أسئلة الـ 15 فارما PPPM (قبل التعديل)

• Antibacterial drugs either kill bacteria or suppress their growth.

Classification of Antibacterial Drugs (According to Mechanism of Action):

• Cell wall synthesis inhibitors: Penicillin
• Protein synthesis inhibitors:
  • Affect ribosomal 30S subunit, e.g., aminoglycosides
  • Affect ribosomal 50S subunit, e.g., macrolides
• Nucleic acid synthesis inhibitors: Quinolones
• Folate metabolism inhibitors: Sulphonamide
• Cell membrane function inhibitors: Anti-fungal (amphotericin) & Azoles

Classification of Antibacterial Drugs (According to Antimicrobial Spectrum):

• Narrow Spectrum Drugs:
  • Active against a specific group of bacteria, mainly one type (limited species)
  • Example: Penicillin G effective against gram-positive bacteria, Aminoglycosides against gram-negative bacteria
• Broad Spectrum Drugs:
  • Affect a wider range of bacterial species, potentially more than one type
  • Active against gram-positive and gram-negative bacteria and may also affect other bacteria
  • Examples: Cephalosporins, quinolones, tetracycline

Classification of Antibacterial Drugs (According to Effect on Microorganisms):

• Bactericidal Agents:
  • Kill microorganisms
  • Rapidly act on growing bacteria
  • Examples: cell wall inhibitors, DNA inhibitors, aminoglycosides, high-dose macrolides
  • Preferred for immunocompromised patients and dangerous infections like endocarditis, meningitis, and osteomyelitis
• Bacteriostatic Agents:
  • Arrest the growth of microorganisms, allowing the immune system to eliminate bacteria
  • Other antibacterial drugs
  • Should not be combined with bactericidal drugs as they inhibit bacterial growth, decreasing the effect of bactericidal drugs

Types & Goals of Antimicrobial (Antibacterial) Therapy:

• Prophylactic:
  • Giving antibacterial to a patient not yet infected, to prevent infection or disease development
  • Consider a narrow-spectrum antibiotic targeted at the most important organism/surgical site
  • Limited duration during procedures with expected contamination
  • Prophylaxis used in surgical/invasive procedures, immunosuppressed patients, patients at risk of endocarditis, and post-exposure prophylaxis
• Empirical:
  • Initiating antimicrobial therapy without waiting for microorganism identification, relying on clinical presentation and experience
  • Gram stain examination of infected secretion is the most time-tested method for immediate identification of bacteria
  • Used in cases like sepsis, osteomyelitis, meningitis
  • Broad-spectrum combination of antibacterial & antifungal agents are given to neutropenic patients with fever
  • Culture is still mandatory to modify antimicrobial therapy.
• Definitive:
  • Once microorganism (bacteria) has been identified with C & S test, choose therapy
  • Narrow targeted antimicrobial should be used to target the most sensitive bacteria
  • Mono-therapy is preferred
  • Combination therapy is generally an exception
  • Using 2 antimicrobial agents where one suffices increases toxicity & causes unnecessary damage to the patient's flora
  • Special Conditions favor combination therapy

General Principles of Antimicrobial Prescription:

• Diagnosis: Is an antimicrobial indicated? Note that diagnosis may be masked if therapy is started before obtaining tests or cultures.
• Proper dose, dose schedule & duration: Maximize efficacy & minimize toxicity. Duration is generally 7-10 days, or 3 days after apparent cure.
• Kinetics of the drug: Take into consideration the route of administration (e.g., aminoglycosides are not absorbed orally) and its ability to penetrate the site of infection.
• Serious infections: Parenteral loading dose of a bactericidal may be needed.
• Abscess: Should be adequately drained.
• Foreign body: Remove any foreign body.
• Know When to Use Antimicrobial Combinations:
  • Special conditions that favor combination therapy:
    • Treat mixed infections
    • Severe infections
    • Prevent resistance to mono-therapy (in certain infection)
    • Accelerate microbial killing in severely ill patients (broad spectrum)
    • Enhance therapeutic efficacy
    • Reduce toxicity when adequate efficacy of a single antibacterial is achieved at doses that are toxic to the patient, by using a second drug to permit lowering the dose of the first one
  • Disadvantages of combination:
    • Increased toxicity
    • Increased cost
    • Increased risk of super-infection
    • Antagonism & resistance if use incorrect combination

Antimicrobial Resistance:

• Resistance occurs when a drug can no longer effectively reach and combine with its target due to:
  • Reduced entry of antibiotic into pathogen.
  • Enhanced export of antibiotic via efflux pumps.
  • Release of microbial enzymes that alter or destroy the antibiotic.
  • Alteration of target proteins.
  • Development of alternative pathways that are not inhibited.

General Adverse Effects of Most Antibacterials:

• Hypersensitivity (allergy): Can manifest as fever, skin rash, arthralgia, cholestatic jaundice, or anaphylaxis. Take allergy history and perform sensitivity test. Cross-hypersensitivity can occur among chemically related drugs.
• Drowsiness and dizziness.
• Gastrointestinal (GIT) upsets: Dyspepsia, nausea, vomiting, or diarrhea can occur.
• Parenteral irritation: Resulting in pain, phlebitis, or thrombophlebitis.
• Teratogenicity: Antibacterials are unsafe during pregnancy, with some exceptions
• Super-infection (Opportunistic infection):
  • Mechanism: Broad-spectrum antibiotics kill normal bacterial flora, allowing opportunistic bacteria and fungi to proliferate.
  • Causes: Staphylococci, Pseudomonas, proteus, Candida albicans, or Clostridia difficile.
  • Types: Can be vaginal, oral, pharyngeal, or systemic. In the GIT, early manifestation includes diarrhea. Severe form is pseudomembranous colitis (caused by Clostridium Difficile bacteria).
  • Treatment: Stop the causative agent, and administer a drug to kill the responsible microorganisms.
    • Pseudomembranous colitis treated by metronidazole (first) or vancomycin orally (if severe)
    • Candidiasis treated with antifungal agents (e.g., Nystatin)

Cell Wall Inhibitors:

• Beta-Lactam Antibiotics
  • Penicillin
  • Cephalosporins
  • Monobactams
  • Carbapenem
  • Vancomycin

1. Penicillins:

• Mechanism of Action:
  • Binds to penicillin binding proteins (PBPs) = (transpeptidase Enzyme), inhibiting transpeptidation reaction needed for cross-linkage between peptidoglycan units.
  • Bactericidal, especially for gram-positive bacteria with thick cell walls.
• Causes of bacterial resistance:
  • Production of beta-lactamase (penicillinase) by bacteria, destroying the beta-lactam ring.
  • Mutation in PBP, such that PBP2A does not bind beta-lactam antibacterials, as seen in meticillin-resistant S. Aureus (MRSA).
• Pharmacokinetics:
  • Absorption:
    • Decreased by food; administer 1 hour before or 2 hours after meals.
    • Oral administration in moderate infection and acid-stable preparations (e.g., penicillin V).
    • Parenteral administration in severe infection and acid-sensitive preparations (e.g., penicillin G).
  • Distribution: Penetrates CSF & ocular fluid only during meningitis. Crosses placental barrier but is not teratogenic.
  • Excretion: Through organic acid secretory system in proximal tubules via the kidney. The renal excretion in proximal tubules can be decreased by co-administration of probenecid, prolonging the duration of action.

Classification of Penicillins:

• Natural (Narrow Spectrum):

  • Mainly Gram + ve (Staph., Strept. ex: pneumococci, diphtheria) and
  • Little Gram - ve (Gonococci & meningococci)
  • Treponema pallidum (causes syphilis)

• Aminopenicillins:

  • Gram +Ve (including listeria monocytogenes) & G - Ve bacteria e.g. Salmonella, H. influenza, Proteus & Shigella (No Pseudomonas).

• Routes:

  • Oral (acid resistant)
  • Injection (IM & IV).

• Natural Penicillin Antibiotics:

  • Penicillin G (benzyl penicillin):
    • Administered parenterally (IM or IV) since it is acid labile
    • Short acting (frequent dosing, every 6-8h)
  • Penicillin V:
    • Administered orally (acid stable)
    • Short acting (frequent dosing)
  • Benzathine penicillin G:
    • Prolonged duration
    • Administered once monthly via deep IM injection only

• Aminopenicillin Antibiotics:

  • Amoxicillin/clavulanic acid (co-amoxiclav):
    • Better absorption & tissue penetration, no effect on the gut flora & less G.I.T upset
    • More active against Salmonella & Streptococcal fecalis
  • Ampicillin/sulbactam (Unasyn):
    • Concentrated in bile making it effective in typhoid carrier
    • Piva-& tala- ampicillin esters of ampicillin which are better absorbed & cause less G.I.T upset

• Beta-Lactamase Inhibitors: Combined with beta-lactam antibiotics to inhibit beta-lactamase produced by specific bacteria, therefore protecting beta-lactams antibiotics from inactivation. Examples: Clavulanic acid, Sulbactam, Tazobactam, Avibactam

• Antipseudomonal Penicillins:

  • Broad spectrum for both Gram + Ve & G -Ve aerobic & anaerobic bacteria
  • Frequently used to treat Pseudomonas aeruginosa
  • Administered parenterally, either IM or IV
  • E.g. Piperacillin& Ticarcillin
  • Inactivated by beta-lactamase, combined with beta-lactamase inhibitors like ticarcillin/clavulanic acid or piperacillin / tazobactam

• Penicillinase-Resistant Penicillins:

  • Resistant to hydrolysis by staphylococcal penicillinase (beta-lactamase).
  • Use is for infections known or suspected to be caused by staphylococci that produce the enzyme
  • MSSA is sensitive to this group of penicillins, while MRSA is resistant to it.
  • E.g. Oxacillin, cloxacillin, Flucloxacillin
  • Flucloxacillin can be combined with amoxicillin
  • Methicillin used only to test staph sensitivity

Therapeutic Uses of Penicillins:

• Treatment Of:
  • Streptococcal infections:
    • Upper resp. tract infections, Otitis media, Sore throat, and Pneumonia, Rheumatic fever
    • Sub- acute bacterial endocarditis and wound sepsis
  • Staphylococcal Infections:
    • Skin, subcutaneous tissue and bone infections
  • Meningococcal Infections: Meningitis
  • Syphilis and Gonorrhea
  • Pseudomonal Infections:
    • Pneumonia, UTI, GIT, Wound infections and Septicemia
  • Typhoid & paratyphoid fevers and Shiglliosis:
    • Amoxicillin & Ampicillin treatment
  • Urinary tract infection (amoxicillin)
  • Diphtheria, Tetanus and Gas gangrene.
• Prophylactic Uses:
  • To prevent recurrence of rheumatic fever
    • Benzathine penicillin G (IM once a month) OR
    • Penicillin V (Oral)
    • Intramuscular penicillin is preferred due to greater effectiveness and better adherence
    • Intravenous injection of benzathine penicillin G can cause cardiorespiratory arrest and death
  • To prevent sub-acute bacterial endocarditis due to bacteremia resulting from
  • In patients with congenital or acquired valvular heart disease or immuno-compromised patients, Benzathine penicillin (IM once a week) is given to prevent against sub-acute bacterial endocarditis during operative procedures (ex: dental extraction, tonsillectomy)

Adverse Effects:

• Hypersensitivity reactions: Occur in 10% of patients, within minutes or up to 12 days
  • Mild: Skin rashes (urticaria) & fever (common)
  • Serious: Anaphylactic shock (rare but may be fatal) (adrenaline IM is lifesaving)
  • The course of penicillin hypersensitivity is considered unpredictable.
  • Never give if individual has a history of severe allergy and test for hypersensitivity before giving penicillin
• Other general adverse effects commonly occurring
• Penicillin in high doses may cause neurotoxicity & seizures in patients with renal failure.
• Co-amoxiclav and flucloxacillin: Hepatotoxicity
• Nafcillin: Decreased WBCs & PLTs
• Amoxicillin-induced rash: infectious mononucleosis