatic hydrolysis – Not metabolized extensively
• Biodisposition

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL

BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS
WALL SYNTHESIS INHIBITORS

PENICILLINS PENICILLINS
B. PHARMACOKINETICS B. PHARMACOKINETICS
• Excreted unchanged in urine via
• Ampicillin and nafcililin
– Glomerular filtration
– Partly excreted in bile
– Tubular excretion
• Plasma half-life vary from 30 min to 1 h
– Inhibited by probenecid

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS PENICILLINS
B. PHARMACOKINETICS C. MOA
• Procaine and benzathine penicillin G • Bactericidal
– Given intramuscularly • Inhibit cell wall synthesis by the following steps
– Long half-lives 1. Binding of the drug to specific receptors
– Drug is released slowly (penicillin-binding proteins [PBPs])
– Cross blood-brain barrier when meninges located in the bacterial cytoplasmic membrane
are inflamed

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND

WALL SYNTHESIS INHIBITORS OTHER CELL WALL SYNTHESIS
INHIBITORS
PENICILLINS PLASMA MEMBRANE CELL WALL
C. MOA GRAM (+)
BACTERIUM
• Bactericidal
• Inhibit cell wall synthesis by the following steps
2. Inhibition of transpeptidase enzymes
•Cross-linked peptidoglycans
that act to cross-link linear peptidoglycan chains
•If damaged will result to cell
lysis (bactericidal)

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS
PENICILLINS
C. MOA
D. RESISTANCE
• Bactericidal
• Beta-lactamases
• Inhibit cell wall synthesis by the following steps
– Penicillinases
3. Activation of autolytic enzymes that cause
lesions in the bacterial cell wall – Formed by most staphylococci and gram (-)
• Enzymatic hydrolysis of the beta-lactam ring results organisms
in the lost of antibacterial activity – Major mechanism for bacterial resistance

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS
D. RESISTANCE PENICILLINS
• Beta-lactamases D. RESISTANCE
– Inhibitors of this enzymes are used in • Structural changes in target PBPs
combination with penicillin to prevent – Another mechanism of bacterial resistance
their inactivation
• Methicillin resistance in staphylococci
• Clavulanic acid
• Penicillin G resistance in pneumococci
• Sulbactam
• Tazobactam

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS PENICILLINS
D. RESISTANCE D. CLINICAL USES
• Changes in the porin structure in the outer 1. Narrow-spectrum penicillinase-susceptible agents
membrane PENICILLIN G
– Contribute to resistance by impeding • Prototype
access of penicillin to PBPs • Parenteral
– Resistance in some gram (-) rods like • Limited spectrum of activity
P. aeruginosa
• Susceptible to beta-lactamases

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS PENICILLINS
D. CLINICAL USES D. CLINICAL USES
1. Narrow-spectrum penicillinase-susceptible agents 1. Narrow-spectrum penicillinase-susceptible agents
PENICILLIN G PENICILLIN G
• Infections caused by • Penicillin-resistant S. pneumoniae (PRSP) strains
– Streptococci • Some strains resistant via production of beta-
– Meningococci lactamases
– Gram (+) bacilli – S. aureus
– N. gonorrhea
– Spirochetes

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS PENICILLINS
D. CLINICAL USES D. CLINICAL USES
1. Narrow-spectrum penicillinase-susceptible agents 1. Narrow-spectrum penicillinase-susceptible agents
PENICILLIN G PENICILLIN V
• Drug of choice for syphilis • Oral
• Activity against enterococci is enhanced by • Oropharyngeal infections
aminoglycoside

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS
D. CLINICAL USES
2. Very-narrow-spectrum penicillinase-resistant agents
METHICILLIN (prototype), NAFCILLIN, OXACILLIN
• Treatment of known or suspected staphylococcal
infections
PENICILLINS
D. CLINICAL USES
2. Very-narrow-spectrum penicillinase-resistant agents
• Methicillin-resistant S. aureus (MRSA) and
S. epidermidis (MRSE) are resistant to other
members of this subgroup and often to multiple
antimicrobial drugs

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS
PENICILLINS D. CLINICAL USES
D. CLINICAL USES 3. Wider spectrum penicillinase-susceptible agents
3. Wider spectrum penicillinase-susceptible agents AMPICILLIN and AMOXICILLIN
AMPICILLIN and AMOXICILLIN • Uses similar to pen G
• Wider spectrum than pen G – Enterococci L. monocytogenes
• Susceptible to penicillinases – E. coli P. mirabilis
– H. influenzae M. catarrhalis

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS PENICILLINS
D. CLINICAL USES D. CLINICAL USES
3. Wider spectrum penicillinase-susceptible agents 3. Wider spectrum penicillinase-susceptible agents
AMPICILLIN and AMOXICILLIN PIPERACILLIN and TICARCILLIN
• Enhanced activity in combination with inhibitors • Activity against gram (-) rods
of penicillinases – Pseudomonas
• Synergistic (1+1=3) with aminoglycosides in enterococcal – Enterobacter
and listerial infections – Some cases of klebsiella species

37 38

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS
D. CLINICAL USES PENICILLINS
3. Wider spectrum penicillinase-susceptible agents E. TOXICITY
PIPERACILLIN and TICARCILLIN 1. Allergy
• Synergistic action with aminoglyclosides – Urticaria Severe pruritus
• Susceptible to penicillinases – Fever Joint swelling
• Enhanced activity in combination with inhibitors – Hemolytic anemia Nephritis
of penicillinases – Anemia

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS PENICILLINS
E. TOXICITY E. TOXICITY
1. Allergy 1. Allergy
• Nafcillin can cause neutropenia • 5-10% of patients with history of allergy will
• Ampicillin causes maculopapular rashes have the same reaction when given again
• Methicillin causes interstitial nephritis more
than other penicillins

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

PENICILLINS
PENICILLINS E. TOXICITY
E. TOXICITY 2. GI disturbances
1. Allergy • Oral penicillins especially ampicillin
• Antigenic determinants include degradation – Nausea and diarrhea
products like penicilloic acid
– Pseudomembranous colitis
• Complete cross-allergenicity exists
• Maybe caused by direct irritation or by
overgrowth of gram (+) organisms or yeasts

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

1 ST GENERATION cephalexin, cefazolin,

cefadroxil, cephalotin,
CEPHALOSPORINS cephadrine, cephapirin
2 ND GENERATION cefuroxime, cefoxitin,
A. CLASSIFICATION
cefotetan, cefamandole
• Derivatives of 7-aminocephalosporanic acid
• Contain the beta-lactam ring structure 3 RD GENERATION ceftriaxone, cefotaxime,
cefoperazone, ceftazidime,
cefixime
4 TH GENERATION cefepime

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

CEPHALOSPORINS
CEPHALOSPORINS
B. PHARMACOKINETICS
B. PHARMACOKINETICS
• Major elimination is via renal tubular excretion
• Oral
• Cefoperazone and ceftriaxone (3rd generation)
• Some given parenterally
– Excreted mainly in the bile
• Cephalosporins with side chains undergo hepatic
metabolism • 1st- and 2nd-generation
– Do not enter the CSF when the meninges
are inflamed

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

CEPHALOSPORINS
D. RESISTANCE CEPHALOSPORINS
• Structural differences from penicillin D. RESISTANCE
• Less susceptible to penicillinases produced • Decrease membrane permeability to the drug
by staphylococci • Changes in PBPs
• Resistance develops through the production • MRSA are also resistant to this drug
of other beta-lactamases

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

CEPHALOSPORINS CEPHALOSPORINS
E. CLINICAL USES E. CLINICAL USES
1. FIRST-GENERATION DRUGS 1. FIRST-GENERATION DRUGS
Cefazolin (IV), cephalexin (oral) • Surgical prophylaxis in selected conditions
• Gram (+) cocci • Minimal activity
– Staphylococci – Gram (-) cocci
– Streptococci – Enteroccoci
• E. coli – MRSA
• K. pneumoniae – Most gram (-) rods

51 52

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

CEPHALOSPORINS CEPHALOSPORINS
E. CLINICAL USES E. CLINICAL USES
2. SECOND-GENERATION DRUGS 2. SECOND-GENERATION DRUGS
• Less activity against gram (+) Cefofetan, cefoxitin
• Extended coverage for gram (-) • B. fragilis
• Marked differences in activity occur Cefamandole, cefuroxime, cefaclor
among the drugs • H. influenzae or M. catarrhalis

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

CEPHALOSPORINS CEPHALOSPORINS
E. CLINICAL USES E. CLINICAL USES
3. THIRD-GENERATION DRUGS 3. THIRD-GENERATION DRUGS
Ceftazidime, cefoperazone, cefotaxime • Providencia
• Increased activity against gram (-) organisms resistant • S. marcescens
to other beta-lactam drugs • Beta-lactamase producing strains
• Ability to penetrate the blood-brain barrier – H. influenzae
– Except cefoperazone, cefixime – Neisseria

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

CEPHALOSPORINS
CEPHALOSPORINS E. CLINICAL USES
E. CLINICAL USES 3. THIRD-GENERATION DRUGS
3. THIRD-GENERATION DRUGS • Individual activity of drugs
• Less active against enterobacter strains that produce a. Cefoperazone, ceftazidime
extended-spectrum beta-lactamases – Pseudomonas
b. Ceftizoxime
– B. fragilis
– a & b for serious infection

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

CEPHALOSPORINS
CEPHALOSPORINS
E. CLINICAL USES
E. CLINICAL USES
4. FOURTH-GENERATION DRUGS
3. THIRD-GENERATION DRUGS
Cefepime
• Individual activity of drugs
• More resistant to beta-lactamases produced
c. Ceftriaxone (IV) and cefixime
by gram (-) organisms
– Drug of choice for gonorrhea
– Enterobacter
d. Ceftriaxone
– Haemophilus
– Single injection for acute otitis media
– Neisseria
– As effective as 10 days of amoxicillin
– Some penicillinase-resistant pneumococci

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

CEPHALOSPORINS CEPHALOSPORINS
E. CLINICAL USES E. TOXICITY
4. FOURTH-GENERATION DRUGS 1. Allergy
Cefepime • Skin rashes to anaphylactic shock
• Combines the gram (+) activity of 1st gen • Occurs less frequently than penicillins
and wider gram (-) spectrum of 3rd gen • Complete cross-hypersensitivity exists

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

CEPHALOSPORINS
E. TOXICITY CEPHALOSPORINS
1. Allergy E. TOXICITY
• Cross-reactivity with penicillins
2. Other adverse effects
– Incomplete (5-10%)
• Pain at IM injection site
– Penicillin allergic patients are sometimes treated
successfully with cephalosporin • Phlebitis after IV injection
– Those with history of anaphylaxis to • Increase nephrotoxicity of aminoglycosides
penicillin should not be treated with drug

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

CEPHALOSPORINS OTHER BETA-LACTAM DRUGS

E. TOXICITY A. ASTREONAM
• Monobactam
2. Other adverse effects
• Resistant to beta-lactamases produced by
• Drugs containing a methlythiotetrazole group
certain gram (-) rods
– Cefamandole, cefoperazone, cefofetan – Klebsiella
– May cause hypoprothrombinemia – Pseudomonas
– Disulfiram-like reactions with ethanol – Serratia

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

OTHER BETA-LACTAM DRUGS OTHER BETA-LACTAM DRUGS

A. ASTREONAM A. ASTREONAM
• No activity against gram (+) and anaerobes
• Given IV
• An inhibitor of cell wall synthesis binding to
• Eliminated via renal tubular secretion
PBP3
• Synergistic with aminoglycosides • Half-life is prolonged in renal failure
• No cross-allergenicity with penicillin

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

OTHER BETA-LACTAM DRUGS

A. ASTREONAM OTHER BETA-LACTAM DRUGS
• Adverse effects B. IMIPENEM, MEROPENEM, and ERTAPENEM
– GI upset with possible superinfection • Carbepenems
– Vertigo • Chemically different from penicillins
• Retain the beta-lactam ring
– Headache
• Low susceptibility to beta-lactamases
– Rare hepatotoxicity
– Skin rash

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

OTHER BETA-LACTAM DRUGS

OTHER BETA-LACTAM DRUGS
B. IMIPENEM, MEROPENEM, and ERTAPENEM
B. IMIPENEM, MEROPENEM, and ERTAPENEM
• Wide activity against
• Given IV
– Gram(+) cocci
• Useful for infections caused by organisms resistant to
– Gram (-) rods other antibiotics
– Anaerobes • Drug of choice for enterobacter
• For pseudomonal infections
– Combine with aminoglycosides

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL

BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS
WALL SYNTHESIS INHIBITORS
OTHER BETA-LACTAM DRUGS
OTHER BETA-LACTAM DRUGS
B. IMIPENEM, MEROPENEM, and ERTAPENEM
B. IMIPENEM, MEROPENEM, and ERTAPENEM
• IMIPENEM
• IMIPENEM
– Rapidly inactivated by renal dehydropep-
– Adverse effects of imipenem-cilastatin
tidases I
• GI distress
– Cilastatin
• Skin rash
• Administered in combination
• At very high plasma levels, CNS toxicity
• Inhibitor of the enzyme
– Confusion, encephalopathy, seizures
• Increases the half-life
– Partial cross-allergenicity with penicillins
• Inhibits formation of nephrotoxic metabolites

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

OTHER BETA-LACTAM DRUGS OTHER BETA-LACTAM DRUGS

B. IMIPENEM, MEROPENEM, and ERTAPENEM
• MEROPENEM
– Similar to imipenem
– Not metabolized by renal dehydropeptidases
– Less likely to cause seizure
B. IMIPENEM, MEROPENEM, and ERTAPENEM
• ERTAPENEM
– Long half-life
– Less active against pseudomonas
– IM injection causes pain and irritation

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BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

OTHER BETA-LACTAM DRUGS

OTHER BETA-LACTAM DRUGS C. BETA-LACTAMASE INHIBITORS
C. BETA-LACTAMASE INHIBITORS • CLAVULANIC ACID, SULBACTAM,
• CLAVULANIC ACID, SULBACTAM, and TAZOBACTAM
and TAZOBACTAM – Plasmid-encoded beta-lactamases
– Used in fixed combination with certain • Gonococci
hydrolyzable penicillins • Streptococci
• E. coli
• H. influenzae

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Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

OTHER INHIBITORS OF CELL WALL OTHER INHIBITORS OF CELL WALL

SYNTHESIS SYNTHESIS
A. VANCOMYCIN A. VANCOMYCIN
• Bactericidal glycoprotein • Inhibits transglycosylation
• Binds to the D-Ala-D-Ala terminal of the • Prevents elongation of peptidoglycan chain
nascent peptidoglycan pentapeptide side • Interferes with cross-linking
chain • Narrow spectrum of activity

79 80

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

OTHER INHIBITORS OF CELL WALL

OTHER INHIBITORS OF CELL WALL
SYNTHESIS
A. VANCOMYCIN
SYNTHESIS
• Vancomycin-resistant enterococci (VRE) A. VANCOMYCIN
and vancomycin-resistant S. aureus • Drug-resistant gram (+) organisms
(VRSA) – MRSA
– Due to decreased affinity of the drug to – Penicillin-resistant pneumococci
the binding site – C. difficile
– Replacement of D-Ala by D-lactate

81 82

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

OTHER INHIBITORS OF CELL WALL OTHER INHIBITORS OF CELL WALL

SYNTHESIS SYNTHESIS
A. VANCOMYCIN A. VANCOMYCIN
• Not absorbed orally • Dosage modification in patients with renal
• Maybe given for bacterial enterocolitis impairment
• Rapid IV infusion may cause diffuse blushing
• When given IV, penetrates most tissues
– “Red man syndrome”
• Eliminated unchanged in urine

83 84
PHARMACOLOGY
CHAPTER 43
BETA-LACTAM ANTIBIOTICS & OTHER CELL
WALL SYTHESIS INIHIBITORS 14
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

OTHER INHIBITORS OF CELL WALL OTHER INHIBITORS OF CELL WALL

SYNTHESIS SYNTHESIS
A. VANCOMYCIN B. FOSFOMYCIN
• Toxic effects • Antimetabolite inhibitor of cytosolic
– Chills
enolpyruvate transferase
– Fever
• Prevents the formation of N- acetylmuramic
– Phlebitis
– Ototoxicity acid which is essential in peptidoglycan chain
formation
– Nephrotoxicity

85 86

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

OTHER INHIBITORS OF CELL WALL OTHER INHIBITORS OF CELL WALL

SYNTHESIS SYNTHESIS
B. FOSFOMYCIN B. FOSFOMYCIN
• Resistance occurs via decreased intracellular • In a single dose
accumulation of the drug – Drug is less effective than the 7-day course of
• Excreted in the kidney with urinary levels exceeding treatment with fluoroquinolones
the MICs for many urinary tract pathogens • Multiple dosing can result to resistance rapidly

87 88

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

OTHER INHIBITORS OF CELL WALL

OTHER INHIBITORS OF CELL WALL
SYNTHESIS
SYNTHESIS C. BACITRACIN
B. FOSFOMYCIN • Peptide antibiotic
• Diarrhea is common • Interferes with a late stage in cell wall
• Synergistic with beta-lactam and quinolones synthesis in gram (+) organisms
in specific infections
• Marked toxicity
• Limited to topical use only

89 90
PHARMACOLOGY
CHAPTER 43
BETA-LACTAM ANTIBIOTICS & OTHER CELL
WALL SYTHESIS INIHIBITORS 15
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

BETA-LACTAM ANTIBIOTICS AND OTHER CELL BETA-LACTAM ANTIBIOTICS AND OTHER CELL
WALL SYNTHESIS INHIBITORS WALL SYNTHESIS INHIBITORS

OTHER INHIBITORS OF CELL WALL

OTHER INHIBITORS OF CELL WALL
SYNTHESIS
SYNTHESIS
D. CYLCOSERINE
D. CYLCOSERINE
• Antimetabolite
• Potentially neurotoxic
• Blocks the incorporation of D-Ala into the
– Tremors
pentapeptide side chain of the peptidoglycan
– Seizure
• Used only in TB caused by organisms resistant to
first-line antituberculous drugs – Psychosis

91 92

PHARMACOLOGY
CHAPTER 43
BETA-LACTAM ANTIBIOTICS & OTHER CELL
WALL SYTHESIS INIHIBITORS 16
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN,
CHLORAMPHENICOL, STREPTOGRAMINS, & LINEZOLID
TETRACYCLINES, MACROLIDES,
CLINDAMYCIN, STREPTOGRAMINS,
& LINEZOLID
o Selectively inhibit bacterial protein synthesis
o Protein synthesis in microorganisms is not
Anita Q. Sangalang, MD, FPOGS identical to mammalian cells
FACULTY OF PHARMACY n 70S ribosomes in bacteria
UNIVERSITY OF SANTO TOMAS
n 80S ribosomes in mammalians

1 2

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

BACTERIAL PROTEIN SYNTHESIS INHIBITORS

o Basis for selective toxicity against microorganisms
without causing major effects on mammalian cells
BROAD SPECTRUM MODERATE SPECTRUM NARROW SPECTRUM
n Differences

o Ribosomal subunits
o Chemical composition
CHLORAMPHENICOL MACROLIDES KETOLIDES LINCOSAMIDES

o Functional specificities of component nucleic TETRACYCLINES STREPTOGRAMINS

acids and proteins LINEZOLID

3 4

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

MECHANISM OF ACTION
o Chloramphenicol
MECHANISM OF ACTION
n Inhibits transpeptidation (catalyzed by peptidyl
o Bacteriostatic inhibitors of protein synthesis transferase)
o 50S ribosome unit n Blocks the binding of aminoacyl moiety of tRNA
n Except of tetracycline to mRNA complex peptide at the donor site
cannot be transferred to the amino acid acceptor

5 6
PHARMACOLOGY
CHAPTER 44
CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN 1
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

MECHANISM OF ACTION
MECHANISM OF ACTION
o Macrolides, telithromycin, and clindamycin
o Tetracyclines
n Bind at 50S-block translocation of peptidyl-
n Bind to 30S
tRNA from the acceptor site to the donor site
n Blocks the binding of amino-acid-charged
n tRNA cannot access the occupied receptor site,
tRNA to the acceptor site
it is not added to the peptide chain

7 8

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

MECHANISM OF ACTION
MECHANISM OF ACTION
o Streptogramins
o Linezolid
n Bactericidal
n Bacteriostatic
n Bind to 50S
n Binds to a unique site at 50S
n Constrict the exit channel on the ribosome
n Blocks formation of tRNA-ribosome-
through which polypeptides are extruded
tRNA synthase activity is inhibited mRNA complex

9 10

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

CHLORAMPHENICOL
CHLORAMPHENICOL
A. CLASSIFICATION
A. CLASSIFICATION
o Simple and distinctive structure
o Enterohepatic cycling
o No other antimicrobials in this class
o Fraction excreted in urine unchanged
o Oral as well as parenteral
o Inactivated by hepatic glucoronosyltransferase
o Distributed throughout all tissues
o Crosses placental and blood-brain barriers

11 12
PHARMACOLOGY
CHAPTER 44
CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN 2
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

CHLORAMPHENICOL CHLORAMPHENICOL
B. ANTIMICROBIAL ACTIVITY B. ANTIMICROBIAL ACTIVITY
o Bacteriostatic o Not effective for chlamydia
o Bactericidal for some strains o Resistance
n H. influenzae n Plasmid mediated-formation of acetyl-
n N. meningitidis transferases that inactivate the drug
n Bacteroides

13 14

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

CHLORAMPHENICOL
CHLORAMPHENICOL
C. CLINICAL USES
C. CLINICAL USES
o Few uses as systemic drug because of toxicity
o Sometimes used for ricketssial infections
o Backup drug for severe infections caused by
salmonella o Infections caused by anaerobes like B. fragilis
o Treatment of pneumococcal and meningococcal o Commonly used as topical agent
meningitis in beta-lactam-sensitive persons

15 16

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

CHLORAMPHENICOL CHLORAMPHENICOL
D. TOXICITY D. TOXICITY
1. GI disturbances 2. Bone marrow
o Direct irritation and superinfection o Inhibition of red cell maturation decrease
n Candidiasis in circulating RBC
o Reversible

17 18
PHARMACOLOGY
CHAPTER 44
CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN 3
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

CHLORAMPHENICOL
CHLORAMPHENICOL D. TOXICITY

D. TOXICITY 4. Gray baby syndrome

3. Aplastic anemia
o Rare idiosyncratic reaction
o Irreversible and maybe fatal
o Premature infants
o Deficiency of hepatic glucoronyltransferase
o Tolerated in older infants
o Decreased RBC, cyanosis and cardiovascular
collapse

19 20

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

TETRACYCLINES
TETRACYCLINES B. PHARMACOKINETICS
A. CLASSIFICATION o Oral absorption is variable especially for older
drugs
o Structural congeners
o Impaired by food and multivalent cations
o Broad range of antimicrobial activity
n Calcium, iron and aluminum
o Minor differences in activity against organisms
o Wide tissue distribution
o Cross the placental barrier

21 22

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

TETRACYCLINES TETRACYCLINES
B. PHARMACOKINETICS C. ANTIBACTERIAL ACTIVITY
o Enterohepatic cycling o Gram (+) and gram (-) bacteria
o All drugs eliminated in the urine n Rickettsia Chlamydia
n Doxycycline n Mycoplasma Some protozoa
o Excreted in the feces o Organisms accumulate the drug intracellularly
o Together with minocycline have longer half-lives via energy-dependent transport systems

23 24
PHARMACOLOGY
CHAPTER 44
CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN 4
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID
TETRACYCLINES
D. CLINICAL USES
TETRACYCLINES
1. Primary uses
C. ANTIBACTERIAL ACTIVITY
o Tetracyclines
o Plasmid-mediated resistance is widespread
n M. pneumoniae (in adults)
n Decrease activity of the uptake systems
n Chlamydia
n Development of efflux pumps for active
extrusion of the drug n Rickettsia

n Vibrio cholera

o Drug of choice

25 26

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID
TETRACYCLINES
D. CLINICAL USES TETRACYCLINES
2. Secondary uses D. CLINICAL USES
o Tetracyclines 3. Selective uses
n Alternative drug for syphilis
o Tetracycline
n Respiratory infections caused by susceptible n Gastrointestinal ulcers caused by H. pylori
organisms o Doxycycline
n Prophylaxis against chronic bronchitis
n Lyme disease
n Leptospirosis
n Treatment of acne

27 28

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID
TETRACYCLINES
D. CLINICAL USES TETRACYCLINES
3. Selective uses D. CLINICAL USES

o Minocycline 3. Selective uses

n Meningococcal carrier state o Demeclocycline
o Doxycycline n ADH-secreting tumors

n Prevention of malaria o Inhibits renal actions of ADH

n Treatment of amoebiasis

29 30
PHARMACOLOGY
CHAPTER 44
CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN 5
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID
TETRACYCLINES
E. TOXICITY TETRACYCLINES
1. GI disturbances E. TOXICITY
o Mild nausea and diarrhea to severe, possibly 2. Bony structures and teeth
life-threatening colitis o Fetal exposure
o Disturbances in the normal flora
n Tooth enamel dysplasia
n Candidiasis (oral and vaginal)
n Irregularities in bone growth
o Bacterial superinfection
o Contraindicated in pregnancy
n S. aureus or C. difficile
n Rare

31 32

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID
TETRACYCLINES
E. TOXICITY TETRACYCLINES
2. Bony structures and teeth E. TOXICITY
o Younger children (under age 8) 3. Hepatic toxicity
n Enamel dysplasia and crown deformation o High doses in pregnant women and
when permanent teeth appears those with preexisting renal disease may
n Bind with calcium and deposit in newly formed impair liver function
bones (impaired long bone formation ) and teeth n Hepatic necrosis

(discolouration of teeth)

33 34

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

TETRACYCLINES
TETRACYCLINES
E. TOXICITY
E. TOXICITY 3. Photosensitivity
4. Renal toxicity o Demeclocycline
o Fanconi’s syndrome n Enhanced skin sensitivity to ultraviolet light
n Renal tubular acidosis 4. Vestibular toxicity
n Intake of outdated tetracycline o Doxycycline and minocycline
n Dose-dependent reversible dizziness and vertigo

35 36
PHARMACOLOGY
CHAPTER 44
CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN 6
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID
MACROLIDES
MACROLIDES A. CLASSIFICATION AND PHARMACOKINETICS
A. CLASSIFICATION AND PHARMACOKINETICS o Azithromycin
o Erythromycin , azithromycin, and clarithromycin n Absorption is impeded by food
n Large cyclic lactone ring structure with attached n Levels in tissues and phagocytes are higher
sugars than in plasma
n Good oral bioavailability n Eliminated slowly in the urine mainly as
n Distribute to most body tissues unchanged drug
n Half-life is 2-4 days

37 38

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

MACROLIDES MACROLIDES
A. CLASSIFICATION AND PHARMACOKINETICS B. ANTIBACTERIAL ACTIVITY
o Erythromycin and clarithromycin o Erythromycin
n Elimination of intact drug is rapid
n Campylobacter
n Biliary excretion
n Chlamydia
o Erythromycin
n Mycoplasma
n Hepatic metabolism and urinary excretion
n Legionella
o Clarithromycin

n Half-life is 2-5 hours n Gram (+) cocci, and some gram (-) organisms

39 40

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

MACROLIDES MACROLIDES
B. ANTIBACTERIAL ACTIVITY B. ANTIBACTERIAL ACTIVITY
o Erythromycin o Azithromycin and clarithromycin
n Same spectra of activity but include greater
n Erythromycin stearate
activity
n Erythromycin lactobionate
o Chlamydia
n Erythromycin estolate
o M. avium complex (MAV)
o Best absorbed oral preparation
o Toxoplasma

41 42
PHARMACOLOGY
CHAPTER 44
CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN 7
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

MACROLIDES MACROLIDES
B. ANTIBACTERIAL ACTIVITY B. ANTIBACTERIAL ACTIVITY
o Resistance in gram (+) organisms o Cross-resistance between individual macrolides
n Efflux pump mechanisms is complete
n Production of methylase that adds methyl group o Partial cross-resistance with other drugs that bind
to the ribosomal binding site to the same site occur in methylase-producing
o Resistance to enterobacteriaceae strains
n Formation of drug-metabolizing esterases n Clindamycin and streptogramins

43 44

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

MACROLIDES MACROLIDES
C. CLINICAL USES C. CLINICAL USES
o Erythromycin o Erythromycin
n M. pneumonia Corynebacterium n Gram (+) cocci like pneumococci

n C. jejuni C. trachomatis (not penicillin-resistant S. pneumoniae [PRSP])

n L. pneumophilia U. urealyticum n Beta-lactamase-producing staphylococci

n B. pertussis (not methicillin –resistant S. aureus [MRSA]

strains)

45 46

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

MACROLIDES
MACROLIDES
C. CLINICAL USES
C. CLINICAL USES
o Azithromycin
o Azithromycin
n Long half-life, single dose is effective
o Similar spectrum of activity but more active
o Urogential infections caused by C. trachomatis
n H. influenzae
n 4-day course is effective for community-acquired
n M. catarrhalis
n Neisseria pneumonia (CAP)

47 48
PHARMACOLOGY
CHAPTER 44
CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN 8
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

MACROLIDES MACROLIDES
C. CLINICAL USES D. TOXICITY
o Clarithromycin o GI irritation is common
n Prophylaxis against and treatment of M. avium
n Stimulation of motolin receptors
complex
n Skin rashes
n Component for drug regimens for ulcers caused
n Eosinophilia
by H. pylori

49 50

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

MACROLIDES
MACROLIDES
D. TOXICITY
D. TOXICITY
o Erythromycin
o Erythromycin estolate
n Inhibits several forms of cytochrome P450
n Hypersensitivity-based acute cholestatic
n Increases the plasma levels
hepatitis
o Anticoagulants Carbamazepine
n Rare in children
o Cisapride Digoxin
n Increased risk in pregnant patients
o Theophylline

51 52

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID
MACROLIDES
D. TOXICITY TELITHROMYCIN
o Clarithromycin o Ketolide
n Similar drug interactions of erythromycin
o Structurally related to macrolides
can occur o Same MOA as erythromycin
o Azithromycin o Similar spectrum of antimicrobial activity
n Structure of lactone ring is slightly different
o Some macrolide-resistant strains are susceptible
n Drug interactions are uncommon because it binds more tightly to ribosomes
n Does not inhibit hepatic cytochrome P450

53 54
PHARMACOLOGY
CHAPTER 44
CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN 9
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

CLINDAMYCIN
TELITHROMYCIN
A. CLASSIFICATION AND PHARMACOKINETICS
o Poor substrate for bacterial efflux pump that mediate
resistance o Lincosamides
o CAP and other upper respiratory tract infections o Lincomycin and clindamycin
n Inhibit bacterial protein synthesis
o Given orally once daily
n Mechanism similar to macrolides but are not
o Eliminated in the bile and urine
chemically related
o Inhibitor of cytochrome CYP3A4 isozyme

55 56

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

CLINDAMYCIN CLINDAMYCIN
A. CLASSIFICATION AND PHARMACOKINETICS A. CLASSIFICATION AND PHARMACOKINETICS
o Resistance o Orally absorbed
n Methylation of the binding site on 50S o Good tissue penetration
n Enzymatic inactivation
o Eliminated partly by metabolism and partly by
o Cross-resistance with macrolides is common biliary and renal excretion

57 58

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID

CLINDAMYCIN CLINDAMYCIN
B. CLINICAL USE AND TOXICITY B. CLINICAL USE AND TOXICITY
o Clindamycin o Clindamycin
n Severe infections n Toxicity
o Anaerobes like bacteroides o GI irritation Skin rashes
n Backup drug against gram (+) cocci o Neutropenia Hepatic dysfunction
n Prophylaxis for endocarditis in valvular heart o Superinfection such as C. difficile and
disease who are allergic to penicillin pseudomembranous colitis
n Active against P. carinii and T. gondii n Treated by oral vancomycin

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PHARMACOLOGY
CHAPTER 44
CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN 10
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

CHLORAMPHENICOL, TETRACYCLINES, CHLORAMPHENICOL, TETRACYCLINES,

MACROLIDES, CLINDAMYCIN, MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID STREPTOGRAMINS, & LINEZOLID
STREPTOGRAMINS
LINEZOLID
o Quinupristin-dalfopristin o First of a new class of antibiotics
n Combination of 2 streptogramins o Oxazolidinones
n Bactericidal o Gram (+) cocci, including strains resistant to
n Postantibiotic effect beta-lactams and vancomycin
o Duration of bacterial activity is longer than the o Binds to a unique site on the 23S ribosomal
half-lives of the 2 compounds RNA of 50S
n Used for PRP, MRSA and vancomycin-resistant o No cross-resistance with other protein synthesis
staphylococci (VRSA) and resistant E. faecium inhibitors

61 62

CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN,
STREPTOGRAMINS, & LINEZOLID

LINEZOLID
o Resistance
n Rare
n Decreased affinity of the drug for its binding site
o Available in oral and parenteral form
o Thrombocytopenia and neutropenia occur in
immunocompromised patients

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PHARMACOLOGY
CHAPTER 44
CHLORAMPHENICOL, TETRACYCLINES,
MACROLIDES, CLINDAMYCIN 11
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

AMINOGLYCOSIDES
AMINOGLYCOSIDES
MODES OF ANTIBACTERIAL ACTION
l Treatment of microbial infection with
antibiotics
Anita Q. Sangalang, MD, FPOGS
• Multiple daily dosing
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS
• Maintain serum concentration level
above the minimum inhibitory
concentration (MIC)

1 2

AMINOGLYCOSIDES AMINOGLYCOSIDES

MODES OF ANTIBACTERIAL ACTION MODES OF ANTIBACTERIAL ACTION

CONCENTRATION DEPENDENT TIME DEPENDENT
l Some drugs and aminoglycosides l Any antibiotics, including penicillin and

• As the plasma level is increased above cephalosporins

the MIC, the drug kills an increasing • Directly related to time above MIC
proportion of bacteria at a more rapid • Independent of concentration once
rate the MIC is reached

3 4

AMINOGLYCOSIDES AMINOGLYCOSIDES

MODES OF ANTIBACTERIAL ACTION MODES OF ANTIBACTERIAL ACTION

POSTANTIBIOTIC EFFECT POSTANTIBIOTIC EFFECT
l Greater efficacy when administered as
l Aminoglycosides’ killing action continues

when the plasma levels have declined a single large dose than when given as
multiple smaller doses
below measurable levels

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PHARMACOLOGY
CHAPTER 45
AMINOGLYCOSIDES 1
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

AMINOGLYCOSIDES AMINOGLYCOSIDES

MODES OF ANTIBACTERIAL ACTION

PHARMACOKINETICS
l Toxicity (in contrast to antibacterial activity)
depends on a critical plasma concentration l Structurally related amino sugars

and on that time such a level is exceeded attached by glycosidic linkages

l Time above such threshold is shorter with l Polar compounds

single large dose l Not absorbed orally

l Basis for once-daily dosing protocols

7 8

AMINOGLYCOSIDES AMINOGLYCOSIDES

PHARMACOKINETICS PHARMACOKINETICS
l Given intramuscularly or intravenously
l Major mode of excretion
for systemic effects • Glomerular filtration
l Limited tissue penetration
l Plasma levels are affected by changes
l Do not readily cross the blood-brain
in renal function
barrier

9 10

AMINOGLYCOSIDES AMINOGLYCOSIDES

PHARMACOKINETICS
PHARMACOKINETICS
l Dosage adjustment must be made in
l Excretion is directly proportional to
renal insufficiency to avoid toxic
creatinine clearance
accumulation
l With normal renal function, elimination
l Monitoring plasma levels is needed for
half-life is 2-3 h
safe and effective dosage selection and
adjustment

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PHARMACOLOGY
CHAPTER 45
AMINOGLYCOSIDES 2
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

AMINOGLYCOSIDES AMINOGLYCOSIDES

PHARMACOKINETICS
l For traditional dosing regimens
MECHANISM OF ACTION
• 2 or 3 times daily
• Peak serum levels l Bactericidal (irreversible) inhibitors of
protein synthesis
• Measured at 30-60 minutes after
administration l Penetration of bacterial cell wall is partly

• Trough serum levels dependent on O2-dependent active

• Measured just before the next dose transport

13 14

AMINOGLYCOSIDES AMINOGLYCOSIDES

MECHANISM OF ACTION
MECHANISM OF ACTION l Bind to 30S ribosomal unit
l Minimal activity against strict anaerobes l Interfere with protein synthesis
l Transport is enhanced by cell wall 1. Block formation of initiation complex
synthesis inhibitors 2. Cause misreading of the code on the
• Antimicrobial synergism mRNA template
3. Inhibit translocation

15 16

AMINOGLYCOSIDES AMINOGLYCOSIDES

MECHANISMS OF RESISTANCE MECHANISMS OF RESISTANCE

l Resistant due to failure to penetrate l Plasmid-mediated formation of inactivating

into the cell enzymes

• Streptococci, including S. pneumoniae • Primary mechanism of resistance
• Enterococci • Varying susceptibility to the enzyme

17 18

PHARMACOLOGY
CHAPTER 45
AMINOGLYCOSIDES 3
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

AMINOGLYCOSIDES AMINOGLYCOSIDES
MECHANISMS OF RESISTANCE
MECHANISMS OF RESISTANCE
l Plasmid-mediated formation of inactivating
l Plasmid-mediated formation of inactivating
enzymes enzymes
• Group transferases • Transferases produced by enterococci
• Catalyze the acetylation of amine can inactivate
functions • Amikacin
• Transfer of phosphoryl or adenyl groups • Gentamicin
to the O2 atoms of hydroxyl groups on • Tobramycin
the aminoglycoside • Not streptomycin

19 20

AMINOGLYCOSIDES AMINOGLYCOSIDES

CLINICAL USES
MECHANISMS OF RESISTANCE GENTAMICIN, TOBRAMYCIN, and AMIKACIN
l Plasmid-mediated formation of inactivating l Serious infections caused by aerobic

enzymes gram (-) bacteria

• Netilmicin is less susceptible and is active • E. coli Enterobacter
against more strains of organisms • Klebsiella Proteus
• Providencia Pseudomonas
• Serratia

21 22

AMINOGLYCOSIDES AMINOGLYCOSIDES

CLINICAL USES CLINICAL USES

GENTAMICIN, TOBRAMYCIN, and AMIKACIN ANTIBACTERIAL SYNERGY
l Used for the following but is not the drug of l Not effective for gram (+) cocci when
choice used alone
• H. influenzae l Combination of aminoglycoside and
• M. catarrhalis cell wall synthesis inhibitors
• Shigella species

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PHARMACOLOGY
CHAPTER 45
AMINOGLYCOSIDES 4
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

AMINOGLYCOSIDES AMINOGLYCOSIDES

CLINICAL USES
CLINICAL USES
STREPTOMYCIN
ANTIBACTERIAL SYNERGY
l Tuberculosis
l Combined with penicillin in the treatment
l Plague
• Pseudomonal l Tularemia
• Listerial l Multi-drug-resistant (MDR) strains of M. tb
• Enterococcal infections resistant to streptomycin maybe susceptible
to amikacin

25 26

AMINOGLYCOSIDES AMINOGLYCOSIDES

CLINICAL USES
NEOMYCIN CLINICAL USES
l Used topically NETILMICIN
l Locally l Reserved for serious infections resistant

• In the GIT to other aminoglycosides

• Eliminate bacterial flora

27 28

AMINOGLYCOSIDES AMINOGLYCOSIDES

TOXICITY
A. OTOTOXICITY
CLINICAL USES
l Auditory or vestibular damage (or both)
SPECTINOMYCIN
maybe irreversible
l Aminocylitol related to aminoglycosides

l Back-up drug
• Auditory impairment
l Intramuscular as single dose for gonorrhea
• Amikacin and kanamycin
• Vestibular dysfunction
• Gentamicin and tobramycin

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PHARMACOLOGY
CHAPTER 45
AMINOGLYCOSIDES 5
Anita Q. Sangalang, MD, FPOGS
FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

AMINOGLYCOSIDES AMINOGLYCOSIDES

TOXICITY
A. OTOTOXICITY TOXICITY
l Risk is proportionate to the plasma B. NEPHROTOXICITY

levels l Acute tubular necrosis

• High if dosage is not modified in renal l Reversible
dysfunction l Most nephrotoxic
l Increased with the use of loop diuretics • Gentamicin and tobramycin
l Contraindicated in pregnancy

31 32

AMINOGLYCOSIDES AMINOGLYCOSIDES

TOXICITY
TOXICITY
B. NEPHROTOXICITY
C. NEUROMUSCULAR BLOCKADE
l More common in elderly patients
l Rare
l Patients concurrently receiving
Curare-like block may occur at high doses
• Amphotericin B l

• Cephalosporins • Respiratory paralysis

Reversible
• Vancomycin l

33 34

AMINOGLYCOSIDES AMINOGLYCOSIDES

TOXICITY
TOXICITY
C. NEUROMUSCULAR BLOCKADE
D. SKIN REACTIONS
l Treatment
l Neomycin
• Calcium • Allergic skin reactions like contact
• Neostigmine dermatitis
• Ventilatory support

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PHARMACOLOGY
CHAPTER 45
AMINOGLYCOSIDES 6