Antimicrobial Agents: Selection and Considerations

• Antimicrobial drugs effectively treat infections by targeting invading microorganisms without harming host cells.
• Selective toxicity of antimicrobial drugs is relative, requiring careful control of drug concentration to attack the microorganism while being tolerated by the host.

Selection of Antimicrobial Agents Considerations

• Identify the infecting organism using a Gram stain on sterile body fluids to identify pathogens.
• Immediate treatment is needed for critically ill patients, often using broad-spectrum therapy if the organism is unknown.
• Consider predictable vs. unpredictable susceptibility patterns and determine MIC and MBC.
• Recognize the blood-brain barrier affects CNS drug delivery; penetration depends on lipid solubility, molecular weight, and protein binding.
• Patient-specific factors include age, immune status, renal/liver function, perfusion, pregnancy, and lactation.
• Safety: Some antibiotics are less toxic while others pose serious toxicity risks.
• Cost effectiveness

Chemotherapeutic Spectra

• Narrow-spectrum antibiotics, like isoniazid, target specific bacteria.
• Extended-spectrum antibiotics, like Ampicillin, target a broader range of bacteria.
• Broad-spectrum antibiotics, like tetracycline, affect diverse bacterial types including Gram-positive, Gram-negative, Mycoplasma, and Chlamydia.

Combination of Antimicrobial Drug Advantages

• Broad-spectrum empiric therapy for critically ill patients
• Effective for polymicrobial infections
• Reduces resistance development
• Decreases dose-related toxicity by lowering individual drug doses
• Enhances bacterial inhibition/killing

Combination of Antimicrobial Drug Disadvantages

• Bacteriostatic drugs interfere with bactericidal drugs
• Increases risk of antimicrobial resistance

Mechanisms of Resistance

• Drug resistance due to altered targets happens when bacteria change the structures that antibiotics attack, preventing the drug from binding effectively.
• Drug resistance due to decreased accumulation occurs when bacteria reduce the amount of antibiotic that reaches its target, either by limiting entry or pumping the drug out.
• Drug resistance due to enzymatic inactivation happens when bacteria produce enzymes that break down or modify the antibiotic, rendering it ineffective.

Prophylactic Antibiotics Usage

• Prevent streptococcal infections in patients with a history of rheumatic heart disease
• Prevent infections in patients undergoing dental extractions with implanted prosthetic devices
• Prevent tuberculosis or meningitis among individuals close to infected patients
• Decrease the incidence of infection prior to most surgical procedures.

Complications of Antibiotic Therapy

• Hypersensitivity reactions to drugs or their metabolic products can range from urticaria to anaphylactic shock.
• High serum levels may directly cause toxicity in the host by affecting cellular processes.
• Broad-spectrum antimicrobials can alter normal microbial flora, leading to overgrowth of opportunistic organisms.

Classification of Antibacterial Drugs by Target

• Some drugs inhibit cell wall synthesis
• Some drugs inhibit protein synthesis
• Some drugs inhibit nucleic acid synthesis
• Some drugs inhibit folate metabolism

Beta-Lactam Antibiotics

• These include penicillins, cephalosporins, carbapenems, and monobactams, contains a beta-lactam ring that inhibits bacterial cell wall synthesis.
• They are bactericidal and act by inhibiting peptidoglycan synthesis.
• They target penicillin-binding proteins (PBPs), essential for bacterial cell wall formation.
• They inhibit transpeptidation, preventing cross-linking of peptidoglycan chains, leading to cell lysis.

Antibacterial Spectrum Factors

• Gram-positive bacteria are more susceptible due to easier cell wall penetration.
• Gram-negative bacteria's outer lipopolysaccharide membrane restricts entry, though porins aid transport.
• Pseudomonas aeruginosa is a notable exception due to lacking porins.

Classification of Natural Penicillins

• Penicillin G is used against Streptococcus, Neisseria meningitidis, Bacillus anthracis, Clostridium species, Corynebacterium diphtheriae, and Treponema pallidum.
• Penicillin V is acid-stable and used for mild infections.

Beta-Lactamase Resistant Penicillins

• Cloxacillin, Flucloxacillin, and Oxacillin are used against penicillinase-producing staphylococci.
• Methicillin is no longer used clinically, but used to detect MRSA.

Extended-Spectrum Penicillins

• Ampicillin is effective against Listeria monocytogenes.
• Amoxicillin is used for Helicobacter pylori eradication and dental prophylaxis
• Amoxicillin + Clavulanic acid extends the spectrum to beta-lactamase-producing strains.

Antipseudomonal Penicillins

• Piperacillin, Ticarcillin, and Carbenicillin are effective against Pseudomonas aeruginosa, with enhanced bacterial killing when combined with aminoglycosides.
• They should not be mixed in the same infusion fluid due to chemical incompatibility.

Resistance Mechanisms of Penicillins

• Beta-Lactamase Production: Hydrolyzes the beta-lactam ring, inactivating the drug.
• Decreased Permeability: Reduces the entry of the antibiotic.
• Altered PBPs: Reduces affinity for beta-lactam antibiotics.

Penicillin Pharmacokinetics

• Administered via oral, intramuscular, or intravenous routes.
• Amoxicillin is well absorbed, whereas most others are incomplete.
• Penicillins distribute widely but cross the BBB only during meningitis.
• Primarily eliminated renally

Penicillin Adverse Reactions

• Hypersensitivity: Maculopapular rash, angioedema, anaphylaxis.
• Cation Toxicity: Sodium or potassium overload.
• Hematologic Issues: Reduced coagulation
• Gastrointestinal Disturbances: Diarrhea.
• Nephritis: Particularly with methicillin.
• Neurotoxicity: Risk of seizures with high doses or intrathecal administration.

Cephalosporins Introduction

• Cephalosporins were first isolated from Cephalosporium acremonium in 1948.
• The structure is structurally related to penicillins, inhibiting bacterial cell wall synthesis by binding to PBPs.
• Cephalosporins are divided into five generations based on antibacterial spectrum.

Cephalosporin First Generation

• Active against G(+) cocci, and some G(-) rods.
• Includes Cephalexin, Cefazolin, Cephalothin, Cefadroxil

Cephalosporins Second Generation

• Extended G(-) coverage and weaker G(+) activity.
• Includes Cefaclor, Cefuroxime, and Cefoxitin.

Cephalosporins Third Generation

• Reduced G(+) activity, enhanced G(-) activity.
• Includes Cefotaxime, Ceftriaxone,Ceftazidime, Cefoperazone and Cefixime

Cephalosporins Fourth Generation

• Broad activity, effective against G(+) and G(-) organisms.
• Includes Cefepime

Cephalosporins Fifth Generation

• Active against MRSA, penicillin-resistant S. pneumoniae, and Enterococcus.
• Includes Ceftaroline and Ceftobiprole

Cephalosporin Pharmacokinetics

• Distribution of cephalosporins occurs readily into body fluids.
• Therapeutic CSF levels are achieved by Cefuroxime, Cefotaxime, and Ceftriaxone.
• Ceftriaxone is excreted in bile; dosage adjustments are required in renal failure.

Cephalosporin Adverse Effects

• Allergy: Cross-reactivity with penicillins
• Disulfiram-like Effect: Cefamandole, Cefotetan
• Nephrotoxicity: Can cause kidney damage
• Diarrhea: Common with oral cephalosporins
• Candidiasis: Associated with 3rd-generation cephalosporins
• Cholelithiasis: Seen with Ceftriaxone

Carbapenems

• Contains a fused beta-lactam ring with a carbon instead of sulfur.
• Have a broad spectrum and are resistant to most beta-lactamases.
• Imipenem is degraded by renal dehydropeptidase; thus is given with Cilastatin.
• Meropenem is not inactivated by renal enzymes.
• Ertapenem has a long half-life.
• Side effects include nausea, vomiting, and seizures at high doses.

Monobactams

• Only effective against aerobic G(-) bacteria.
• Used for septicemia, complicated UTI, and gonorrhea.
• Side effects include skin rash, GI upset, and hepatitis.

Glycopeptides

• Vancomycin binds D-alanyl-D-alanine, inhibiting peptidoglycan synthesis.
• Active against Gram-positive organisms and C. difficile.
• Oral for C. difficile pseudomembranous colitis and IV for MRSA, MRSE, and enterococcal endocarditis.
• Adverse effects include Red Man Syndrome, nephrotoxicity, ototoxicity, and thrombophlebitis.

Other Beta-Lactam Antibiotics

• Teicoplanin is similar to Vancomycin but with longer half-life.
• Bacitracin is used topically for infected skin, wounds, and mucous membranes; systemically associated with nephrotoxicity