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CHEMOTHERAPEUTIC AGENTS

A. Q. Sangalang, MD, FPOGS


FACULTY OF PHARMACY
UNIVERSITY OF SANTO TOMAS

MICROBIAL RESISTANCE
1. Production of antibiotic-inactivating enzymes
2. Changes in the structure of target receptors
3. Increased efflux via drug transporters
4. Decrease in the permeability of microbes cellular membrane to antibiotics

STRATEGIES AGAINST MICROBIAL RESISTANCE


1. Use of adjunctive agents that can protect against antibiotic inactivation
2. Use of antibiotic combinations
3. Introduction of new (and often expensive) chemical derivatives of established
antibiotics
4. Efforts to avoid indiscriminate use or misuse of antibiotics

MICROORGANISMS & ANTIMICROBIALS


Bacteria - Antibacterial
Viruses - Antiviral
Fungi - Antifungal
Parasites - Antiparasitic

BETA-LACTAM ANTIBIOTICS AND OTHER CELL WALL SYNTHESIS INHIBITORS


l Major antibiotics that inhibit cell wall synthesis
Penicillins
Cephalosporins
l Beta-lactams because of the unusual 4-member ring that is common to all
members
l Most effective

l Widely used
l Well-tolerated
l More than 50 drugs that act as cell wall inhibitors are currently available

PENICILLINS

A. CLASSIFICATION
l Derivatives of 6-aminopenicillanic acid
l Contains a beta-lactam ring structure
Essential for antibacterial activity
l Subclasses
Additional chemical substituents that confer differences in
l Antimicrobial activity
l Susceptibility to acid and enzymatic hydrolysis
l Biodisposition

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B. PHARMACOKINETICS
l Vary in resistance to gastric acid
l Vary in their oral bioavailability
l Polar compounds
Not metabolized extensively
l Excreted unchanged in urine via
Glomerular filtration
Tubular excretion
Inhibited by probenecid
l Ampicillin and Nafcillin
Partly excreted in bile
l Plasma half-life vary from 30 min to 1 h
l Procaine and benzathine penicillin G
Given intramuscularly
Long half-lives
Drug is released slowly
Cross blood-brain barrier when meninges are inflamed

C. MOA
l Bactericidal
l Inhibit cell wall synthesis by the following steps
1. Binding of the drug to specific receptors (penicillin-binding proteins
[PBPs]) located in the bacterial cytoplasmic membrane
2. Inhibition of transpeptidase enzymes that act to cross-link linear
peptidoglycan chains
3. Activation of autolytic enzymes that cause lesions in the bacterial cell wall
l Enzymatic hydrolysis of the beta-lactam ring results in the lost of antibacterial
activity

D. RESISTANCE
l Beta-lactamases
Penicillinases
Formed by most staphylococci and gram (-) organisms
Major mechanism for bacterial resistance
Inhibitors of this enzymes are used in combination with penicillin to
prevent their inactivation
l Clavulanic acid
l Sulbactam
l Tazobactam
l Structural changes in target PBPs
Another mechanism of bacterial resistance
l Methicillin resistance in staphylococci
l Penicillin G resistance in pneumococci
l Changes in the porin structure in the outer membrane
Contribute to resistance by impeding access of penicillin to PBPs
Resistance in some gram (-) rods like P. aeruginosa

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D. CLINICAL USES
1. Narrow-spectrum penicillinase-susceptible agents

PENICILLIN G
l Prototype
l Parenteral
l Limited spectrum of activity
l Susceptible to beta-lactamases
l For infections caused by
l Streptococci
l Meningococci
l Gram (+) bacilli
l Spirochetes
l Penicillin-resistant S. pneumoniae (PRSP) strains
l Some strains resistant via production of beta-lactamases
l S. aureus
l N. gonorrhea
l Drug of choice for syphilis
l Activity against enterococci is enhanced by aminoglycoside

PENICILLIN V
l Oral
l Oropharyngeal infections

2. Very-narrow-spectrum penicillinase-resistant agents

METHICILLIN (prototype), NAFCILLIN, OXACILLIN


l Treatment of known or suspected staphylococcal infections
l Methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE) are resistant
to other members of this subgroup and often to multiple antimicrobial drugs

3. Wider spectrum penicillinase-susceptible agents

AMPICILLIN and AMOXICILLIN


l Wider spectrum than pen G
l Susceptible to penicillinases
l Uses similar to pen G
Enterococci L. monocytogenes
E. coli P. mirabilis
H. influenzae M. catarrhalis
l Enhanced activity in combination with inhibitors of penicillinases
l Synergistic (1+1=3) with aminoglycosides in enterococcal and listerial infections

PIPERACILLIN and TICARCILLIN


l Activity against gram (-) rods
Pseudomonas
Enterobacter
Some cases of klebsiella species
l Synergistic action with aminoglycosides
l Susceptible to penicillinases
l Enhanced activity in combination with inhibitors of penicillinases

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E. TOXICITY
1. Allergy
Urticaria Severe pruritus
Fever Joint swelling
Hemolytic anemia Nephritis
Anemia

Nafcillin can cause neutropenia


Ampicillin causes maculopapular rashes
Methicillin causes interstitial nephritis more than other penicillins
5-10% of patients with history of allergy will have the same reaction when
given again
Antigenic determinants include degradation
products like penicilloic acid
Complete cross-allergenicity exists

2. GI disturbances
l Oral penicillins especially ampicillin
Nausea and diarrhea
Pseudomembranous colitis
l Maybe caused by direct irritation or by overgrowth of gram (+)
organisms or yeasts

CEPHALOSPORINS

A. CLASSIFICATION
l Derivatives of 7-aminocephalosporanic acid
l Contain the beta-lactam ring structure

1ST GENERATION cephalexin, cefazolin, cefadroxil,


cephalotin, cephadrine, cephapirin

2ND GENERATION cefuroxime, cefoxitin, cefotetan,


cefamandole

3RD GENERATION ceftriaxone,cefotaxime,


cefoperazone, ceftazidime, cefixime

4TH GENERATION Cefepime, cefpirome

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

C. MOA
l Bind to PBPs on bacterial cell membranes
to inhibit bacterial cell wall synthesis
l Mechanism similar to penicillin
l Bactericidal

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

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

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

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3. THIRD-GENERATION DRUGS
Ceftazidime, cefoperazone, cefotaxime
l Increased activity against gram (-) organisms resistant to other beta-lactam drugs
l Ability to penetrate the blood-brain barrier
Except cefoperazone, cefixime
l Providencia
l S. marcescens
l Beta-lactamase producing strains
H. influenzae
Neisseria
l Less active against enterobacter strains that produce extended-spectrum beta-
lactamases
l Individual activity of drugs
a. Cefoperazone, ceftazidime
Pseudomonas
b. Ceftizoxime
B. fragilis
a & b for serious infection
c. Ceftriaxone (IV) and cefixime
Drug of choice for gonorrhea
d. Ceftriaxone
Single injection for acute otitis media
As effective as 10 days of amoxicillin

4. FOURTH-GENERATION DRUGS
Cefepime
l More resistant to beta-lactamases produced
by gram (-) organisms
Enterobacter
Haemophilus
Neisseria
Some penicillinase-resistant pneumococci
Combines the gram (+) activity of 1st gen and wider gram (-) spectrum of 3rd gen

E. TOXICITY
1. Allergy
l Skin rashes to anaphylactic shock
l Occurs less frequently than penicillins
l Complete cross-hypersensitivity exists
l Cross-reactivity with penicillins
l Incomplete (5-10%)
l Penicillin allergic patients are sometimes treated successfully with
cephalosporin
l Those with history of anaphylaxis to penicillin should not be treated with
drug

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2. Other adverse effects
l Pain at IM injection site
l Phlebitis after IV injection
l Increase nephrotoxicity of aminoglycosides
l Drugs containing a methlythiotetrazole group
Cefamandole, cefoperazone, cefofetan
May cause hypoprothrombinemia
Disulfiram-like reactions with ethanol

OTHER BETA-LACTAM DRUGS

A. ASTREONAM
l Monobactam
l Resistant to beta-lactamases produced by certain gram (-) rods
Klebsiella
Pseudomonas
Serratia
l No activity against gram (+) and anaerobes
l An inhibitor of cell wall synthesis binding to
PBP3
l Synergistic with aminoglycosides
l Given IV
l Eliminated via renal tubular secretion
l Half-life is prolonged in renal failure
l No cross-allergenicity with penicillin
l Adverse effects
l GI upset with possible superinfection
l Vertigo
l Headache
l Rare hepatotoxicity
l Skin rash

B. IMIPENEM, MEROPENEM, and ERTAPENEM


l Carbepenems
l Chemically different from penicillins
l Retain the beta-lactam ring
l Low susceptibility to beta-lactamases
l Wide activity against
l Gram(+) cocci
l Gram (-) rods
l Anaerobes
l For pseudomonal infections
l Combined with aminoglycosides
l Given IV
l Useful for infections caused by organisms resistant to other antibiotics
l Drug of choice for enterobacter

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l IMIPENEM
Rapidly inactivated by renal dehydropeptidases I
Cilastatin
l Administered in combination
l Inhibitor of the enzyme
l Increases the half-life
l Inhibits formation of nephrotoxic metabolites
Adverse effects of imipenem-cilastatin
l GI distress
l Skin rash
l At very high plasma levels, CNS toxicity
Confusion, encephalopathy, seizures
Partial cross-allergenicity with penicillins

MEROPENEM
Similar to imipenem
Not metabolized by renal dehydropeptidases
Less likely to cause seizure

ERTAPENEM
Long half-life
Less active against pseudomonas
IM injection causes pain and irritation

C. BETA-LACTAMASE INHIBITORS
l CLAVULANIC ACID, SULBACTAM, and TAZOBACTAM
Used in fixed combination with certain hydrolyzable penicillins
Effective against plasmid-encoded beta-lactamases
Gonococci
Streptococci
E. coli
H. influenzae

OTHER INHIBITORS OF CELL WALL SYNTHESIS

A. VANCOMYCIN
l Bactericidal glycoprotein
l Binds to the D-Ala-D-Ala terminal of the nascent peptidoglycan pentapeptide side
chain
l Inhibits transglycosylation
l Prevents elongation of peptidoglycan chain
l Interferes with cross-linking
l Narrow spectrum of activity
l Vancomycin-resistant enterococci (VRE) and vancomycin-resistant S. aureus
(VRSA)
Due to decreased affinity of the drug to the binding site
Replacement of D-Ala by D-lactate
Drug-resistant gram (+) organisms
MRSA
Penicillin-resistant pneumococci
C. difficile

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Not absorbed orally
Maybe given for bacterial enterocolitis
When given IV, penetrates most tissues
Eliminated unchanged in urine
Dosage modification in patients with renal impairment
Rapid IV infusion may cause diffuse blushing
Red man syndrome
Toxic effects
Chills
Fever
Phlebitis
Ototoxicity
Nephrotoxicity
B. FOSFOMYCIN
l Antimetabolite inhibitor of cytosolic enolpyruvate transferase
l Prevents the formation of N- acetylmuramic acid which is essential in
peptidoglycan chain formation
l Resistance occurs via decreased intracellular accumulation of the drug
l Excreted in the kidney with urinary levels exceeding the minimum inhibitory
concentration (MIC) for many urinary tract pathogens
l In a single dose
Drug is less effective than the 7-day course of treatment with
fluoroquinolones
l Multiple dosing can result to resistance rapidly
l Diarrhea is common
l Synergistic with beta-lactam and quinolones in specific infections

C. BACITRACIN
l Peptide antibiotic
l Interferes with a late stage in cell wall synthesis in gram (+) organisms
l Marked toxicity
l Limited to topical use only

D. CYLCOSERINE
l Antimetabolite
l Blocks the incorporation of D-Ala into the pentapeptide side chain of the
peptidoglycan
l Used only in TB caused by organisms resistant to first-line antituberculous drugs
l Potentially neurotoxic
l Tremors
l Seizure
l Psychosis

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