Chemotherapy

General Principles

Chemotherapy

• The treatment of disease by means of chemicals that have a specific toxic effect upon the disease producing microorganisms (antimicrobial) or that selectively destroy cancerous tissue (anticancer therapy)

Antibiotics – Desirable Characteristics

• Selective toxicity

• Microcidal

• Stable

• Can be given orally or intravenously

• Complementary to host defense

• Extensive tissue distribution

• Remain active in presence of organic compounds

Selective Toxicity:Selective toxicity refers to the ability of the drug to target sites that are relatively specific to the microorganism responsible for infection.

• Sometimes these sites are unique to the microorganism or simply more essential to survival of the microorganism than to the host.

• Examples of such specific or relatively specific sites include specific fungal or bacterial cell wall synthesizing enzymes, the bacterial ribosomal or the molecular machinery of viral replication.

Many of the same basic principles apply to antimicrobial, antiparasitic and anticancer chemotherapy

Chemotherapeutic Drug TargetsTargets for Antimicrobial/Antiviral Drugs

• Bacterial Cell Wall Synthesis Inhibitors • Agents that Increase Cell Membrane Permeability • Protein Synthesis Inhibitors: interfere with 30S or 50S

bacterial ribosome function • Agents that interfere with nucleic acid synthesis • Antimetabolites • Inhibitors of viral replication

Figure 30.13 Classification of some antibacterial agents by their sites of action. (THFA = tetrahydrofolic acid; PABA = p-aminobenzoic acid)

Beta-lactam antibiotics

Penicillins and cephalosporins

Gram-positive Membrane • The lipid bilayer cell

membrane of most of the Gram-positive bacteria is covered by a porous peptidoglycan layer

Peptidoglycan layer

Cytoplasmc membrane

Gram-negative Cell Membrane Model

• Gram-negative bacteria are surrounded by two membranes.

• The outer membrane functions as an efficient permeability barrier containing lipopolysaccharides (LPS) and porins

Peptidoglycan layer

Cytoplasmc membrane

Cell membrene

Beta lactam antibacterial

Family Members• Penicillins (Penems) : 6-aminopenicillanic acid derivatives • Cephalosporins -- Cephems : 7-aminocephalosporanic acid

derivatives • Related to cephalosporins : Oxacephems and cephamycins • Carbapenems -- imipenem • Monobactams -- aztreonam • Beta-lactamase inhibitors : e.g., clavulanic acid

Core structure of beta-lactam antibiotics

Carbapenem: Imipenem

Penem: 6-aminopenicillanic acid Cephem: 7-aminocephalosporanic acid

Monobactam: Aztreonam

Characteristics of the -Lactam Ring

• Inhibits transpeptidease• Substrate for -

lactamases• An unstable structure

– Acid labile– Immunogenic

breakdown products

Stages of Cell Wall Synthesis & Inhibitors Stage Process Site Inhibitor

1 Precursorformation

Inside cell Cycloserine

2 Transport &Peptidoglycanformation

Cellmembrane

BacitracinVancomycin

3 Crosslinkingpeptidoglycanchains

Outside cell PenicillinsCephalosporins

Penicillins classification

1. Penicillins (e.g, penicillin G): Penicillin G is bactericidal for gram positive, gram negative cocci, and non β-lactamase producing anaerobes

2. Antistaphylococcal penicillins (e.g, nafcillin) resistant to staphylococcal β-lactamases. They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and gram-negative cocci and rods.

3. Extended spectrum penicillins : Aminopenicillins• improved activity against gram-negative organisms. Like

penicillin, however, they are relatively susceptible to hydrolysis by b-lactamases.

Antimicrobial Agents: A Review Gail Gesin, Pharm.D.

PENICILLINS

• The prototype Penicillin G

• Acid resistant Penicillin V

• Penicillinase resistant Methicillin, Oxacillin

• “Broad Spectrum” Amoxicillin, Ampicillin

• “Antipseudomonas” Azlocillin, piperacillin• Combinations (+ -lactamase inhibitor)

Natural Penicillins

1. PENICILLIN G • NARROW SPECTRUM

– Strep, Meningococci, enterococci, non-β-lactamase-producing staphylococcianaerobes, spirochetes (Treponema pallidum), clostridium species, actinomyces, and other gram-positive rods, and non-β-lactamase-producing gram-negative

• PHARMACOKINETICS– Acid labile– Widely distributed– Rapid renal excretion

• BACTERIAL RESISTANCE – Degraded by -lactamases– Does not pass Gm(-) cell envelope very well

2. Penicillin G Procaine & B

• It can be administered IM one to three times a day for the treatment of Syphilis

• In the past, the main indication was for the treatment of gonorrhea. Due to the increasing prevalence of penicillinase-producing Neisseria gonorrheae, it has been replaced by ceftriaxone

• This agent was also used in the past for the treatment of uncomplicated pneumococcal pneumonia, but its use has decreased secondary to the emergence penicillin-resistant S. pneumoniae

3. Penicillin G Benzathine • Benzathine penicillin and procaine penicillin G for IM inj are

used when low but prolonged drug levels are requested . • A single IM injection of benzathine penicillin, 1.2 million units,

is effective treatment for b-hemolytic streptococcal pharyngitis; given IM once every 3-4 weeks, it prevents reinfection.

• Benzathine penicillin G, 2.4 million units IM once a week for 1-3 weeks, is effective in the treatment of syphilis.

4. Penicillin VK • An oral formulation that resists degradation by gastric acid • Absorption occurs in the upper part of the small bowel and

produces peak serum levels within 60 minutes • Primarily indicated for mild infections involving the throat,

respiratory tract, or soft tissue

Penicillins resistant to Staphylococcal β-lactamase

• Methicillin, Nafcillin (IV), oxacillin, Dicloxacillin (PO) • When susceptibility results for Staphylococcus are known and

sensitivity has been documented, these agents should be used preferentially over vancomycin because of their more rapid killing

• Methicillin has been discontinued in the US because of the occurrence of interstitial nephritis

• Nafcillin (& oxacillin) are primarily excreted through the liver. Reduction in dosage for renal dysfunction is not necessary due to biliary excretion

Extended-spectrum Penicillins (Aminopenicillins, Carboxypenicillins, & Ureidopenicillins)

• These agents possess activity against gram-negative bacilli b/c of their greater penetration through the outer membrane of gram-negative bacteria and higher affinity for penicillin-binding proteins (PBPs)

a. Aminopenicillins (ampicillin & amoxicillin)– Antibacterial spectrum is similar to penicillin G but are

more effective against gram-negative bacilli

Ampicillin • After its introduction, ampicillin was found to

have more activity than penicillin G against enterococci and Haemophilus influenzae

• Unlike penicillin G, ampicillin initially had activity against many gram-negative bacteria including E. coli, Proteus mirabilis, Salmonella, Shigella, and Listeria

• DOC for Listeria Monocytogenes

Amoxicillin • Amoxicillin has more complete oral absorption than

ampicillin (resulting in twice the serum level for comparable doses)

• Due to more complete absorption, less drug remains in the GI tract and the incidence of diarrhea is decreased

• Due to predictable absorption, amoxicillin has replaced penicillin VK in certain clinical situations (ie, prevention of bacterial endocarditis)

• Amoxicillin, 250-500 mg three times daily, is equivalent to the same amount of ampicillin given four times daily

Carboxypenicillin (Ticarcillin)

• With the emergence of more resistant gram-negative bacilli and the increasing frequency of P. aeruginosa, penicillins with a broader spectrum of antibacterial activity were needed.

• Ticarcillin has activity against gram-negative bacilli, including P. aeruginosa.

Ureidopenicillin (Piperacillin)

• is a semi-synthetic penicillin derived from the ampicillin molecule

• It has enhanced gram-negative (including anti-Pseudomonal) activity due to greater cell wall penetration and increased affinity for PBPs.

• The ureidopenicillins, piperacillin, mezlocillin, and azlocillin, are also active against Klebsiella pneumoniae.

Resistance: ß-Lactams 1. Most common elaboration of the enzyme ß-lactamase, which hydrolyzes the ß-lactam ring (loss of bactericidal activity)• ß-lactamase genes may be found in both gram-positive and gram-negative bacteria

2. alteration of penicillin-binding proteins (PBPs) either by mutation of existing PBP genes or, more importantly, by acquiring new PBP genes (e.g. staphlococcal resistance to methicillin) or by acquiring new "pieces" of PBP genes (e.g. pneumococcal, gonococcal and meningococcal resistance)

3. Resistance seen in gram-negative bacteria, is due to alteration of genes that specify outer membrane proteins (porins) and reduce permeability to penicillins. (e.g. resistance of Enterbacteriaceae to some cephalosporins and that of Pseudomonas spp. to ureidopenicillins)

• Multiple resistance mechanisms may be found in the same bacterial cell

β-lactamase inhibitors

• Clavulanic acid, sulbactam, & tazobactam

• They Contain β-lactam ring but do not have significant antibacterial activity

• They bind to & inactivate β-lactamases, thereby protecting the antibiotics that are normally substrates for these enzymes

Penicillin plus β-lactamase Inhibitors

• Amoxicillin-clavulanic acid

• Ticarcillin-clavulanic acid

• Ampicillin-sulbactam

• Piperacillin-tazobactam

 Adverse Reactions to Penicillins

• Hypersensitivity reactions are the most common

– Macropapular rash – Urticarial rash – Fever – Bronchospasm – Vasculitis – Exfoliative dermatitis – Stevens-Johnson syndrome – Anaphylaxis (very rare-0.05% of recipients)

Other adverse reactions

Cephalosporins are β-lactam antibiotics that are closely related both structurally and functionally

to the Penicillins

Characteristics of Cephalosporins

• Broader spectrum than penicillins

• More stable than penicillins to many bacterial B-lactamases

• Are not active against enterococci and Listeria monocytogens

• Are not active against MRSA

• Are active against E.coli, Klebsiella pnemoniae and Proteus mirabilis

• Poor activity against: P aeruginosa, indole-positive proteus, enterobacter, Serratia marcesens, citrobacter and actinobacter

Characteristics of Cephalosporins

• Inhibit synthesis of the bacterial cell wall• Absorption, distribution, elimination - similar to

penicillins• Adverse reactions:

• Hypersensitivity• Thrombophlebitis• Nephrotoxicity

• Incidence of resistance is lower than penicillins

Clinical Uses of Cephalosporins

• Hospital-acquired pneumonias - Cefotaxime• Meningitis - Cefotaxime, Ceftriaxone• Sepsis (initial Rx) - Third and fourth generation

cephalosporins• Gonorrhea• Acute UTI

From: The Medical Letter, 1999

Classification

• The cephalosporins are classified by generation based on their spectrum of activity

Major differences in generations :

• Increasing activity vs. various gram negative bacteria

• Decreasing susceptibility to beta-lactamases

• Use equally effective less expensive alternatives when appropriate

FIRST generation– Agents: Cefadroxil, cefazolin, cephalexin,

cephalothin, cephapirin, & cephradine

– cephalexin :oral, q6h, t-half 0.9 h, prototype first generation; q12h good for pharyngitis

– cefazolin [IV/IM, longer duration and similar spectrum to other first gens., Good into bone(the only first generation parenteral now in use)

– cefadroxil, oral, q12h, t-half 1.5 h

– cephradine : PO

– Cephalothin: (IV/IM), q4h, t-half 0.6h

– Cephapirin: (IV/IM), q4h, 1.2 h

FIRST generation

• In patients with impaired renal function, dosages must be reduced

• Excretion mainly by GF and tubular secretion into the urine

FIRST generation-Clinical Uses

• Although the first-generation cephalosporins have a broad spectrum of activity and are relatively nontoxic, they are rarely the drug of choice for any infection

• Cefazolin penetrates well into most tissues. It is the drug of choice for surgical prophylaxis.

• Cefazolin does not penetrate the central nervous system and cannot be used to treat meningitis

Second Generation

• Cefaclor,• cefamandole,• cefonicid • cefuroxime• cefprozil• loracarbef• ceforanide

+ structrurally related cephamycins: (cefoxitin, cefmetazole and cefotetan)

Second Generation

• Extended gram –ve coverage resistant Klebsiella

• Cefaclor, cefamandole, cefonicid, cefuroxime, ceforanide: active against H influenza but NOT serratia or B fragilis

• The opposite: cefoxitin, cefmetazole and cefotetan active against B fragilis but NOT H influenza

• As with 1st generation: none is active against enterococci or P aeuroginosa

Second Generation

• Orally: cefaclor, cefuroxime axetil, cefprozil and loracrbef

• Parenterally (IV): cefuroxime, cefonicid, ceforanide, cefoxitin, cefprozil and cefotetan

• IM injection is too painful to be used• Different half lives

Clinical Uses

1. Used to treat otitis, sinusitis and lower RTI (H influenza & B catarrhallis)

2. Cefoxitin, cefotetan or cefmetazole: used to treat mixed anaerobic infections such as peritonitis or diverticulitis

3. Cefuroxime community acquired pneumonia

The only to cross the BBB, however less effective 3rd generation

Third Generation- characteristics

• Expanded gram negative coverage (except cefoperazone)

• The ability to cross the BBB• Active against citrobacter, Serratia marscens and

providentia (but not the resistant strains) • Active against B-lactamase producing strains of

haemophilus and neisseria• Ceftazidime & cefoperazone: the 2 third generation

which are active against P aeureginosa

Third Generation- characteristics

• Like the 2nd generation: third generation drugs are not reliably active against enterobacter species, serratia, provedentia and citrobacter (because of emergence of resistance)

• Only ceftizoxime and moxalactam are active against B fragilis

Third Generation-kinetics

• They penetrate body fluids and tissues well

• Achieve levels in the CSF (With the exception of cefoperazone, cefixime, cefpodoxime proxetil) sufficient to inhibit most pathogens

• Excretion of cefoperazone and ceftriaxone is mainly through biliary tract

• The rest are excreted by the kidney

Third Generation- clinical uses

1. Ceftriaxone (as single 125 mg injection) and cefixime (as single 400 mg oral dose) are first-line drugs for treatment of gonorrhea

2. Can be used to treat meningitis caused by pneumococci, meningiococci, H influenza, but not Listeria monocytogens

3. Should be used in combination with aminoglycosides to treat meningitis caused by P aeurginosa

Third Generation- clinical uses

4. Ceftriaxone and cefotaxime are the most active cephalosporins against penicillin-resistant strains of pneumococci and are recommended for empirical therapy of serious infections that may be caused by these strains.

5. empirical therapy of sepsis of unknown cause in both the immunocompetent and the immunocompromised patient

Fourth Generation

Cefepime• it may be useful in treatment of

enterobacter infections. Otherwise, its clinical role is similar to that of third-generation cephalosporins.

• cefepime has good activity against most penicillin-resistant strains of streptococci

Adverse Effects of cephalosporins

• AllergyIdentical to penicillins- cross allerginicity 5-10%

• ToxicitySevere pain (IM), thrombophelebitis (IV), renal toxicity,

hypoprothrombinemia, disulfiram like reaction

• Superinfection

Other Inhibitors of Cell Wall Synthesis

NEWER -LACTAMS

• Monobactams: e.g. Aztreonam

• Carbapenems: e.g. Imipenem

Aztreonam

• It is a monobactam, resistant to B-lactamases produced by certain G-ve rods, including Klebsiella, pseudomonas and serratia

• It has no activity against G+ve bacteria or anaerobes• Inhibits the cell wall synthesis by binding to PBP3• Given IV. Eliminated via renal secretion• No cross-allerginicity with penicillin• AD.E: GI upset, superinfection, vertigo, HA, rarely

hepatotoxicity

Imipenem

• It is a carbapenem with low susciptibility to B-lactamses

• Wide activity: G+ve cocci (including penicillin resistant pneumococci), G-ve rods and anaerobes

• Administered parenterally• The drug of choice for enterobacter infections• Rapidly metabolised by tubular dehydropeptidase

IMIPENEM-CILASTATIN

• CILASTATIN is a peptidase inhibitor that blocks renal degradation of Imipenem

• Cilastatin increases the plasma half-life of imipenem and inhibits the formation of potentially nephrotoxic metabolite

• AD.E: GI distress, skin rash and at very high plasma levels CNS toxicity (confusiion, encephalopathy and seizures)

• Partial cross allergenicity with penicillins

Other cell wall synthesis inhibitors:

o Vancomycin

o Teicoplanin

o Fosfomycin

o Bacitracin

o Cycloserine