Antibiotics: Classification and Spectrum

Antibiotics

• Antibiotics are medicines that fight infections caused by bacteria in humans and animals.
• Antibiotics achieve this by either killing the bacteria or making it difficult for the bacteria to grow and multiply.
• Antimicrobials are medicines, chemicals, or other substances that kill, inactivate, or slow the growth of microbes, including bacteria, viruses, fungi, and parasites.

Classification of antibiotics

• Bacteriostatic antibiotics inhibit bacterial growth without killing the bacteria.
• Bactericidal antibiotics kill bacteria directly.
• Bacteriostatic antibiotics allow for natural immunity to deal with the microbe
• Bactericidal antibiotics might lead to the release of toxins, as well as microbial content and can lead to potentially inflammatory responses.

Spectrum of Activity

• Spectrum of activity relates to the number of microbes susceptible to the action of an antibiotic and the types of pathogens that the antibiotic covers.
• Narrow-spectrum antibiotics target a limited number of microbes.
• Broad-spectrum antibiotics have a wide range of activity.
• Penicillin G is a narrow-spectrum antibiotic.
• Tetracyclines, such as doxycycline, are broad-spectrum antibiotics.

Classes of Antibiotics

• Penicillins include Penicillin V, Benzathine, Procaine, Amoxycillin, Ampicillin, and Piperacillin/tazobactam.
• Cephalosporins include Cefotaxime, Ceftriaxone, Cefepime, and Ceftazidime.
• Aminoglycosides include Gentamycin, Amikacin, Kanamycin, and Streptomycin.
• Macrolides include Erythromycin, Clarithromycin, and Azithromycin.
• Fluoroquinolones include Ciprofloxacin and Levofloxacin.
• Tetracyclines include Doxycycline.
• Sulphonamides include Cotrimoxazole (contains Sulphamethoxizole and Trimethoprim).
• Carbapenems include Imipenem and Meropenem.
• Glycopeptides include Vancomycin.
• Linezolid does not have a class.

Mechanism of Action

• Antibiotics operate through four main mechanisms:
• Inhibition of Cell Wall Synthesis
• Disruption of Cell Membrane
• Inhibition of Protein Synthesis
• Interference with Metabolic Processes

Inhibitors of Cell Wall Synthesis

• Most bacteria possess a cell wall to protect their contents from osmotic pressures.
• Microbes need to create a new cell wall when dividing.
• Inhibitors of Cell Wall Synthesis include:
  • Penicillins
  • Cephalosporins
  • Vancomycin
  • Carbapenems
• Interruption of the cell wall leads to new microbes being susceptible to external influences.
• Cell rupture leads to microbe death.

Disruptors of the microbial cell membrane

• disrupt transportation in and out of the cell through the cell membrane
• disruptors increase permeability of the cell membrane, which can lead to microbe death
• Disruptors of the microbial cell membrane include:
  • Polymyxin
  • Colistin
• These options are more toxic than antibiotics that inhibit cell wall synthesis

Inhibitors of Protein Synthesis

• Can act either at site of protein synthesis (ribosome) or within the nucleus by inhibiting synthesis of nucleic acids
• DNA replication / RNA synthesis = TRANSCRIPTION
• Exploit structural differences between microbial and human cells
• Inhibitors of Protein Synthesis include:
  • Tetracyclines (e.g., doxycycline)
  • Aminoglycosides (e.g., gentamycin)
  • Macrolides (e.g., erythromycin)

Interference with metabolic processes

• Agents are structurally similar to Para-aminobenzoic acid (PABA) – a component of folic acid
• Folic acid is essential for nucleic acid synthesis.
• Microbes cannot produce proteins for growth without it
• This process exploits the fact that microbes need to create their folic acid, while humans get it in their diets.
• Sulphonamides, Cotrimoxazole (contain sulphamethoxazole and trimethoprim)

Indications

• Antibiotics are indicated for:
  • Treatment of bacterial infections empirically
  • Treatment of bacterial infections definitively based on culture and sensitivity testing
  • Prophylaxis
    • Surgical procedures
    • Meningitis contacts
    • Surgical/ dental procedures in patients with artificial heart valves or heart valve lesions.

Bacterial Infections

• May be treated based on the clinical presentation and likely causative agents.
• Requires consideration of organisms, severity of infection, antibiogram results, history, host factors, medicine factors such as PK and PD, and the ability to penetrate tissues, and concentrate in fluids.
• Physical examinations and laboratory findings may be used to rule out meningitis, endocarditis, pneumonia, and urinary tract infections.

Administration

• Dosing depends on the nature and severity of infection, the weight, age, and renal function of the patient, and the dosing schedule of some antibiotics.
• Gentamicin and vancomycin require therapeutic monitoring of venous blood samples.
• Severe infections need to be treated via intravenous infusion.
• Veins need to be observed for signs of phlebitis, especially with penicillins and vancomycin.
• Administration routes include:
  • I.V.
  • I.M.
  • Oral

Considerations

• Intramuscular injections are painful and avoided in children.
• Food affects antibiotics such as penicillins.
• Antibiotics should be administered an hour before meals or 2 hours after meals.
• Some antibiotics require meals to reduce nausea and vomiting.

Cautions and Contraindications

• Hypersensitivity to penicillins is often associated with hypersensitivity to cephalosporins and vice versa.
• Patients allergic to sulphonylureas may be allergic to sulphonamides.
• Impaired renal function can cause some drugs to accumulate => toxicity
• Some penicillins, vancomycin, ciprofloxacin, can all accumulate due to renal impairment.
• Impaired liver function causes some drugs to accumulate => toxicity
  • e.g. metronidazole, rifampicin.
• Aminoglycosides and quinolones exacerbate myasthenia gravis.
• Penicillins are usually the antibiotics of first choice if pregnant.
• Tetracyclines, cotrimazole, vancomycin and aminoglycosides are avoided if possible if pregnant.
• Breastfeeding allows small amounts of antibiotic to pass from mother to infant.
• Hypersensitivity responses and adverse effects may occur in the infant when breastfeeding.

Medicines Interactions

• Adverse effects may be cumulative when medicines causing similar problems are co-administered.
  • gentamincin, vancomycin, furosemide may cause damage to the inner ear when co-administered
• A disulfiram reaction ('antabuse-like reaction') may occur if metronidazole is taken with alcohol
  • Symptoms include dilatation of blood vessels, causing flushing, headache and hypotension, fainting, falls and cardiovascular collapse
• Rifampicin renders oral contraceptives ineffective.
• Broad-spectrum antibiotics can increase the risk of 'pill failure' for combined oral contraceptives, resulting in pregnancy.
• Many antibiotics should not be combined with other medicines.
  • gentamicin and heparin and penicilin is not a safe combination, loss of antibiotic activity may result
• Aminoglycosides intensify the action of muscle relaxants like suxamethonium.
• Macrolides are inhibitors of metabolism, which can lead to the accumulation of other drugs and increased risk of toxicity
  • e.g. digoxin, corticosteroids, anti-coagulants

Specific Medicines

Amoxycillin

• Amoxycillin can be used for:
  • Ear, nose and throat infections
  • Urinary tract infections
  • Lower respiratory tract infections
  • Used in peptic ulcer disease as part of triple therapy.
• Effective against gram-positive pathogens:
  • Streptococcus spp
  • E. coli
  • H. pylori
  • Not effective against beta-lactamase positive pathogens

Mechanism of action

• Inhibits synthesis of cell => cell lysis and => bacterial death

Adverse effects

• Anaphylactic reaction
• Steven Johnson Syndrome
• Nausea
• Diarrhea
• Candidiasis

Interactions

• Increases the effects of methotrexate and warfarin

Combinations

• May be combined with clavulanate or clavulanic acid (e.g., Augmentin)
  • => inhibits inactivation of amoxicillin by beta-lactamase enzymes

Pharmacokinetics

• Absorption following oral is up to 90%
• Distribution is to the liver, lungs and other parts of the body.
• Protein binding is limited.
• Hepatic metabolism.
• Half-life is up to 2 hours in adults and children.
• Excretion mainly through urine

Cephalosporins

• For Cefotaxime the uses/indications include:
  • Sepsis
  • CNS bacterial infections (e.g., meningitis) due to Strep pneumonia, Klebsiella spp.
  • Urinary tract infections
  • Pneumonia
  • Intra-abdominal infections
• For Ceftriaxone the uses/indications include:
  • Sepsis
  • Acute bacterial otitis media
  • CNS bacterial infection
  • Urinary tract infections
  • Pelvic inflammatory disease (PID), uncomplicated gonorrhoea
  • Pneumonia
  • Intra-abdominal infections

Doxycycline

• Is a broad spectrum antibiotic, and its Uses/indications include:
  • Uncomplicated gonorrhoea
  • Lower respiratory tract infections
  • Severe acne

Mechanism of action

• Inhibits protein synthesis by binding to the 30S ribosomal subunit of bacteria, therefore preventing bacterial replication

Adverse effects

• Nausea, vomiting or diarrhoea (N/V/D), abdominal pain, or anorexia
• Clostridium difficile-associated diarrhea
• Discoloration of teeth in children less than 8 years old

Pharmacokinetics

• Absorption is completely absorbed following oral administration, and is effected by food and milk.
• Distribution is to most parts of the body.
• Approximately 90% protein binding
• Metabolism is no hepatic metabolism
• Has a half-life of 12 - 15 hours (up to 24 hours with multiple doses)
• Excretion: Urine and faeces

• It is important to consider the most likely organism when selecting antibiotics, for example:
  • For Acute otitis media, the most likely organisms are S, pneumonia (most common bacteria), H. influenza, M. catarrhalis
  • Amoxycillin or Amoxycillin plus clavulanate (if amoxicillin was used before)

Sexually Transmitted Illnesses (STIs)

• STIs are treated based on Botswana STI Guidelines and a syndromic approach.
• The syndromic approach covers all possible organisms:
  • In males:
    • Common infections are gonorrhoea and chlamydia
    • Treated with Ceftriaxome or Azythromycin
  • In females:
    • Common infections are gonorrhoea, chlamydia and trichomoniasis
    • Treated with Ceftriazome, Azythromycin or Metronidazole

Conditions difficult to treat:

• Infections caused by Staphylococcus areaus organisms
  • If Methicillin-sensitive is suspected then:
    • can use antibiotics such as:
      • cloxacillin
      • piperacillin/tazobactam
  • If Methicillin-resistant is suspected then:
    • Requires:
      • vancomycin I.V
      • linezolid
• Infections caused by Pseudomonas aeruginosa organisms
  • Consider:
    • piperacillin/tazobactam
    • cefepime
    • ceftazidine
    • meropenem
    • imipenem/cilastin

Other issues for consideration include:

• Irrational use of antibiotics
  • Can lead to antibiotic resistance
  • Use antibiotics for bacterial infections only and for the shortest period possible
  • Sample collection to be done prior to administering antibiotics
  • Culture and sensitivity tests and utilizing results is vital
• Antimicrobial Stewardship Committees can curb antimicrobial misuse and prevent development of resistance
• Prescribing and utilization antibiotics should consider the WHO AWARE
  • Access = antibiotics with activity against a wide range of commonly encountered pathogens with low and slow potential to develop resistance.
  • examples: amoxycillin, amoxycillin-clavulanic acid, ampicillin, benzylpenicillin, doxycycline
  • Watch = antibiotics with higher potential to develop resistance and therefore should be monitored through antimicrobial stewardship.
  • examples: Azythromycin, cefotaxime, ceftriaxone
  • Reserve = antibiotics reserved for treatment of confirmed or suspected infections due to multi-drug resistant organisms. -examples: colistin, polymyxin, linezolid

AWARE Book

• Published by WHO to guide in the:
  • Selection, dosing and utilization of antibiotics to prevent emergence of resistance
  • Monitoring and evaluation of antibiotic use
  • Monitoring and evaluation of the Antimicrobial Stewardship activities

Nursing implications

• For Penicillins & cephalosporins:
  • Assess for improvement of clinical signs and symptoms including vital signs
  • Assess for known previous allergies and possible new allergies
  • Discontinue immediately if signs of allergic reactions occur
  • Monitor for seizures in clients with renal failure
  • If allergic to Penicillin then may also be allergic to cephalosporins
• For Tetracycline i.e. Doxycycline:
  • Avoid milk and milk products
  • Do not prescribe to children and pregnant women
• For Chloramphenicol:
  • Contraindicated in premature babies
  • may precipitate Gray baby syndrome which is often fatal
  • Monitor WBC as it is associated with bone marrow depression and aplastic anemia
• For Aminoglycosides:
  • Assess for hearing loss (are hepatotoxic)
  • Monitor renal function
  • Use with caution with anesthetics and muscle relaxants
  • Give with plenty of water i.e. 8 glasses of water to protect the liver
  • Once daily dosing is better tolerated than q8 hours dosing
• For Macrolides e.g. erythromycin:
  • Assess for frequent diarrhea and if not tolerated, advise to take after meals
  • Monitor for interactions
• For Sulfonamides e.g. Cotrimoxazole:
  • Give with plenty of water 8 glasses of water per day to prevent crystallization and effects on kidneys -Monitor Full Blood Count
• Monitor therapeutic response
  • Overall clinical response i.e. alleviation of signs and symptoms associated with the infection.
  • Improved fever in 8 – 24 hours
  • Decreased WBC
  • Adverse drug reactions specific to the medicines prescribed
  • Assess adherence and nonresponse to therapy – may be sign of resistance
• Be able to do PDs and PKs for most of the commonly encountered antibiotics