Antimicrobial Agents: Selective Toxicity

Introduction: Overview

• Selective toxicity refers to the ability of an antimicrobial to harm or kill an invading microorganism without damaging host cells.
• The action of antimicrobials is not always absolute.
• Antimicrobials target different sites to achieve their function.

Selection of Antimicrobial Agents

• Requires knowledge of the identity and susceptibility of the organism, the site of infection, patient factors, safety and efficacy of the agent, and the cost of therapy.

Identification of the Infecting Organism

• Gram staining is a diagnostic tool used in sterile body fluids like blood and CSF.
• Culturing allows for conclusive diagnosis and identification of susceptibility to antimicrobial agents.
• Microbial antigens like DNA or RNA and host inflammatory or immune markers can be used to identify infecting organisms.

Empiric Antimicrobial Therapy

• Antimicrobial treatment starts before lab results for cultures and susceptibility tests are available.
• Immediate treatment is needed for critically ill, neutropenic, or meningitis patients.
• Specimens for lab analysis should be collected before treatment starts, if possible.
• Broad-spectrum antibiotics are used, taking into account the origin of the infection such as gram-positive cocci in spinal fluid.
• Newborns with gram-positive cocci likely have Streptococcus agalactiae and are sensitive to penicillin G.
• Older patients likely have S. pneumoniae, resistant to penicillin G but sensitive to third-generation cephalosporin or vancomycin.

Bacteriostatic vs Bactericidal

• Bacteriostatic agents stop growth and replication.
• Bactericidal agents kill bacteria, achieving a reduction of ≥99.9%.
• Bactericidal antibiotics are not always more effective than bacteriostatic ones; both have similar efficacy.
• Bacteriostatic antibiotics can kill bacteria to a lesser extent and this is organism-dependent.

Patient Factors Affecting Antibiotic Selection

• An intact immune system helps eliminate the invading organism.
• Reduced immunocompetence due to conditions like diabetes, HIV, malnutrition, autoimmune diseases, pregnancy, or advanced age increases the need for higher doses or longer treatments.
• Renal dysfunction can lead to accumulation of antibiotics cleared by the kidneys.
• Hepatic dysfunction can affect antibiotic metabolism and clearance.
• Newborns have poorly developed renal or hepatic elimination.
• Elderly patients may have decreased renal or liver function.
• Product labeling should be checked regarding pregnancy and lactation.
• The cost of therapy plays a role in antibiotic selection.
• Risk factors for multidrug-resistant organisms include prior antimicrobial therapy in the past 90 days, hospitalization, admission from a nursing home, high local resistance rates, and immunosuppressive conditions or therapies.

Chemotherapeutic Spectra

• Narrow-spectrum antibiotics target a single or limited group of microorganisms.
• Isoniazid is effective against Mycobacterium tuberculosis.
• Extended-spectrum antibiotics are effective against Gram-positive and a significant number of Gram-negative bacteria.
• Ampicillin acts against gram-positive and some gram-negative bacteria.
• Broad-spectrum antibiotics affect a wide variety of microbial species.
• Broad-spectrum antibiotics can alter normal bacterial flora and may lead to superinfections like Clostridium difficile.
• Tetracycline, fluoroquinolones, and carbapenems are examples of broad-spectrum antibiotics.

Combinations of Antimicrobial Drugs

• Combinations of β-lactams and aminoglycosides are synergistic.
• Combinations can be used for infections of unknown origin or conditions like tuberculosis where sensitivity is variable.
• Bacteriostatic antibiotics can interfere with the action of bactericidal antibiotics.
• Antibiotic combinations can cause selection pressure for resistance and increased toxicity.
• Combinations are only used when required.

Prophylactic Use of Antibiotics

• Prevention is preferred over treatment when benefits outweigh risks.
• Pretreatment can prevent streptococcal infections in patients with a history of rheumatic heart disease.
• Pretreatment of patients undergoing dental extractions with prosthetic devices prevents seeding of the prosthesis.
• Pretreatment can prevent tuberculosis or meningitis in those in close contact with infected patients.
• Surgical prophylaxis decreases the risk of post-surgical infection, targeting the most likely organism, not every potential pathogen.

Complications of Antibiotic Therapy

• Hypersensitivity reactions occur in about 10% of patients.
• Hypersensitivity can range from rashes to angioedema and anaphylaxis.
• Cross-allergic reactions can occur among β-lactam antibiotics.
• Diarrhea happens, mostly with extended-spectrum drugs.
• Diarrhea may be caused due to disruption of gut flora.
• Less common complications are ototoxicity, superinfections, and nephritis.

Bacterial Cell Wall

• Bacterial cell wall--mammalian cells do not possess this
• The cell wall is a polymer of peptidoglycan consisting of glycan units (polysaccharide) cross-linked by peptides.
• Inhibitors of cell wall synthesis require actively proliferating microorganisms.

Penicillins

• Penicillins have a beta-lactam structure.
• Penicillins inhibit transpeptidation, disrupting cell wall cross-linking, weakenning the cell wall and causing cell death.
• Penicillins are bactericidal.

Antibacterial Spectrum: Natural Penicillins

• Penicillin G and V come from the mold genus Penicillium.
• Penicillin was considered a "miracle drug" - WWII
• Treatment choice for syphilis caused by Treponema pallidum.
• Penicillin V is available orally, while penicillin G is administered intravenously or intramuscularly.

Antibacterial Spectrum: Extended Spectrum Penicillins

• Ampicillin and amoxicillin are examples.
• They extend to gram-negative bacteria like Haemophilus influenzae and Escherichia coli.
• Ampicillin treats bacterial meningitis and respiratory diseases.
• Amoxicillin treats ENT infections like tonsillitis, pharyngitis, and otitis media and prevents endocarditis.
• β-lactamase inactivates them, making them inactive against MSSA.
• Beta-lactamase inhibitors prevent resistance.

Antibacterial Spectrum: Antistaphylococcal Penicillins

• Methicillin and nafcillin belong to this group.
• They are β-lactamase (penicillinase)-resistant.
• They are restricted to penicillinase-producing staphylococci (MSSA) infections.
• Methicillin identifies MRSA in labs but is not used clinically due to toxicity.

Antibacterial Spectrum: Antipseudomonal Penicillin

• Piperacillin is in this group.
• They are active against gram-negative bacilli like Pseudomonas aeruginosa.
• They can be combined with tazobactam (a β-lactamase inhibitor).

Resistance To Penicillins

• β-Lactamase production is the major cause.
• Decreased drug permeability, mainly in gram-negative bacteria, like Pseudomonas aeruginosa happens.
• Efflux pumps remove drugs from the cell, e.g., in Klebsiella pneumoniae.
• Altered PBPs means lower affinity for β-lactam antibiotics, as seen in MRSA.

Penicillins: Pharmacokinetics

• Routes of administration depend on the drug's stability in gastric acid and severity of the infection.
• Only about 1/3 of oral penicillin V is absorbed.
• It should be taken on an empty stomach.
• Oral Amoxicillin can be taken with or without food.
• Amoxicillin/clavulanic acid: best taken with food.
• Metabolism: Insignificant
• Exceptions Nafcillin and oxacillin metabolized in the liver
• Excreted via kidneys/urine, with dosage exceptions
• Also excreted in breast milk

Penicillins: Adverse Effects

• Hypersensitivity happens in ~10% of patients.
• Adverse reactions include rashes to angioedema and anaphylaxis.
• Cross-allergic reactions occur among β-lactam antibiotics.
• Extended-spectrum PCNs cause diarrhea from intestinal flora imbalance
• Infrequent effects: nephritis (methicillin)

Cephalosporins

• Cephalosporins are β-lactam antibiotics.
• They are closely related to penicillins, share the same mode of action and resistance mechanisms.
• Cephalosporins are more resistant to certain β-lactamases.
• They are classified into generations based on bacterial susceptibility and resistance to β-lactamases.
• First-generation cephalosporins include cephalexin and cefazolin,.
• These are penicillin G substitutes.
• They are resistant to staphylococcal penicillinase, cover MSSA, but not MRSA.
• Second-generation cephalosporins include cefuroxime sodium.
• Second-generation cephalosporins have greater activity against Gram-negative organisms, H. influenzae, Klebsiella species, and Escherichia coli.
• Third-generation cephalosporins include Cefotaxim and Ceftazidime.
• The third generation is useful against Gram-negative bacilli, including β-lactamase producing strains of H. influenzae and Neisseria gonorrhoeae.
• Beta-lactams are the agents of choice in the treatment of meningitis.
• Third-generation cephalosporins must be used cautiously to avoid drug-resistance.
• Fourth-generation cephalosporins include Cefepime, it exhibits a broad spectrum, effective against streptococci and most staphylococci
• Fourth-generation cephalosporins are active against aerobic Gram-negative organisms.
• These generations of cephalosporins do not treat MRSA
• Fifth-generation cephalosporins include Ceftaroline.
• Ceftaroline, a beta-lactam, is active against MRSA
• Ceftaroline is used only for MRSA complicated skin infections and pneumonia.
• Cross-reactivity with penicillin.
• Third-generation cephalosporins can create multi-drug resistance infections.

Other β-Lactam Antibiotics

• Carbapenems: broad-spectrum, active against producing Gram-positive and Gram-negative organisms, anaerobes, and P. aeruginosa.
• Monobactams: Aztreonam is the only available.
• Monobactams treat Gram-negative pathogens, including P. aeruginosa.
• Monobactams lack activity against Gram-positive organisms and anaerobes.
• Monobactams: little cross-reactivity with other β-lactams, they are safe for patients allergic to penicillins, cephalosporins, or carbapenems.

β-Lactamase Inhibitors

• Clavulanic acid, sulbactam, and tazobactam are examples.
• They contain a β-lactam ring but have no antibacterial activity.
• They inactivate β-lactamases.
• They are used in combination with β lactamase-sensitive antibiotics like amoxicillin, ampicillin, and piperacillin.
• Amoxicillin/clavulanic acid and ampicillin/sulbactam covers MSSA.
• They are also formulated with cephalosporins and carbapenems.

Vancomycin

• Vancomycin binds to peptidoglycan precursors, disrupting cell wall cross-linking.
• Vancomycin kills bacteria (bactericidal).
• It targets aerobic and anaerobic Gram-positive bacteria, including MRSA, MRSE, and Clostridium difficile.
• Vancomycin is used for skin/soft tissue infections, infective endocarditis, and pneumonia.
• Adverse events: nephrotoxicity, red man syndrome, and ototoxicity.
• Alterations in the peptidoglycan binding is a resitance mechanism.