UNIT 13: CHEMOTHERAPEUTIC AGENTS

BACTERICIDAL
● An antimicrobial drug that can eradicate an
TRANS OUTLINE infection in the absence of host defense
mechanisms
I. CHEMOTHERAPEUTIC AGENTS ● Kills bacteria
A. Bactericidal ○ Example:
B. Bacteriostatic ■ Aminoglycosides
C. Beta-Lactam Antibiotics ■ Beta-lactams
D. Beta-Lactamases
■ Vancomycin
E. Beta-Lactam Inhibitors
■ Quinolones
F. Minimal Inhibitory Concentration (Mic)
■ Rifampacin
G. Penicillin Binding Proteins (Pbps)
■ Metronidazole
H. Peptidoglycans
I. Selective Toxicity
BACTERIOSTATIC
J. Transpeptidase
● An antimicrobial drug that inhibits
II. MICROBIAL RESISTANCE
antimicrobial growth but requires host defense
III. STRATEGIES
mechanisms to eradicate the infection
IV. MICROORGANISMS AND ANTIMICROBIALS
● Does not kill bacteria
V. BETA-LACTAM ANTIBIOTICS AND OTHER CELL
○ Example:
WALL SYNTHESIS INHIBITORS
■ Chloramphenicol
VI. PENICILLINS
■ Erythromycin
A. Classification
■ Clindamycin
B. Pharmacokinetics
■ Sulfonamides
C. Mechanism of Action
■ Trimethoprim
D. Resistance
■ Tetracyclines
E. Clinical Uses
a. Narrow Spectrum
BETA-LACTAM ANTIBIOTICS
Penicillinase-Resistant Agents
● Drugs with structures containing a
b. Very Narrow Spectrum
beta-lactam ring: includes the penicillins,
Penicillinase-Resistant Agents
cephalosporins, and carbapenems. The ring
c. Wider Spectrum
must be intact for antimicrobial action
Penicillinase-Resistant Agents
VII. OTHER BETA-LACTAM DRUGS ○ Beta-lactam enters cell wall of bacteria
A. Aztreonam and disrupts its synthesis
B. Imipenem, Meropenem, and Ertapenem ○ No new antibiotics lately, antibiotics
C. Beta-Lactamase Inhibitors do not evolve but bacteria do
VIII. OTHER INHIBITORS OF CELL WALL SYNTHESIS
A. Vancomycin BETA-LACTAMASES
B. Fosfomycin ● Bacterial enzymes (penicillinases,
C. Bacitracin cephalosporinases) that hydrolyze the
D. Cycloserine beta-lactam ring of certain penicillins and
cephalosporins.
○ Produced as a defense mechanism by
CHEMOTHERAPEUTIC AGENTS the bacteria in response to
● Term now used associated with cancer drugs beta-lactam antibiotics
but also refers to antibiotics
BETA-LACTAM INHIBITORS
● Potent inhibitors of some bacterial
beta-lactamases used in combinations to
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 protect hydrolyzable penicillins from 4. Efforts to avoid indiscriminate use or misuse of
inactivation. antibiotics
○ Strategy employed by drug developers
to counteract beta-lactamase MICROORGANISMS AND ANTIMICROBIALS
○ It interrupts beta-lactamases
Bacteria Antibacterial
MINIMAL INHIBITORY CONCENTRATION (MIC)
● Lowest concentration of antimicrobial drug Viruses Antiviral
capable of inhibiting growth of an organism in
a defined growth medium. Fungi Antifungi

PENICILLIN BINDING PROTEINS (PBPS)
● Bacterial cytoplasmic membrane proteins that
act as the initial receptors for penicillins and
other beta-lactam antibiotics.
PEPTIDOGLYCANS
● Chains of polysaccharides and polypeptides
that are cross-linked to form the bacterial cell
wall.
SELECTIVE TOXICITY
● More toxic to the invader than to the host; a
property of useful antimicrobial drugs.
Parasite Antiparasitic
BETA-LACTAM ANTIBIOTICS AND OTHER CELL WALL
SYNTHESIS INHIBITORS
● Major antibiotics that inhibit cell wall
synthesis
○ It can cause osmotic lysis
○ Penicillins (such as Penicillin G
[benzylpenicillin] below)
NOTE: Penicillin G is the wonder drug of people with
syphilis. However, it may cause allergy

TRANSPEPTIDASE
● Bacterial enzymes involved in the cross-linking
of linear peptidoglycan chains, the final step in
cell wall synthesis.
○ Some antimicrobials target this final
step

MICROBIAL RESISTANCE Penicillin G (benzylpenicillin)

1. Production of antibiotic-inactivating enzymes
2. Changes in the structure of target receptors
● Changes in dna lead to changes in
receptor which is not recognized by the
antibiotic
3. Increased efflux via drug transporters
4. Decreases in the permeability of microbes’
cellular membrane to antibiotics

STRATEGIES
1. ​Use of adjunctive agents that can protect Cephalosporins
against antibiotic inactivation
2. Use of antibiotic combinations ● Beta-lactams because of the unusual
3. Introduction of new (and often expensive) 4-member ring that is common to all members
chemical derivatives of established antibiotics ● Cross resistance
○ If the bacteria is resistant against one
type of cephalosporin it may also be
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 somewhat resistant to a type of ● Narrow Spectrum: The drug is highly selective
penicillin on what bacteria it kills
● Most effective ● Wider Spectrum: The drug is not highly
● Widely used selective
○ According to Doc they are also ● Carbapenem and Aztreonam are last resort.
relatively cheap
● Well-tolerated PENICILLINS
○ Very minimal side effects CLASSIFICATION
■ “Common” side effect: ● Derivatives of 6-aminopenicillanic acid
allergic reactions ● Contains a beta-lactam ring for structure
● Antibiotics that inhibit cell wall synthesis ○ Essential for antibacterial activity
● Not as important as beta-lactam drugs ● Subclasses
○ Essentially what is “reserved” for ○ Additional chemical substituents that
“monster cases”/highly resistant confer differences in
○ “Last resort” ■ Antimicrobial activity
■ Vancomycin ■ Susceptibility to acid and
■ Fosfomycin enzymatic hydrolysis
■ Bacitracin – topical antibiotic, ■ Biodisposition
many toxicities if taken orally.
PHARMACOKINETICS
● More than 50 drugs that act as cell wall ● Vary in resistance to gastric acid
inhibitors are currently available. ● Vary in their oral bioavailability
● Polar compounds (most are excreted in urine)
○ Not metabolized extensively
○ Contributes somewhat to toxicity
● Excreted unchanged in urine via
○ Glomerular filtration
○ Tubular excretion
■ inhibited by probenecid
● Ampicillin and Nafcillin
○ Partly excreted in bile
○ Plasma half-life vary from 30min to 1hr
■ Frequent dosage since it is
BACTERIAL CELL WALL SYNTHESIS INHIBITORS
hard to keep the steady state
● Penicillins
concentration
○ Narrow Spectrum
● Procaine and Benzathine Penicillin G
■ Penicillinase susceptible
○ Given intramuscularly
Vancomycin
○ Long half-lives
■ Penicillinase resistant
○ Drug is released slowly
○ Wider Spectrum
○ Cross blood-brain barrier when
● Cephalosporins
meninges are inflamed
○ Narrow Spectrum
■ 1st Generation Mechanism of Action
■ 2nd, 3rd, and 4th Generation ● Bactericidal
○ Wider Spectrum ● Inhibit cell wall synthesis by following the
● Miscellaneous following steps:
○ Carbapenem ○ (1) Binding of the drug to specific
○ Aztreonam receptors (penicillin-binding proteins
NOTE:

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 [PBPs]) located in the bacterial ● Enzymatic hydrolysis of the beta-lactam ring
cytoplasmic membrane results in the loss of antibacterial activity
○ (2) Inhibit Transpeptidase enzymes
that act to cross-link linear RESISTANCE
peptidoglycan chains ● Beta-lactamases
■ Transpeptidation: finishing ○ Penicillinases
touches; it makes the cell wall ○ Formed by most staphylococci and
hard gram (-) organisms
■ Gram (-) is a term related to
staining procedure
○ Major mechanism for bacterial
resistance
○ Inhibitors of this enzymes are used in
combination with penicillin to prevent
their inactivation
■ Clavulanic acid - most popular
Co-amoxiclav
■ Sulbactam
■ Tazobactam
● Structural changes in their target PBPs
○ Another mechanism for bacterial
resistance
■ Methicillin resistance in
staphylococci
■ Penicillin G resistance in
pneumococci
● Changes in the porin structure in the outer
■ Cross-linked peptidoglycans membrane
■ If damaged will result to cell ○ Contribute to resistance by impeding
lysis (bactericidal) access of penicillin to PBPs
○ Resistance in some gram (-) rods like P.
aeruginosa

CLINICAL USES
NARROW SPECTRUM
PENICILLINASE-RESISTANT AGENTS
PENICILLIN G
● Mother compound
● Prototype
● Parenteral
● Can also be intramuscular
● Limited spectrum of activity
● Susceptible to beta-lactamases
● Infections caused by:
○ Streptococci
○ Meningococci
○ (3) Activation of automatic enzymes ○ Gram (+) bacilli
that cause lesions in the bacterial cell ○ Spirochetes
wall

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 ○ This include Treponema ● Susceptible to penicillinases
pallidum ○ Thus is paired with inhibitors to
● Penicillin-resistant S. pneumoniae (PRSP) counteract
strains ○ Penicillinases - an enzyme that is
● Some strains resistant via production of developed by the bacteria to kill
beta-lactamases beta-lactam rings.
○ S. aureus ● Uses similar to penicillin G
○ It is already developing ○ Enterococci
resistance to Penicillin G ○ E. coli
○ Example of infection: cellulitis ○ H. influenzae
and stye ○ L. monocytogenes
○ N. gonorrhea ○ P. mirabilis - notorious bacteria
○ Drug of choice for syphilis causing UTI
○ May cause allergic ○ M. catarrhallis
reaction but can be ● Enhanced activity in combination with
prevented by inhibitors of penicillinases
desensitizing them ● Synergistic (1+1=3) with aminoglycosides
(start with giving a (different class of antibiotics) in enterococcal
small dose then and listeria infections
increase it little by
little until it can be PIPERACILLIN and TICARCILLIN
recognized by the body) ● Activity against gram (-) rods
● Activity against enterococci ○ Pseudomonas
(which is resistant to most ○ Enterobacter
antibiotics) is enhanced by ○ Some cases of klebsiella species (UTI
aminoglycoside in women)

PENICILLIN V
● Oral
● Used for oropharyngeal infections

VERY NARROW SPECTRUM

PENICILLINASE-RESISTANT AGENTS
METHICILLIN, NAFCILLIN, AND OXACILLIN
● Treatment of known or suspected
staphylococcal infections
● Methicillin (prototype)
● Methicillin-resistant S. aureus (MRSA)
● S. Epidermidis (MRSE) are resistant to other
members of this subgroup and offer to
multiple antimicrobial drugs

WIDER SPECTRUM
PENICILLINASE-RESISTANT AGENTS
AMPICILLIN and AMOXICILLIN
● Used for shotgun therapy
○ Not really a good practice
○ Useful for life threatening conditions ● Synergistic action with aminoglycosides
● Wider spectrum than Penicillin G ● Susceptible to penicillinases
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 ● Enhanced activity in combination with CLASSIFICATION
inhibitors of penicillinases ● Derivatives of 7-aminocephalosporanic acid
● Piperacillin is largely IV ● Contain the beta-lactam ring structure

TOXICITY 1st Cephalexin, Cefazolin, Cefadroxil,

Allergy Generation Cephalothin, Cephradine, Cephariprin
● Exhibited as:
2nd Cefuroxime, Cefoxitin, Cefotetan,
○ Urticaria - hives; itchy rash Generation Cefamandole
○ Fever
○ Hemolytic anemia - may cause 3rd Ceftriaxone, Cefotaxime, Cefoperazone,
jaundice Generation Ceftazidime, Cefixime
○ Anemia - caused by the hemolysis of
4th Cefepime (last resort)
RBCs
Generation
○ Severe pruritus
○ Joint swelling
○ Nephritis - kidney problems; more PHARMACOKINETICS
common in piperacillin ● Oral
● Nafcillin can cause neutropenia (decrease in ● Some given parenterally
neutrophils) ● Cephalosporins with side chains undergo
● Ampicillin causes maculopapular rashes hepatic metabolism
● Methicillin causes interstitial nephritis more ● Major elimination is via renal tubular excretion
than other penicillins ● Cefoperazone and Ceftriaxone (3rd Generation)
○ Methicillin is no longer used for ○ Excreted mainly in the bile
staphylococcal infections (an ● 1st and 2nd generation do not enter the CSF
alternative for this is oxacillin) when the meninges are inflamed
● 5-10% of patients with history of allergy will
have the same reaction when given again. RESISTANCE
● Antigenic determinants include degradation ● Structural differences from penicillin
products like penicillin acid ○ Most of the time when the bacteria is
● Complete cross-allergenicity exists resistant to penicillin, it is also
resistant cephalosporin
GI Disturbances ● Less susceptible to penicillinases produced by
● Oral Penicillins especially ampicillin staphylococci
○ Nausea and diarrhea ● Resistance develops through the production of
○ Pseudomembranous colitis other beta-lactamases
■ Maybe caused by direct ● Decrease membrane permeability to the drug
irritation or by overgrowth of ● Changes in PBPs
gram positive (+) organisms or ● MRSA are also resistant to this drug
yeasts
CLINICAL USES
CEPHALOSPORINS 1st Generation Drugs
● Cefazolin (IV), Cephalexin (oral)
○ Gram (+) cocci
■ Staphylococci
■ Streptococci
○ E. coli
○ K. pneumoniae
○ E.coli + K. pneumoniae are more
common in UTI

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 ○ More resistant to beta-lactamases
● Surgical Prophylaxis in selected conditions produced by gram (-) organisms
● Minimal activity ■ Enterobacter
○ Gram (-) cocci ■ Haemophilus
○ Enterococci ■ Neisseria
○ MRSA ■ Some penicillinase-resistant
○ Most gram (+) rods pneumococci
○ Combines the gram (+) activity of 1st
2nd Generation Drugs gen and wider gram (-) spectrum of 3rd
● Less activity against gram (+) gen
● Extended coverage for gram (-)
● Marked differences in activity occur among the TOXICITY
drugs Allergy
● Cefotetan, cefoxitin ● Skin rashes to anaphylactic shock
○ B. Fragilis ● Occurs less frequently than penicillins
● Cefamandole, cefuroxime, cefaclor ● Complete cross-hypersensitivity exists
○ H. Influenzae (common cause of ● Cross-reactivity with penicillins
pneumoniae) or M. catarrhalis ○ Incomplete (5-10%)
○ Penicillin allergic patients are
3rd Generation Drugs sometimes treated successfully with
● Increased activity against gram (-) organisms cephalosporin
resistant to other beta-lactam drugs ○ Those with history of anaphylaxis to
○ Halos wala na sa gram (+) penicillin should not be treated with
● Ability to penetrate the blood brain barrier drug
○ Except Cefoperazone, Cefixime
● Effective against: Other Adverse Effects
○ Providencia ● Pain at IM injection site
○ S. marcescens ● Phlebitis after IV injection
○ Beta-lactamase producing strains ● Increase nephrotoxicity of aminoglycosides
● H. influenzae ● Drugs containing methylthiotetrazole group
● Neisseria ○ Cefamandole, Cefoperazone, Cefotetan
● Less active against enterobacter strains that ○ May cause hypoprothrombinemia
produce extended-spectrum beta-lactamases ○ Disulfiram-like reactions with ethanol
● Individual activity of drugs :
○ Cefoperazone, Ceftazidime OTHER BETA-LACTAM DRUGS
■ Pseudomonas AZTREONAM
○ Ceftizoxime ● Monobactam
■ B. fragilis ● Resistant to beta-lactamases produced by
■ Anaerobic infections certain gram (-) rods
■ a & b for serious infection ○ Klebsiella
○ Ceftriaxone (IV) and Cefixime ○ Pseudomonas
■ Drug of choice for gonorrhea ○ Serratia
○ Ceftriaxone ● No activity against gram (+) and anaerobes
■ Single injection for acute otitis ● An inhibitor of cell wall synthesis binding to
media PBP3
■ As effective as 10 days of ● Synergistic with aminoglycosides
amoxicillin ● Given IV
4th Generation Drugs ● Eliminated via renal tubular secretion
● Cefepime ● Half-life is prolonged in renal failure

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 ● No cross-allergenicity with penicillin ● Not metabolized by renal dehydropeptidase
● Adverse effects: (but can still be somewhat nephrotoxic, safer
○ GI upset with possible superinfection then imipenem)
○ Vertigo ● Less likely to cause seizure
○ Headache
○ Rare hepatotoxicity ERTAPENEM
○ Skin rash ● Long half-life
● Less active against pseudomonas
IMIPENEM, MEROPENEM, AND ERTAPENEM ● IM injection causes pain and irritation
● Carbapenems ● Only one of the three with an IM form
● Chemically different from penicillins
● Retain the beta-lactam ring IMIPENEM, MEROPENEM, AND ERTAPENEM
● Low susceptibility to beta-lactamases ● CLAVULANIC ACID, SULBACTAM, and
● Very expensive, not advisable as firstline due to TAZOBACTAM
price ● Used in fixed combination with certain
● Wide activity against hydrolyzable penicillins
○ Gram (+) cocci ● Plasmid-encoded beta-lactamases
○ Gram (-) rods ○ These previously did not produce
○ Anaerobes beta-lactamase but mutated and now
■ Possibly toxic due to its wide do:
spectrum ■ Gonococci
● For pseudomonal infections ■ Streptococci
○ Combine with aminoglycosides ■ E. coli
● Given IV ■ H. influenzae
● Useful for infections caused by organisms
resistant to other antibiotics OTHER INHIBITORS OF CELL WALL SYNTHESIS
● Drug of choice for Enterobacter infections VANCOMYCIN
● Bactericidal glycoprotein
IMIPENEM ● Binds to the D-Ala-D-Ala terminal of the
● Rapidly inactivated by renal dehydropeptidase nascent peptidoglycan pentapeptide side
I chain
● Cilastatin ● Inhibits transglycosylation
○ Administered in combination with ● Prevents elongation of peptidoglycan chain (for
imipinem gram positive bacteria)
○ Inhibitor of the enzyme ● Interferes with cross-linking
○ Increases half-life ● Narrow spectrum of activity
○ Inhibits formation of nephrotoxic ● Vancomycin-resistant enterococci (VRE) and
metabolites vancomycin-resistant S. aureus (VRSA)
● Adverse effects of imipinem-cilastatin ○ Due to decreased affinity of the drug to
○ GI distress the binding site
○ Skin rash ○ Replacement of D-Ala by D-lactate
○ At very high plasma levels, CNS toxicity ○ Use of vancomycin must be approved
■ Confusion, encephalopathy, after many layers of questioning as we
seizures want to avoid the development of more
○ Partial cross-allergenicity with antibiotic resistant bacteria
penicillins ● Drug resistant gram (+) organisms
○ MRSA
MEROPENEM ● Penicillin-resistant pneumococci
● Similar to imipenem ● C. difficile

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 ● Not absorbed orally ● Used only in TB caused by organisms resistant
● Maybe given for bacterial enterocolitis to first-line antituberculous drugs
● When given IV, penetrates most tissues ● Potentially neurotoxic
● Eliminated unchanged in urine ○ Tremors
● Dosage modification in patients with renal ○ Seizure
impairment ○ Psychosis
● Rapid IV infusion may cause diffuse blushing a
syndrome known as
○ “Red man syndrome”
■ Not lethal but can be alarming
● Toxic effects
○ Chills
○ Fever
○ Phlebitis (swelling of injection site)
○ Ototoxicity (causes deafness)
○ Nephrotoxicity

FOSFOMYCIN
● Antimetabolite inhibitor of cytosolic
enolpyruvate transferase
● Prevents the formation of N-acetylmuramic
acid which is essential in peptidoglycan chain
formation
● Resistance occurs via decreased intracellular
accumulation of the drug
● Excreted in the kidney with urinary levels
exceeding the MICs for many urinary tract
pathogens
● In a single dose
○ Drug is less effective than the the 7-day
course of treatment with
fluoroquinolones
● Multiple dosing can result to resistance rapidly
● Diarrhea is common
● Synergistic with beta-lactate and quinolones in
specific infections

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

CYCLOSERINE
● Antimetabolite
● Blocks the incorporation of D-Ala into the
pentapeptide side chain of the peptidoglycan

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