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 Targets Targets 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 peptidoglycan Cross linked polysaccharide peptide complex of indefinite size found in the inner cell wall of all bacteria (50% of the wall in gram-negative, 10% in gram-positive). Consists of chains of approximately 20 residues of _(1-4) linked N acetyl glucosamine and N acetyl muramic acid cross linked by small peptides (4-10 residues).

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 Cell membrene Peptidoglycan layer Cytoplasmc membrane

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 Cephem: 7-aminocephalosporanic acid Penem: 6-aminopenicillanic acid Monobactam: Aztreonam Carbapenem: Imipenem

Characteristics of the b-Lactam Ring Inhibits transpeptidease Substrate for b-lactamases An unstable structure Acid labile Immunogenic breakdown products

Peptidoglycan, also known as murein, is a polymer consisting of sugars and amino acids that forms a mesh-like layer outside the plasma membrane of bacteria (but not Archaea), forming the cell wall. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine and N-acetylmuramic acid.

Stages of Cell Wall Synthesis & Inhibitors

Penicillins classification Penicillins (e.g, penicillin G): Penicillin G is bactericidal for gram positive, gram negative cocci, and non β-lactamase producing anaerobes 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. Extended spectrum penicillins : Aminopenicillins improved activity against gram-negative organisms. Like penicillin, however, they are relatively susceptible to hydrolysis by b-lactamases. 1. Penicillins (eg, penicillin G)¾ These have greatest activity against gram-positive organisms, gram-negative cocci, and non- b-lactamase-producing anaerobes. However, they have little activity against gram-negative rods, and they are susceptible to hydrolysis by b-lactamases. 2. Antistaphylococcal penicillins (eg, nafcillin)¾ These penicillins are resistant to staphylococcal b-lactamases. They are active against staphylococci and streptococci but not against enterococci, anaerobic bacteria, and gram-negative cocci and rods. 3. Extended-spectrum penicillins (ampicillin and the antipseudomonal penicillins)¾ These drugs retain the antibacterial spectrum of penicillin and have 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 (+ b-lactamase inhibitor)

Natural Penicillins PENICILLIN G NARROW SPECTRUM PHARMACOKINETICS 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 b-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) 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 Penicillin V, the oral form of penicillin, is indicated only in minor infections because of its relatively poor bioavailability, the need for dosing four times a day, and its narrow antibacterial spectrum. Amoxicillin (see below) is often used instead.

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.

is a semi-synthetic penicillin derived from the ampicillin molecule 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 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 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) 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 In Jordan: Cephadroxil: Cedrox, Cefadril, Droxil, Midroxil Cefazoline: Cefamezin and Zolecef Parenteral: Cefazolin is the only first generation parenteral cephalosporin still in general use Oral: Cephalexin, cephradine, cefadroxil

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 Oral drugs may be used for the treatment of urinary tract infections, for minor staphylococcal lesions, or for minor polymicrobial infections such as cellulitis or soft tissue abscess. However, oral cephalosporins should not be relied upon in serious systemic infections. Second- and third-generation cephalosporins offer no advantage for surgical prophylaxis for most procedures, are far more expensive, and generally should not be used for that purpose. Cefazolin may be a choice in infections for which it is the least toxic drug (eg, K pneumoniae) and in persons with staphylococcal or streptococcal infections who have a history of a mild penicillin hypersensitivity reaction but not anaphylaxis. Cefazolin does not penetrate the central nervous system and cannot be used to treat meningitis. Cefazolin is an alternative to an antistaphylococcal penicillin for patients who are allergic to penicillin.

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 Except for cefuroxime axetil, these drugs are not predictably active against penicillin-resistant pneumococci and should be used cautiously, if at all, to treat suspected or proved pneumococcal infections. Cefaclor is more susceptible to beta-lactamase hydrolysis compared with the other agents, and its utility is correspondingly diminished. For cefoxitin (50-200 mg/kg/d), the interval is 6-8 hours. Cefotetan is administered every 12 hours; cefonicid or ceforanide, every 12-24 hours; and cefprozil, every 24 hours. In Jordan: Cefaclor: Ceclor, Cefabac, Cloracef, Forticef, Midocef, Pharmaclor Cafemandole: Mandol (inj) Cefoxitin: Mefoxin Cefprozil: Cefzil Cefuroxime Axetil: Zinnat, Cefutil, Froxime, Oraxim Cefuroxime (inj): Furocef, Maxil, Zinacef Cephradine: Cefamid, Doral, Eskacef, Velocef

Clinical Uses Used to treat otitis, sinusitis and lower RTI (H influenza & B catarrhallis) Cefoxitin, cefotetan or cefmetazole: used to treat mixed anaerobic infections such as peritonitis or diverticulitis Cefuroxime community acquired pneumonia Answer: because of their activity against anerobes (ncluding B fragilis) Cefuroxime is used to treat community-acquired pneumonia, particularly in cases where beta-lactamase-producing H influenzae or Klebsiella pneumoniae is a consideration, but this drug has few other uses. Cefuroxime is the only second-generation drug that crosses the blood-brain barrier, but it is less effective in treatment of meningitis than ceftriaxone or cefotaxime and should not be used. 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 Ceftriaxone (half-life 7-8 hours) can be injected once every 24 hours at a dosage of 15-50 mg/kg/d. A single daily 1 g dose is sufficient for most serious infections, with 4 g once daily recommended for treatment of meningitis. Cefoperazone (half-life 2 hours) can be injected every 8-12 hours in a dosage of 25-100 mg/kg/d. The remaining drugs in the group (half-life 1-1.7 hours) can be injected every 6-8 hours in dosages between 2 and 12 g/d, depending on the severity of infection. Cefixime can be given orally (200 mg twice daily or 400 mg once daily) for respiratory or urinary tract infections. Cefpodoxime proxetil and ceftibuten are administered as a 200 mg dose twice daily. The excretion of cefoperazone and ceftriaxone is mainly through the biliary tract, and no dosage adjustment is required in renal insufficiency. The others are excreted by the kidney and therefore require dosage adjustment in renal insufficiency.

Third Generation- clinical uses Ceftriaxone (as single 125 mg injection) and cefixime (as single 400 mg oral dose) are first-line drugs for treatment of gonorrhea Can be used to treat meningitis caused by pneumococci, meningiococci, H influenza, but not Listeria monocytogens Should be used in combination with aminoglycosides to treat meningitis caused by P aeurginosa Meningitis caused by highly penicillin-resistant strains of pneumococci (ie, penicillin MICs > 1 μg/mL) may not respond even to these agents, and addition of vancomycin is recommended.

Third Generation- clinical uses 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. empirical therapy of sepsis of unknown cause in both the immunocompetent and the immunocompromised patient Meningitis caused by highly penicillin-resistant strains of pneumococci (ie, penicillin MICs > 1 μg/mL) may not respond even to these agents, and addition of vancomycin is recommended.

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 It has good activity against P aeruginosa, Enterobacteriacea, S aureus and S pneumoniae more resistant to hydrolysis by chromosomal beta-lactamases (eg, those produced by enterobacter) and some extended-spectrum beta-lactamases that inactivate many of the third-generation cephalosporins.

Adverse Effects of cephalosporins Allergy Identical to penicillins- cross allerginicity 5-10% Toxicity Severe pain (IM), thrombophelebitis (IV), renal toxicity, hypoprothrombinemia, disulfiram like reaction Superinfection Allergy: Cephalosporins are sensitizing and may elicit a variety of hypersensitivity reactions that are identical to those of penicillins, including anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, and hemolytic anemia. However, the chemical nucleus of cephalosporins is sufficiently different from that of penicillins so that some individuals with a history of penicillin allergy may tolerate cephalosporins. The frequency of cross-allergenicity between the two groups of drugs is uncertain but probably is around 5-10%. However, patients with a history of anaphylaxis to penicillins should not receive cephalosporins. Toxicity Local irritation can produce severe pain after intramuscular injection and thrombophlebitis after intravenous injection. Renal toxicity, including interstitial nephritis and even tubular necrosis, has been demonstrated and has caused the withdrawal of cephaloridine. Cephalosporins that contain a methylthiotetrazole group (eg, cefamandole, moxalactam, cefmetazole, cefotetan, cefoperazone) frequently cause hypoprothrombinemia and bleeding disorders. Administration of vitamin K, 10 mg twice weekly, can prevent this. Moxalactam can also interfere with platelet function and has induced severe bleeding. It has been largely abandoned. Drugs with the methylthiotetrazole ring can also cause severe disulfiram-like reactions; consequently, alcohol and alcohol-containing medications must be avoided. Superinfection Many second- and particularly third-generation cephalosporins are ineffective against gram-positive organisms, especially methicillin-resistant staphylococci and enterococci. During treatment with such drugs, these resistant organisms, as well as fungi, often proliferate and may induce superinfection.

Other Inhibitors of Cell Wall Synthesis NEWER b-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 Aztreonam is synergestic with aminoglycosides It is considered an alternative to aminoglycosides, 3rd generation cephalosporins

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 Imipinem is usually administered in fixed combination with cilastatin

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: Vancomycin Teicoplanin Fosfomycin Bacitracin Cycloserine TEICOPLANIN Teicoplanin is a glycopeptide antibiotic that is very similar to vancomycin in mechanism of action and antibacterial spectrum. Unlike vancomycin, it can be given intramuscularly as well as intravenously. Teicoplanin has a long half-life (45-70 hours), permitting once-daily dosing. This drug is available in Europe but has not been approved for use in the United States.