Anti-Microbials

Question 1

Penicillins

What is the mechanism and adverse effects of penicillins?

Answer 1

1. Mechanism: bactericidal; interfere with cell wall synthesis. Diffuse well into body tissues and fluids, but poor penetration of CSF. Urinary excretion.
2. **Adverse Effects: **
   
   1. Diarrhoea
   2. **Hypersensitivity: **allergy common (1-10%), anaphylaxis in <0.05%. Allergy is carried across all classes as hypersensitivty related to basic penicillin structure.
   3. **Encephalopathy: **rare, secondary to cerebral irritation in high doses (excessive dosing or renal failure)
   4. Electrolyte accumulation: most injectable forms contain Na or K.

Question 2

Broad Spectrum Penicillins: Ampicillin / Amoxicillin

What are examples of broad spectrum penicillins, which bacterial classes are sensitive, and what is a common side effect?

Answer 2

1. Ampicillin / Amoxicillin:
   
   1. Amoxicillin derived from ampicillin, but with higher availability and absorption not affected by presence of food in the stomach.
   2. Active against gram +ve and -ve, but inactivated by penicillinases (e.g. *S. aureus *and E. coli) → majority of Staph are resistant, *S. pneumoniae *usually sensitive.
   3. Commonly cause maculopapular rash, almost always in patients with glandular fever → avoid for ‘blind’ treatment of sore throat

Question 3

Broad Spectrum Penicillins: Co-amoxiclav

What is the formulation of Co-amoxiclav, what are the indications and what are the adverse effects?

Answer 3

1. Formulation: amoxicillin, with β-lactamase inhibitor clavulanic acid → effective against β-lactamase producing organisms resistant to amoxicillin. Includes *S. aureus *(but flucloxacillin more reliable), *E. coli *and H. influenzae.
2. Indications: known or likely amoxicillin resistant β-lactamase producing strains
3. Adverse effects: as amoxicillin, with additional risk of cholestatic jaundice (> risk over 65 years) and ↑ risk of hepatotoxicitiy

Question 4

Penicillinase-Resistant Penicillins

What are the penicillinase resistant penicillins, what are their indications for use?

Answer 4

1. **Flucoxacillin → **only penicillin that is β-lactamase stable. Acid stable, therefore given by mouth and injection.
2. Indications: sole indication for use is **penicillin resistant staphylococci **(commonly used for S. aureus infections).

Question 5

Anti-Pseudomonal Penicillins

Which penicillins have activity against pseudomonal species?

Answer 5

1. **Ticarcillin **or **Piperacillin **(usually formlated with clavulanic acid) with **gentamicin **useful in pseudomonal infections

Question 6

Cephalosporins

What is the mechanism and spectrum of cephalosporins? What are adverse effects?

Answer 6

1. Mechanism: β-lactam - inhibits mucopeptide synthesis in bacterial cell wall → osmotically instability and lysis. Similar pharmacology to penicillins: renal excreted, poor penetration of CSF unless meninges inflamed.
2. Spectrum: broad spectrum, used in septicaemia, pneumonia, meningitis, biliary tract infection, peritonitis and UTI.
3. Adverse effects:
   
   1. ​Hypersensitivity: ~1% penicillin sensitive patients allergic to cephalosporins → do not give if immediate hypersensitivty to penicillin. If use is unavoidable, ceftriaxone or cefuroxime suitable choices.

Question 7

Cephalosporins: Generations

Which are the first, second and third generation cephalosporins?

Answer 7

1. First: cefalexin
2. Second generation: cefuroxime → less susceptible than earlier cephalosporins to inactivation by β-lactamase, active agains *H. influenzae *and N. gonorrrhoeae
3. Third generation: cefotaxime, ceftazidime and ceftriaxone → greater activity against certain gram-ves, but less active against Gram +ves, particularly Staph aureus.
   
   1. ​Ceftazidime: active against pseudomonas
   2. Ceftriaxone: long half-life → only give OD. Indications are serious infections (septicaemia, pneumonia, meningitis). Calcium salt of ceftriaxone may preipitate in gall bladder.

Question 8

Macrolides

What is the mechanism of macrolides, and examples of classes and spectrum.

Answer 8

1. Mechanism: bind to 50S ribosomal subunit inhibiting protein synthesis → bacteriostatic
2. **Examples: **erythromycin, clarithromycin, azithromycin
3. **Spectrum: **similar to penicillins → good alternative in pen allergic patients:
   
   1. Activate against chlamydia, legionella and mycoplasma → indicated in severe CAP
   2. Also active against RTI, whooping cough, legionnaires disease, campylobacter enteritis.

Question 9

Macrolides: Adverse Effects and Interactions

What are the adverse effects and interactions of macrolides

Answer 9

1. Adverse effects:
   
   1. Common: GI intolerance, diarrhoea, phlebitis with I.V administration
   2. Occasional:
      
      1. Prolonged QTc (particularly in high I.V doses)
      2. Cholestatic hepatitis
      3. LFT elevation
      4. Generalized rash
2. ​Interactions:
   
   1. **Erythromycin **is a potent inhibitor of CYP3A4 and CYP1A2 → many interactions including:
      
      1. Theophylline: ↑ serum level; monitor
      2. Warfarin: ↑ anti-coagulation; monitor
      3. Statin: ↑ risk myositis

Question 10

Tetracyclines

What is the mechanism, examples, spectrum, indications and contra-indications for tetracyclines?

Answer 10

1. Mechanism: inhibit protein synthesis by binding to 30S ribosomal subunit
2. **Examples: **doxycycline, lymecycline, minocycline
3. **Spectrum and indications: **active against many gram+ve and -ve organisms, including H. influenzae, suitable for respiratory and ENT infections and chlamydia. Widely used for acne.
4. Contraindications: deposition in growing bone and teeth (binds to calcium) → staining and dental hypoplasia. Do not give under 12, or pregnant / breast-feeding women.

Question 11

Tetracyclines: adverse effects

What are the adverse effects of tetracyclines?

Answer 11

1. Common:
   
   1. GI intolerance (dose-related)
   2. Stained and deformed teeth in children
   3. Diarrhoea
2. **Rare: **
   
   1. ​Exacerbation of renal failure (with exception of doxycycline and minocycline → do not give in renal disease)
   2. Hepatitis
   3. Dysphagia / oesophageal ulcerations
   4. Candidiasis

Note: **doxycycline **preferred → safe in renal failure, no interactions with food. First line for exacerbation COPD in penicillin allergic patients

Question 12

Quinolones

What is the mechanism, examples, spectrum and indication of quinolones?

Answer 12

1. **Mechanism: **inhibit DNA topoisomerases (DNA gyrase and topoisomerase 4), interfering with replication and some aspects of transcription, repair and recombination
2. Examples:
   
   1. Ciprofloxacin → active against enteric Gram +ves and -ves, including salmonella, shigella, campylobacter and neisseria. Anaerobes are not susceptible. Considered **second line **due to ↑ C. diff risk
   2. **Moxifloxacin → **reserved for treatment resistant CAP, sinusitis or exacerbations COPD. Associated with life threatening hepatotoxicity
   3. Levofloxacin → greater activity against pneumococcus; licenced but second line.

Question 13

Quinolones: Adverse Effects and Contraindications

What are the adverse effects and contraindications of quinolones?

Note: AKA fluoroquinolones

Answer 13

1. Contraindications: pregnancy, breast feeding, epilepsy
2. Occasional:
   
   1. Nausea and diarrhoea (and ↑ **c. diff)
   2. CNS: headache, malaise, restlessness, dizziness
3. Rare:
   
   1. Tendon rupture (↑ over age 60, corticosteroids)
   2. QTc prolongation
   3. Peripheral neuropathy
   4. Transaminases, rarely hepatic failure
   5. Severe allergic reactions (TEN , SJS, allergic pneumonitis)
   6. Interterstitial nephritis

Question 14

Aminoglycosides

What are the mechanisms, examples, spectrum and indications of aminoglycosides

Answer 14

Mechanism: inhibit protein synthesis; irreversibly bind to 30S ribosomal subunit

1. Examples: gentamicin, neomycin, streptomycin
2. Spectrum: some gram +ve, many gram-ve organisms. Streptomycin is active against M. tuberculosis; reserved almost entirely for this.
3. Indications: Gentamicin is aminoglycoside of choice, used for:
   
   1. UTI
   2. Intra-abdominal sepsis
   3. Sepsis of unknown origin

Note: when using in “blind” therapy, combined with penicillin, metronidazole or both. Has to be given by **injection **as no enteric absorption.

Question 15

Aminoglycosides: Adverse Effects and Interactions

What are the adverse effects and interactions of aminoglycosides

Answer 15

1. Adverse effects: note - most dose related; take care with dosing and don’t treat for > 7 days. If renal failure or elderly, increase interval between doses or reduce dose
   
   1. Ototoxicity
   2. Nephrotoxicity
   3. Interfere with neuromuscular transmission → avoid in patients with MG. May cause transient myaesthenic syndrome in large doses.
2. Interactions: avoid with other ototoxics e.g. furosemide

.

Question 16

Metronidazole

What is the mechanism, spectrum and indications and adverse effects of metronidazole

Answer 16

1. Mechanism: uncertain, but reduced to metabolite that disrupts DNA and inhibits nucleic acid synthesis
2. Spectrum: mainly active against anaerobes
3. Indications: include abdominal sepsis, C. difficile colitis, trichomoniasis, amoebiasis and giardiasis
4. Adverse effects:
   
   1. Common: GI intolerance, metallic taste, headache, dark urine
   2. Occasional: peripheral neuropathy, phlebitis at injection sites, disulfiram-like reaction with alcohol

Question 17

Clindamycin

What is the mechanism, spectrum, indications and adverse effects of clindamycin

Answer 17

1. Mechanism: inhibits bacterial synthesis binding to 50S ribosomal subunit
2. Spectrum:** **gram +ve cocci (including strep and penicillin resistant staph) and many anaerobes.
3. **Indications: **
   
   1. ​Staphylococcal** **bone and joint infections e.g. osteomyelitis (concentrated in bone)
   2. Intra-abdominal sepsis
   3. Eryspleas or cellulitis: alternative to macrolides
4. Adverse effects: higher than averge risk of C. difficile

Question 18

Trimethoprim and Co-Trimoxazole

What is the mechanism and indications for trimethoprim and co-trimoxazole

Answer 18

1. Mechanism: trimethoprim binds dihydrofolate reductase, inhibiting reduction of dihydrofolic acid. Combined with **sulphamethoxazole **in co-trimoxazole due to synergystic activity
2. Indications:
   
   1. Trimethoprim: urinary and respiratory tract infection, and prostatitis, shigellosis and invasive salmonella infection. ↑ level of E.coli resistance so not first line for cystitis.
   2. Co-trimoxazole: PCP, toxoplasmosis, nocardiasis. Rare but serious S/E of SJS, blood dyscrasias, BM suppression and agranulocytosis.

Question 19

Nitrofurantoin

What is the mechanism, indication and adverse effects of nitrofurantoin

Answer 19

1. Mechanism: reduced by flavoproteins (bacterial enzymes) to active intermediates that damage / inactivate ribosomal proteins
2. **Indication: **good activity against E.coli → uncomplicated UTI is only current indication. Concentrated in urine → not effective in urosepsis or renal failure
3. Adverse effects:
   
   1. **​Common: **GI intolerance
   2. Rare: hypersenstivity with acute pulmonary symptoms (within hours / weeks of dose). **IPF **with prolonged use

Question 20

Vancomycin and Teicoplanin

What is the mechanism, spectrum and indications of vancomycin and teicoplanin

Answer 20

1. Mechanism: bind to D-ala-D-ala precursor, inhibiting cell wall biosynthesis
2. Spectrum: bactericidal activity against aerobic and anaerobic gram +ve, including multi-resistant staphylococci.
3. Indications:
   
   1. I.V → endocarditis, and serious infections caused by Gram+ve cocci
   2. Oral: C. difficile unresponsive to metronidazole, or moderate / severe infections (not given by mouth for systemic infections as not significantly absorbed)

Question 21

Vancomycin and Teicoplanin: Adverse Effects

What are the adverse effects associated with vancomycin and teicoplanin

Answer 21

1. Occasional
   
   1. ​Red man syndrome: flushing over chest / face ± hypotension and pruritis; not a true allergy
   2. Phlebitis
   3. Impaired renal function (particularly if combined with aminoglycosides)
   4. Back spasms
2. Rare
   
   1. Neutropaenia / thrombocytopaenia
   2. Drug fever
   3. Tissue irritation
   4. Ototoxicity

Question 22

Treatment of Tuberculosis

What is the normal treatment regimen for tuberculosis, and the timeframes (initiation & continuation) involved.

Answer 22

1. Initiation phase: 2 months, Continuation phase: 4 months (total 6 months):
   
   1. Rifampicin: (initiation + continuation)
   2. Isoniazid: (initiation + continuation)
   3. Pyrazinamide (initation)
   4. **Ethambutol **(initiation)
2. General notes:
   
   1. Start treatment w/o culture results if clinical features / histology consistent with TB. Continue even if initial culture negative
   2. Longer treatment required for meningitis, direct spinal cord involvement, resistance
   3. Fully supervise treatment if patients cannot comply reliably with treatment.
   4. Regiment is safe in pregnancy

Question 23

Treatment of Tuberculosis: Monitoring

What monitoring is required in the treatment of TB?

Answer 23

1. Liver function: isoniazid, rifampicin and pyrazinamide all associated with liver toxicity → check more frequently with pre-existing liver disease / alcohol dependence
2. Renal function: avoid **streptomycin **and **ethambutol **in those with renal impairment
3. Visual acuity: test before ethambutol

Question 24

Isoniazid

What are the adverse effects of isoniazid?

Answer 24

1. Common
   
   1. ​Peripheral neuropathy: more likely when pre-existing risk (diabetes, alcohol dependence, chronic renal failure, malnutrition, HIV). **Pyridoxine **(vit B6) can be given prophylactically from the start
2. Uncommon
   
   1. ​hepatitis
   2. psychosis
   3. SLE like syndrome

Question 25

Rifampicin

What are the adverse effects associated with rifampicin?

Answer 25

Note: induces hepatic enzymes; accelerates metabolism of oestrogens, corticosteroids, phenytoin, sulphonylureas and anticoagulants

1. Common
   
   1. ​Disturbance of LFT: during first two months, ↑↑ serum transaminases common, but generally does not interrupt treatment. May be more serious if pre-existing liver disease
   2. Body secretions turn yellow / orange
2. Occasional: six toxicity syndromes recognised, occurring in 20 - 30%:
   
   1. Influenza like
   2. Abdominal symptoms
   3. Respiratory symptoms
   4. Shock
   5. Renal failure
   6. Thrombocytopenic purpura

Question 26

Pyrazinamide

What are the adverse effects of pyrazinamide

Answer 26

Note: bactericidal, only active against intracellular dividing forms of M. tuberculosis, exerts effect only in first 2 - 3 months. Useful in tuberculous meningitis → meningeal penetration.

Adverse effects: **serious liver toxicity **occasionally occurs

Question 27

Ethambutol

What are the adverse effects of ethambutol?

Note: included if isoniazid resistance suspected → may be ommited if low risk

Answer 27

1. Visual disturbance: loss of acuity, colour blindness, restriction of visual fields. Manifests first as red-green colour blindness → seek medical treatment and discontinue (eyesight almost always recovers)

Question 28

Infective Endocarditis

What are the recommended treatment regiments for endocarditis in the following situations:

1. “Blind” therapy
2. Endocarditis caused by staphylococcus
3. Endocarditis caused by streptococcus (e.g. viridans)
4. Endocarditis caused by enterococcus (e.g. E. faecalis)
5. Endocarditis caused by HACEK organisms

Answer 28

1. Flucloxacillin and gentamicin. Substitute flucloxacillin for vancomycin & rifampicin if cardiac prosthesis present or MRSA suspected.
2. Flucloxacillin (vancomycin + rifampicin if pen allergic / suspected MRSA
3. Benzylpenicillin and gentamicin (substitute ben pen with vancomycin if highly penicillin-resistant or pen-allergic)
4. Amoxicillin and gentamicin
5. Amoxicillin (or ceftriaxone if amoxicillin resistant) and low dose gentamicin