Chemotherapy Agents and Antibacterial Drugs

Chemotherapy Agents

• Chemotherapeutic agents include:
  • Antimicrobial agents like antibacterial, antiviral, and antifungal drugs
  • Antiparasitic and antiprotozoal agents
  • Antineoplastic agents

Antibacterial Drug Classifications

• Antibacterial drugs are classified based on their effect on bacteria

Mechanism of Action on Bacteria

• Bactericidal drugs eradicate infection by killing microorganisms, eliminating the need for body defense mechanisms; examples include penicillins and aminoglycosides
• Bacteriostatic drugs halt microorganism growth, requiring body defense mechanisms to eradicate infection; examples include tetracyclines and chloramphenicol
• Bactericidal and bacteriostatic agents should not be combined because the bacteriostatic drug will inhibit the growth of the bacteria, abolishing the action of the bactericidal drug which acts only on rapidly growing or dividing organisms

Spectrum of Activity Against Bacteria

• Drugs effective against gram-positive organisms include penicillin G, beta-lactamase-resistant penicillin, vancomycin, and macrolides
• Drugs mostly effective against gram-negative organisms include aminoglycosides and are considered narrow-spectrum chemotherapeutic agents
• Drugs effective against both gram-positive and gram-negative organisms, such as tetracycline and chloramphenicol, have a broad spectrum of activity and are known as broad-spectrum antibiotics

Mechanism of Action

• Cell wall synthesis inhibitors include penicillin, cephalosporine, vancomycin, and bacitracin
• Protein synthesis inhibitors include chloramphenicol, tetracyclines, erythromycin, and clindamycin
• Metabolic pathway inhibitors: Metabolites are essential for bacterial function, such as sulphonamides/trimethoprim
• Nucleic acid synthesis inhibitors, such as Rifampin

Antibiotic Pharmacodynamics

• Concentration-dependent antibiotics with post-antibiotic effect (PAE) have bactericidal effects that depend on drug concentration, with the optimum effect achieved at 10 times the minimum inhibitory concentration (MIC)
• Trough drug concentration can fall below MIC during dosing without efficacy loss due to PAE, which reduces resistance. Maximize concentration and use large, infrequent doses
  • Examples: gentamycin, ciprofloxacin, azithromycin
• Time-dependent antibiotics with minimal/no PAE have bactericidal effects that depend on the duration drug level exceeds the MIC; maintain concentrations 2 to 4 times the MIC throughout dosing to prevent bacterial regrowth
• Maximize exposure duration with frequent, small doses and IV infusions
  • Examples: vancomycin, cephalosporins, penicillins, erythromycin
• Post-antibiotic effect (PAE) is the persistence of antibiotic effects after the drug level falls below the minimum inhibitory concentration (MIC)

Antibiotic Combinations: Indications

• Used for mixed bacterial infections
• Used for therapy of severe infections where the specific cause is unknown
• Can enhance antibacterial activity in specific infections, like using penicillin-aminoglycoside combinations for enterococcal endocarditis
• Help prevent the emergence of resistant microorganisms, improving cure rates in tuberculosis treatment with multiple drugs
• Can reduce dose-related toxicity by using lower doses of both drugs
• Reduce the chance of superinfection

Antibiotic Combinations: Synergism

• Block sequential metabolic pathway steps with two drugs like sulfonamide and trimethoprim for complete growth inhibition
• Clavulanic acid or sulbactam inhibit beta-lactamase or penicillinase to protect ampicillin or amoxicillin from inactivation

Antibiotic Combinations: Disadvantages

• Antagonism of antibacterial effects when bactericidal and bacteriostatic drugs are given together
• Increased costs
• Increased adverse effects

Inhibitors of Cell Wall Synthesis

• Exhibit selective toxicity by targeting bacterial cell walls, which are absent in mammalian cells

Pencillins

Key points

• Members of the penicillin family differ due to groups attached to the beta-lactam ring
• These differences can affect the drugs spectrum and stability in gastric acid
• Can change how likely they are to be impacted by bacterial beta-lactamase

Mechanism of Action

• Bactericidal action is time-dependent; the penicillins interfere with the last step of bacterial cell wall synthesis (transpeptidation), leading to cell lysis
• Penicillins work by activating autolysins
• Penicillins are effective against rapidly growing organisms that synthesize a peptidoglycan cell wall

Resistance to Penicillins

• Three mechanisms are involved:
  • Alterations in penicillin-binding proteins (PBPs), which are important for cell wall synthesis and maintenance of cellular morphology; mutations in PBPs lead to bacterial resistance
  • Inhibition of transpeptidase, PBPs that catalyze transpeptidation
  • Production of autolysins, which bacteria secrete to remodel the cell wall
• Natural resistance happens when bacteria lack peptidoglycan, or when the cell walls are impermeable to the drug. And from beta-lactamase activity
• Acquired resistance happens when mutations in PBPs lower affinity to penicillins.

Types of Penicillin Preparations

• Natural penicillins like penicillin G (benzyl penicillin) and penicillin V have a narrow spectrum (gram-positive cocci & bacilli and gram-negative cocci)
  • Penicillin G is not acid-stable and must be administered parenterally
  • Penicillin V is acid-stable and can be given orally
• Long-acting penicillins, such as benzathine penicillin-procaine penicillin, are insoluble salts of penicillin G that allow slow drug absorption and have a long duration of action
  • Procaine penicillin is given every 12 hours
  • Benzathine penicillin is given once per month IM
• Anti-Staph penicillins (beta-lactamase resistance) such as oxacillin, cloxacillin, flucloxacillin & nafcillin
  • Stable to gastric acidity and beta-lactamase
  • Methicillin is a first-generation drug but is no longer used due to nephrotoxicity
• Broad-spectrum penicillins like ampicillin & amoxicillin are more effective against gram-negative bacilli
  • Ampicillin is the drug of choice for gram-positive bacillus or respiratory infections
  • Amoxicillin is used prophylactically by dentists for patients with abnormal heart valves undergoing extensive oral surgery
• Amoxicillin has better absorption, higher plasma levels, and fewer GIT disturbances than ampicillin,
• Beta-lactamase inhibitors such as tazobactam, sulbactam, or clavulanic acid protect amoxicillin or ampicillin from enzymatic hydrolysis and extend their antimicrobial spectrum

Continued

• Antipseudomonal penicillins, such as ticarcillin & carbenicillin, have a broad spectrum, including Pseudomonas & many Gram-negative bacilli
  • Unstable to gastric acidity so given parenterally
  • Inactivated by beta-lactamase
• Penicillins and aminoglycosides have synergistic antibacterial effects, but should not be mixed in the same IV fluid, because the positively charged aminoglycosides form an inactive complex with negatively charged penicillins when in contact
• This combonation should not be given in the same site

Routes of Administration

• Dependent on stability to gastric acidity and severity of infection
  • Oral: For moderate infections and with acid-stable preparations like penicillin V & ampicillin
  • Parenteral (IV or IM): For severe infections or acid-unstable preparations; penicillin G is preferred in severe infections with susceptible organisms, and ticarcillin & carbenicillin are also given parenterally
  • Depot IM preparations: procaine penicillin (given every 12-24 hours) or benzathine penicillin (long-acting, given monthly), used as prophylaxis against rheumatic fever

Pharmacokinetics

• Absorption: Most preparations are incompletely absorbed orally, e.g., ampicillin
• Distribution: Penicillins can cross the placenta (non-teratogenic.) cross blood brain barrier when inflammed such as in Meningitis
• Excretion: Via renal elimination
• Probenecid inhibits renal tubular secretion of penicillin, prolonging penicillin action
• Nafcillin is excreted by bile

Therapeutic Uses

• Streptococcal infections such as acute throat infections and wound sepsis
• Bacterial endocarditis: Penicillin is given with an aminoglycoside to facilitate penetration by interfering with bacterial cell wall synthesis for a synergistic bactericidal effect and should be administered as separate IV bolus
• Staphylococcal infections
• Pneumococcal infections
• Syphilis & gonorrhea
• Meningococcal meningitis: Penicillin G or ampicillin IV plus chloramphenicol
• Typhoid & paratyphoid fever: Amoxicillin & ampicillin
• Prophylaxis against:
  • Rheumatic fever: benzathine penicillin (1.2 million units/mon)
  • Bacterial endocarditis (plus an aminoglycoside)

Adverse Reactions

• Hypersensitivity: Rashes, angioedema, and anaphylaxis; cross-allergic reactions occur among beta-lactam antibiotics
• Diarrhea: Disruption of the normal balance of intestinal microorganisms, most common with broad-spectrum agents like ampicillin
• Nephritis: All penicillins, especially methicillin, can cause acute interstitial nephritis
• Neurotoxicity: Irritation of neuronal tissue can provoke seizures if injected intrathecally or at high blood levels; epileptic patients are at risk of procaine penicillin
• Platelet dysfunction: A concern when treating patients predisposed to hemorrhage or those receiving anticoagulants; ticarcillin
• Cation toxicity: Penicillins are administered as sodium or potassium salts; potassium in penicillin G can cause hyperkalemia

Cephalosporins

• Are beta-lactam antibiotics, semi-synthetically produced by chemical attachment of side chains to 7-aminocephalosporanic acid, with a mechanism similar to penicillin but more resistant to beta-lactamase

Antibacterial Spectrum

• Classified into first, second, third, and fourth generations based on bacterial susceptibility patterns and resistance to beta-lactamases

Generation Specific Details

• 1st Generation: drugs include cephalexin, cephadroxil, and cefazolin
  • Spectrum: Mainly gram-positive, with some gram-negative coverage
  • Susceptibility: Yes
  • Penetration to CSF: No
  • Cross Allergy: High
  • Elimination: Renal
  • Clinical Uses: Used for upper respiratory tract infection, surgical prophylaxis with parentral of cefazolin, and used a single dose in orthopedic surgery
• 2nd Generation: drugs include cephomycin, cefuroxime, and cefaclor
  • Spectrum: Maintain gram+ ve coverage and enhanced gram –ve coverage
  • Susceptibility: Yes
  • Penetration to CSF: Not usually cephuroxime only
  • Cross Allergy: High
  • Elimination: Renal
  • Clinical Uses: Ceclacor is a treatment for sinutis and ottis media, Cefuroxime is treatment for pneumonia, and can be also used for anerobic infection

Continued

• 3nd Generation: drugs include cefotaxime, ceftriaxone, cefoperazone
  • Spectrum: Great gram -ve coverage, also covers pseudomonas
  • Susceptibility: No
  • Penetration to CSF: Yes (except cefoperazone)
  • Cross Allergy: Low
  • Elimination: Renal, biliary
  • Clinical Uses: Serious infection, Gonorrhea, Menengitis for Ceftriaxone
• 4th Generation: drugs include cefipime
  • Spectrum: Wide Gram coverage
  • Susceptibility: No
  • Penetration to CSF: Yes
  • Cross Allergy: Low
  • Elimination: Renal, biliary
  • Clinical Uses: Wide antibacterial Spectrum, resistance in Streptococci and Staphloccoci, parenteral, mixed infection

Ceftriaxone

Key notes

• Has a long half-life and good penetration into bone, making it useful for osteomyelitis
• Crosses the blood-brain barrier, so can be used in meningitis

Resistance

• Mechanisms of bacterial resistance to cephalosporins are similar to those for penicillins

Pharmacokinetics

• Some members are absorbed orally, but most are given parentrally
• First and second-generation agents cannot cross the blood-brain barrier, while third-generation agents (except cefoperazone) can cross, making them useful in meningitis
• Cephalosporins penetrate the placenta and are considered safe
• Elimination is mainly renal; adjust dose in renal dysfunction. Cefoperazone and ceftriaxone are excreted mainly in bile, making them useful in biliary infection and in patients with renal dysfunction

Adverse Effects

• Allergic manifestations should be avoided or used with caution in individuals allergic to penicillins (about 5 to 15% show cross-sensitivity)
• A disulfiram-like effect happens if ingested with alcohol or alcohol-containing medications
• Bleeding can occur with cefamandole or cefoperazone due to anti-vitamin K effects; administration of the vitamin corrects the problem

Monobactams

• Aztreonam (Given IV & IM), Narrow spectrum, effective against aerobic gram -ve organisms, and resistant to beta-lactamase
• Does not have cross-allergy with beta-lactams
• Is Relatively non-toxic: Unlike aminoglycosides, it is not nephrotoxic or ototoxic

Carbapenems

• Imipenem (Last resort) (Given IV) is a Broadest-spectrum beta-lactams. Effective against Gram +ve,-ve organisms and anaerobes, and is Resistant to beta-lactamase
• Increased cross-allergy with penicillin, plus Increased Risk of toxicity
• Metabolized in kidney by dehydropeptidase, so you need cilastatin to inhibit renal metabolism
• Increased risk of convulsion
• Meropenem & Ertapenem which is similar to imipenem with less renal degradation (cilastatin is not required) and reduced risk of convulsions

Key questions to help you learn

• The mechanism of action of beta-lactam antibiotics, like penicillin, is the inhibition of cell wall synthesis
• The adverse effect associated with using Methicillin is acute interstitial nephritis
• It's true about carbapenems like imipenem that they require co-administration with cilastatin to prevent nephrotoxicity
• The most important side effect of cephalosporins is hypersensitivity reactions
• Cefazolin is the cephalosporin used for surgical prophylaxis