Pharm Week 10 Antibiotics

• Here are study notes on anti-infective drugs:

Bactericidal vs. Bacteriostatic

• Bactericidal agents directly kill bacteria by destroying the cell wall, interfering with cellular processes or disrupting the bacterial membrane.
• Examples include penicillins, cephalosporins, and aminoglycosides.
• Bacteriostatic agents inhibit bacterial growth and reproduction, allowing the immune system to clear the infection.
• They interfere with protein synthesis or metabolic pathways.
• Examples include tetracyclines, macrolides, and sulfonamides.

Broad-Spectrum vs. Narrow-Spectrum Antibiotics

• Broad-spectrum antibiotics act against a wide variety of bacteria, including both gram-positive and gram-negative types.
• They are useful in empiric therapy when the exact causative pathogen is unknown, often started before culture results.
• Use can disrupt the balance of normal, beneficial bacteria, leading to GI disturbances, superinfections (GI infections, yeast infections, C.Diff).
• Wide activity contributes to antibiotic resistance.
• Narrow-spectrum antibiotics target specific types or families of bacteria.
• Prescribed after culture results are available for specific coverage, this decreases the risk of resistance.
• Preferred when the pathogen is identified, allowing for targeted treatment and severe infections from gram positive (staph aureus, MRSA)
• Causes less disruption to normal bacterial flora, reducing side effects, this minimizes selection pressure for resistance.

Mechanisms of Antibiotic Resistance

• Genetic mutations in bacterial DNA can alter target sites for antibiotics, reduce drug binding, or modify metabolic pathways.
• Organisms change the structure of the channel or pores used by antibiotics like PCN and tetracyclines.
• Enzymatic inactivation involves bacteria producing enzymes (e.g., β-lactamases) that degrade or modify and deactivate antibiotics.
• Some Haemophilus influenzae strains produce beta-lactamase, destroying penicillin and ampicillin, making them resistant.
• Efflux pumps in Gram-negative bacteria pump antibiotics out of the cell, reducing the drug concentration inside.
• Resistance to tetracycline is an example, and MRSA.
• Reduced permeability involves changes in the bacterial cell wall or membrane decreasing antibiotic uptake.
• Gram-negative bacteria have an outer lipopolysaccharide membrane presenting a barrier, but has porins which allow lipophilic drugs to enter.
• Resistant strains have less permeable outer membranes/porin channels, which is why pseudomonas aeruginosa is resistant to gentamycin.
• Alteration of the target site occurs when bacteria produce a different protein target site where an antibiotic normally binds.
• An example is methicillin-resistant Staph. aureus (MRSA), which has an altered penicillin-binding protein.

Pseudomembranous Colitis

• Pseudomembranous colitis is an inflammatory condition of the colon commonly associated with Clostridioides difficile (formerly Clostridium difficile) overgrowth.
• C. difficile, the primary pathogen, produces toxins A and B that damage the colonic mucosa, leading to pseudomembrane formation.
• Clinical manifestations include diarrhea, abdominal pain and cramping, fever, leukocytosis (↑ WBC), nausea, and loss of appetite.
• Risk factors related to antibiotic use include broad-spectrum antibiotics (clindamycin, cephalosporins, fluoroquinolones, penicillins).
• Increased risk with cephalosporin use (especially IV), but C. diff seen in up to 20% of patients on oral cephalosporins.
• Disruption of normal flora allows C. difficile to overgrow as well as hospitalization and healthcare exposure.
• Other contributing factors inlude age, immunocompromised status, comorbidities

Processes Involved in Antibiotic Selection

• Identification of the Likely Pathogen/Susceptibility begins with empiric therapy based on clinical data to cover likely pathogens.
• Culture and sensitivity tests identify the exact pathogen and its susceptibility profile.
• This information guides adjustment to narrow-spectrum therapy.
• Spectrum of Activity: Choosing an antibiotic with the appropriate range of action.
• Broad-spectrum agents may be used initially, while the goal is often a narrow-spectrum antibiotic once the pathogen's identified
• Resistance Trends: Local resistance patterns are reviewed to avoid agents with high resistance rates.
• De-escalation involves narrowing the antibiotic spectrum based on clinical and microbiological data, minimizing resistance and side effects.
• Patient Characteristics: Factors such as age, weight, organ function, allergies, pregnancy status, and comorbidities influence antibiotic selection and dosing.
• Host Factors: Defenses, the immune system and phagocytic cells (macrophages, neutrophils) are critical.
• The antibiotic must be present at an effective site of infection. Other factors include previous allergic reactions and genetic factors, which determines metabolism rate, impacts antibiotic choice.
• Duration of Therapy: Determining the appropriate treatment length ensures infection eradication while minimizing resistance and side effects.
• Appropriate duration based on the type and severity of infection.

Client Factors in Antibiotic Selection

• Pediatric and Geriatric Considerations: Dosage and antibiotic choice varies due to metabolism and organ function differences.
• Weight-Based Dosing: Ensures therapeutic drug levels without causing toxicity.
• Drug Allergies: Prior reactions necessitate alternative agents to avoid severe reactions.
• Safety Profiles: Some antibiotics are contraindicated due to risks to the fetus or infant.
• Dosing Adjustments: Kidney/liver function affects drug clearance, requiring dosage modifications to prevent toxicity.
• Drug Selection: Many antibiotics are metabolized by the liver or excreted by the kidneys that is crucial for patients with dysfunction.
• Underlying Health Issues: i.e. diabetes, immunosuppression, or cardiovascular disease might affect drug selection, dosing, or drug interactions.
• For example, certain antibiotics might exacerbate conditions or interact with other treatments the client is receiving.
• Current Medications: Review client's medication list to avoid interactions that reduce antibiotic effectiveness or increase side effects.
• Site of Action: The chosen antibiotic should have good penetration to the infection site (e.g., central nervous system, lung tissue).
• Severity of Illness: More aggressive infections may require broader-spectrum or higher-dose therapies initially.
• Drug selected and route for treatment depends on the client's ability to adhere.

Treatment and Compliance

• Outpatient vs. inpatient care influences antibiotic routes and forms.
• Infection Type and Severity: The nature and severity of the infection play a role i.e. localized vs systemic infection.
• Patient education is extremely important to stop antimicrobial resistance (AMR)

Mechanism of Action: Penicillins

• Penicillin, a beta-lactam works by binding to penicillin-binding proteins (PBPs), and inhibits transpeptidation (crosslinking) in peptidoglycan synthesis.
• This compromises cell wall synthesis, leading to bacterial lysis, most effective against actively dividing bacteria.

Mechanism of Action: Cephalosporins

• Cephalosporin, a beta-lactam with a similar action to penicillins: binds to PBPs, inhibiting peptidoglycan crosslinking.
• Cephalosporins are classified by "generations" with varying spectra

Mechanism of Action: Fluoroquinones

• Fluoroquinon inhibits DNA gyrase (topoisomerase II) and topoisomerase IV, preventing proper DNA replication and segregation
• The result is broad-spectrum coverage which is effective against various Gram + and Gram - organisms.

Mechanism of Action: Macrolides

• Macrolidies bind to the 50S ribosomal subunit and inhibit translocation during protein elongation.
• They are bacteriostatic (or bactericidal at higher doses), commonly used for respiratory infections

Mechanism of Action: Vancomycin

• Vancomycin binds to D-alanyl-D-alanine termini on peptidoglycan precursors and blocks polymerization and crosslinking of cell wall components
• It is important for the treatment of MRSA and other resistant gram-positive infections (cell wall synthesis inhibitor)

Drug Classes, Spectrum, and Uses

• Natural penicillins like Penicillin G treat gram-positive bacteria, such as streptococcal infections, typically administered IV/IM.
• Broad-spectrum penicillins like Amoxicillin are effective against most gram-positive/gram-negative bacteria and respiratory, UTI, and ear infections.
• Penicillinase-resistant drugs like Methicillin help treat penicillinase-producing S. aureus, this has declined due to MRSA.
• Antipseudomonal penicillins like Piperacillin are broad-spectrum and combat serious infections, particularly in immunocompromised patients.

Reactions Associated with Penicillin Use

• Allergic Reaction results in rash, itching, hives, swelling, mild fever within minutes/hours of exposure and is a moderate immune response
• Anaphylactic Shock is a severe and life-threatening reaction that causes difficulty breathing, swelling of the throat/tongue and fast HR within seconds/minutes of exposure
• Serum Sickness is indicated by fever, arthralgia (joint pain), rash, lymphadenopathy, edema, occurs days/weeks after exposure.

Drug Cross Sensitivity

• Cross-sensitivity occurs when someone allergic to one substance (e.g., drug) reacts to another with a similar chemical structure, which is why it’s crucial for patient safety.
• Cross-sensitivity happens when the immune system recognizes similar epitopes (antibody recognition points).
• Someone might recognize similar structures in another drug, which results in an allergic reaction.
• People allergic to penicillin at risk for cephalosporin, as well as one NSAID reacting to another
• Healthcare must assess allergies and doctors might consider different medication
• Alternative options should be sought, essential to inform providers about allergies

Cephalosporins Generations

• Identify the generation that crosses the blood-brain barrier:
• 3rd generation (e.g., Ceftriaxone, Cefotaxime) effectively penetrate the BBB, making them first-line for bacterial meningitis cases.
• 4th generation cephalosporin (Cefepime) also crosses the BBB and is used in hospital-acquired meningitis

Fluoroquinolones

• Fluoroquinolones are generally avoided in pediatric patients to prevent cartilage damage and tendon rupture risks.
• They may be used if necessary for UTIs, pyelonephritis, Pseudomonas (cystic fibrosis specifically)

Macrolides

• Drugs with a Narrow Therapeutic Index/High Risk of Interaction:
• Warfarin – Affected by multiple drugs via CYP2C9 and CYP3A4 (e.g., macrolides, fluoroquinolones, antifungals, anticonvulsants)
• Digoxin - Interacts with macrolides and P-glycoprotein inhibitors, increasing toxicity risk
• Theophylline – Affected by macrolides and fluoroquinolones.