Antibiotics

Question 1

Signs and symptoms of infection

Answer 1

• Temperature >38C or <36C
  
  • Low indicative of sepsis
• Tachycardia (↑ pulse rate 90 beats/min), ↓BP
  
  • Low BP - sepsis?
• Respiratory rate >20/min
• Haematological signs: ↑WBC - ↑ neutrophil count, ↑ lymphocyte count, ↑ eosinophil count (less common)
• ↑ platelets
• Inflammatory markers – CRP, ESR
  
  • CRP raised in bacterial, not really viral
  • ESR long term, CPT acute
• LFTs, renal function
  
  • livertoxicity
• • specific signs/symptoms

Question 2

What are examples of penicillin antibiotics?

• Beta-lactam resistant
• Non-resistant

Answer 2

Resistant:

• Co-amoxiclav
• Flucloxacillin
• Temocillin

Non-resistant:

• Amoxicillin
• Phenoxymethylpenicillin
• Benzylpenicillin

Question 3

What is an example of mecillinam penicillin?

Answer 3

• Pivmecillinam hydrochloride

Question 4

What are examples of antipseudomonal penicillins?

Answer 4

• Piperacillin (only available in combination with the beta-lactamase inhibitor tazobactam)
• Ticarcillin

Question 5

What is the mode of action of B-lactams such as penicillin

Advantage of this mode?

Answer 5

Interferes with synthesis of bacterial cell wall peptidoglycan

via Inhibition of transpeptidation enzyme that cross links peptide chains attached to peptidoglycan

This results in weak cell wall and osmotic lysis

• Advantage of this mode of action – they do not kill any cells in the body

Question 6

What type of bacteria are penicilins effective against?

What type of infections can they be used for?

Answer 6

They are effective against gram positive and negative bacteria. Some have a more predominant Gram positve or negative affect depending on the individual penicillin and specific chains

Clinical use:

• septicaemia
• pneumonia
• meningitis
• UTI
• sinusitis
• bone & joint infections
• skin & soft tissue infections (e.g. cellulitis, “diabetic foot”)

Question 7

Describe the pharmacokinetics of penicillins

Answer 7

• Benzylpenicillin - not absorbed from gut - given IM / IV
  
  • inactivated by gastric acid and absorption from GI low
• Penicillin V – given orally
• Widely distributed into body fluids - breast milk, across placenta
• elimination mostly renal & occurs rapidly

Question 8

What are unwanted side effects of penicillins?

Answer 8

• Relatively free from direct toxic effects due to selectivity of action on bacterial cells
• Main unwanted effect of penicillin = HYPERSENSITIVITY
• Skin rashes & fever common
• Acute anaphylactic shock

Common side-effects:

• diarrhoea, nausea, skin reactions, thrombocytopenia
  
  • Diarrrhoea most common with broad spectrum penicillins and can cause AB-associated collitis

Question 9

What are cautions to penicillins?

What are Contraindications to Penicillins?

Answer 9

Cautions

• history of allergy, renal impairment

Contraindications

• penicillin hypersensitivity

Question 10

What are drug interactions with Penicillins?

Answer 10

• very few
• broad spectrum penicillins may ↑INR if patient on warfarin

Question 11

How do resistance to penicillins develop?

How can this be avoided?

Answer 11

Resistance developed due to:

• Production of betalactamases
  
  • These are enzymes which breakdown B-lactam ring in penicillin structure
    
    • Betalactamase inhibitor - Clavulanic acid (Augmentin®/Timentin®)
      
      • Clavulanic acid contains a beta-lactam ring in its structure that binds in an irreversible fashion to beta-lactamases, preventing them from inactivating certain beta-lactam antibiotics, with efficacy in treating susceptible gram-positive and gram-negative infections.
    • Betalactamase-resistant penicillin e.g. flucloxacillin
      
      • Flucloxacillin has an acyl side chain attached to the β-lactam ring, which prevents access of β-lactamase to the ring and makes the drug resistant to inactivation by the enzyme.
• A decrease in permeability of outer membrane occurs in G-ve organisms

Question 12

What patient groups is at higher risk of an anaphlaytic reaction to penicillins?

Answer 12

Patients with a history of atopic allergy (e.g. asthma, eczema, hay fever) are at a higher risk of an anaphlaytic reaction to penicillins.

Question 13

1. If you have an allergy to one penicillin can you have other penicillins?
2. Is there any other classes of drugs that should be avoided too?

Answer 13

1. Allergic to ALL penicllins
2. Cephlasporins

Question 14

What are examples of cephlasporins?

Answer 14

cefixime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime; cefaclor, cefadroxil, cefalexin, cefradine, ceftaroline fosamil

Question 15

What type of bacteria are cephalosporins effective against?

What are examples of indications for cephalosporins?

Answer 15

Broad spectrum AB which are effective against Gram positive and Gram negative bacteria

Clinical uses:

• Septicaemia
• Pneumonia
• Meningitis
• Biliary-tract infections
• UTIs
• Peritonitis

Question 16

What is the mechanism of action for cephlasporins?

Answer 16

Attach to penicillin binding proteins/ transpeptidase enzyme, inhibiting cross-linking of peptide chains. This to interrupt cell wall biosynthesis, leading to weakened cell wall, osmotic lysis and cell death

Question 17

What are the pharmacokinetics associated with administration of cephalsporins?

Answer 17

The pharmacology of the cephalosporins is similar to that of the penicillin’s.

• Mostly IV/ IM delivery, some oral
• All distribute well in body fluids e.g. breast milk and cross the placenta.
• Cephalosporins penetrate the cerebrospinal fluid poorly unless the meninges are inflamed; cefotaxime and ceftriaxone are suitable cephalosporins for infections of the CNS (e.g. meningitis).
• Excreted renally

Question 18

What are cautions associated with cephalosporins?

What are contraindications of cephalosporins?

Answer 18

Cautions: Renal impairment, history of allergies to penicillin and cephalosporins

Contraindicated: Hypersensitivity to cephalosporins

Question 19

What are unwanted side-effects with cephlasporins?

Answer 19

Unwanted side effects

• Hypersensitivity
• Allergies

Common or very common: Abdominal pain; diarrhoea; dizziness; eosinophilia; headache; leucopenia; nausea; neutropenia; pseudomembranous enterocolitis; skin reactions; thrombocytopenia; vomiting; vulvovaginal candidiasis.

Question 20

What are interactions with cephlasporins?

Answer 20

• Cephalosporins may increase the chance of bleeding if you’re taking blood-thinning medications (anticoagulants) such as heparin and warfarin.
• Aminoglycosides increase risk of nephrotoxicity

Question 21

What are examples of aminoglycosides?

Answer 21

amikacin, gentamicin, neomycin sulfate, streptomycin, and tobramycin

Question 22

What type of bacteria are aminoglycosides effective against?

Answer 22

Active against some Gram positive and many Gram-negative bacteria. Used for aerobic bacteria NOT anaerobic bacteria.

Question 23

What type of infections can aminoglycoside antibiotics be used for?

Question 24

What is the mechanism of action of aminoglycoside antibiotics?

Answer 24

• Inhibition of protein synthesis
• Binds to 30s ribosomal subunit and causes a misreading of genetic code

Streptomycin: Binding blocks formation of 30S initiation complex needed to start protein synthesis

Spectinomycin: Inhibits elongation phase. Inhibits normal translocation (movement) of ribosome along mRNA molecule.

Gentamycin, Tobramycin, neomycin: Elongation stopped by preventing binding of elongation factor (EF-G) to ribosome.

Question 25

What are the route of administration for aminoglycosides and their pharmacokinetic profiles?

Answer 25

• Not absorbed from GUT so must be given via injections (IV/IM)
• Gentamycin most common choice
• Majority excreted by kidneys, small amount in bile
• MUST MONITOR GENTAMYCIN

Question 26

What are unwanted side-effects of aminoglycosides?

Answer 26

Unwanted side effects:

• Nephrotoxicity
• Ototoxicity
• Skin reactions
• Tinnitus

Question 27

What aminoglycoside is too toxic for parenteral administration and what route should this be given?

Answer 27

Neomycin sulfate is too toxic for parenteral administration and can only be used for infections of the skin or mucous membranes or to reduce the bacterial population of the colon prior to bowel surgery or in hepatic failure. Oral administration may lead to malabsorption. Small amounts of neomycin sulfate may be absorbed from the gut in patients with hepatic failure and, as these patients may also be uraemic, cumulation may occur with resultant ototoxicity.

Question 28

what are cautions to aminoglycosides?

What are contraindications to aminoglycosides?

Answer 28

Cautions

• Muscle weakness, renal impairment?
• Used with caution in premature infants because of their renal immaturity. Elderly, impaired renal function, diabetes, auditory vestibular dysfunctions, otitis media.
• history of otitis media, previous use of ototoxic drugs and a genetically determined high sensitivity to aminoglycoside induced ototoxicity, are other main factors which may pre-dispose the patient to toxicity.

Contra-indications

• Myasthenia Gravis
• Hypersensitivity to aminoglycoside

Question 29

What are drug interactions with aminoglycosides?

Answer 29

(i) Antibacterials: increased risk of nephrotoxicity with cephalosporins notably cephalothin.
(ii) Gentamicin has been known to potentiate anticoagulants such as warfarin and phenindione.
(iii) Antifungals: increased risk of nephrotoxicity with amphotericin B.
(iv) Cholinergics: antagonism of effect of neostigmine and pyridostigmine.
(v) Cyclosporin, cisplatin: increased risk of nephrotoxicity.
(vi) Cytotoxics: increased risk of nephrotoxicity and possible risk of ototoxicity with cisplatin.
(vii) Diuretics: increased risk of ototoxicity with loop diuretics.
(viii) Muscle relaxants: effect of non-depolarising muscle relaxants such as tubocurarine enhanced. Neuromuscular blockade and respiratory paralysis have been reported from administration of aminoglycosides to patients who have received curare-type muscle relaxants during anaesthesia.

Question 30

1. What is co-trimoxazole made off?
2. What class of antibiotic is this?

Answer 30

1. Sulfamethoxazole and trimethoprim
2. Sulphonamides

Question 31

1. What type of bacteria is trimethoprim effective against?
2. What type of bacteria is sulfonamides effective
3. What type of bacteria is co-trimoxazole effective against?

Answer 31

1. It is effective against most gram-positive aerobic cocci and some gram-negative aerobic bacilli
2. Effective against gram positive and negative

3. The combination of TMP-SMX is active against most aerobic gram-positive and gram-negative organisms.

Question 32

What types of infections is co-trimoxazole used for?

Answer 32

Co-Trimoxazole tablets are indicated in children (>12 to <18 years old) and adults (>18 years old) for the treatment of the following infections when owing to sensitive organisms (see section 5.1):

• Treatment and prevention of Pneumocystis jirovecii pneumonitis or “PJP”.
• Treatment and prophylaxis of toxoplasmosis.
• Treatment of nocardiosis.

The following infections may be treated with Co-Trimoxazole where there is bacterial evidence of sensitivity to Co-Trimoxazole and good reason to prefer the combination of antibiotics in Co-Trimoxazole to a single antibiotic:

• Acute uncomplicated urinary tract infection.
• Acute otitis media.
• Acute exacerbation of chronic bronchitis.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Question 33

What are the pharmacokinetics of Co-trimoxazole

Answer 33

• 50% protein bound
• Renal excretion primarily

Question 34

What are unwanted side-effects of co-trimoxazole?

Answer 34

Unwanted side-effects:

Co-trimoxazole is associated with rare but serious side effects. Discontinue immediately if blood disorders (including leucopenia, thrombocytopenia, megaloblastic anaemia, eosinophilia) or rash (including Stevens-Johnson syndrome or toxic epidermal necrolysis) develop.

Severe respiratory toxicity including potential progression to Adult Respiratory Distress Syndrome.

Common:

Diarrhoea; electrolyte imbalance; fungal overgrowth; headache; nausea; skin reactions, hyperkalaemia

NICE:

• Blood disorders (including leucopenia, thrombocytopenia, anaemia, and eosinophilia) are rare but serious adverse effects of co-trimoxazole.
  
  • Discontinue treatment with co-trimoxazole immediately if blood disorders develop.
• Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been rarely reported with co-trimoxazole.
  
  • Advise people taking co-trimoxazole to monitor closely for skin reactions. The highest risk for occurrence of SJS, TEN, or DRESS is within the first weeks of treatment.
  • If symptoms or signs of SJS, TEN, or DRESS (for example progressive skin rash often with blisters or mucosal lesions) occur, discontinue treatment with co-trimoxazole.
  • If a person develops SJS or TEN with the use of co-trimoxazole, co-trimoxazole must not be re-started at any time.

Question 35

What are contraindications to using co-trimoxazole?

Answer 35

• Severe renal impairment - Avoid if eGFR less than 15 mL/minute/1.73 m² and if plasma-sulfamethoxazole concentration cannot be monitored.
• Severe hepatic impairment
• Acute porphyrias
• Severe haematological disorders (Such as blood dyscrasias)

Question 36

What are cautions to co-trimoxazole?

Answer 36

Asthma; avoid in blood disorders (unless under specialist supervision); avoid in infants under 6 weeks (except for treatment or prophylaxis of pneumocystis pneumonia) because of the risk of kernicterus; elderly (increased risk of serious side-effects) (in adults); G6PD deficiency (risk of haemolytic anaemia); maintain adequate fluid intake; predisposition to folate deficiency; predisposition to hyperkalaemia

Question 37

What are potential drug interactions with co-trimoxazole?

Answer 37

Potential drug interactions: hyperkalaemia agents (e.g. K+ sparing diuretics, ACEi, ARBs), bone marrow depressants (trimethoprim is an immunosupressant), cytotoxic agents e.g. azathioprine, mercaptopurine, methotrexate (increased risk of haematologic toxicity).

• Interactions with co-trimoxazole (trimethoprim/sulfamethoxazole) include:
  
  • Digoxin — concurrent use of trimethoprim with digoxin has been shown to increase plasma digoxin levels in some elderly people.
    
    • If there are symptoms of digoxin toxicity (for example, nausea, anorexia, or disturbance of colour vision), check serum digoxin levels.
    • Diuretics — in elderly people concurrently receiving diuretics, mainly thiazides, there appears to be an increased risk of thrombocytopenia with or without purpura.
      
      • Manufacturer makes no recommendation.
  • Drugs that can cause hyperkalaemia (for example angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers, and diuretics) — concurrent use with co-trimoxazole may result in clinically significant hyperkalaemia.
    
    • Concurrent use should be done cautiously.
  • Methotrexate — co-trimoxazole may increase free plasma levels of methotrexate. In addition, methotrexate and trimethoprim are both anti-folate drugs.
    
    • Avoid concurrent use with co-trimoxazole.
    • If co-trimoxazole treatment is necessary, a folate supplement should be considered.
  • Phenytoin — co-trimoxazole may prolong the half-life of phenytoin, resulting in increased serum phenytoin levels.
    
    • If symptoms of phenytoin toxicity (confusion, blurred vision, nystagmus, ataxia, or drowsiness) are present, monitor serum phenytoin levels and reduce the dose if necessary.
  • Warfarin — concurrent treatment with co-trimoxazole may increase the anticoagulant effect of warfarin.
    
    • Monitor the international normalized ratio (INR), and adjust the warfarin dose accordingly.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after a course of co-trimoxazole [FSRH, 2017].
  
  • However, advise women on the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the section on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.
• Azathioprine: There are conflicting clinical reports of interactions between azathioprine and trimethoprim-sulfamethoxazole, resulting in serious haematological abnormalities.

Question 38

What is the mechanism of action of trimethoprim?

Answer 38

Trimethoprim is a dihydrofolate reductase inhibitor. It works by inhibiting DHR from reducing THF (tetrahydrofolate acid) to DHF (Dihydrofolate acid). DHF is an important precursor is pyrimidine and purine synthesis important for DNA synthesis – this ultimately prevents multiplication

Question 39

What is the mechanism of action of sulfamethoxazole?

Answer 39

Sulfamethoxazole competitively inhibits dihydropteroate synthase, the enzyme responsible for bacterial conversion of PABA to dihydrofolic acid. Inhibition of this pathway prevents the synthesis of tetrahydrofolate and, ultimately, the synthesis of bacterial purines and DNA, resulting in a bacteriostatic effect.

Question 40

What is the mechanism of action of sulfamethoxazole?

Answer 40

Sulfamethoxazole competitively inhibits dihydropteroate synthase, the enzyme responsible for bacterial conversion of PABA to dihydrofolic acid. Inhibition of this pathway prevents the synthesis of tetrahydrofolate and, ultimately, the synthesis of bacterial purines and DNA, resulting in a bacteriostatic effect.

Question 41

What are examples of quinolone antibiotics?

Answer 41

ciprofloxacin, delafloxacin, levofloxacin, moxifloxacin, and ofloxacin

Question 42

What is the general mechanism of action of quinolone antibiotics?

Answer 42

They exert their actions by inhibiting bacterial nucleic acid synthesis through disrupting the enzymes topoisomerase IV and DNA gyrase, and by causing breakage of bacterial chromosomes

Question 43

What are important side-effects of quinolone antibiotics?

Answer 43

The drug should be discontinued if neurological, psychiatric, tendon disorders or hypersensitivity reactions (including severe rash) occur. For more information regarding the safety of fluoroquinolones, please see Important Safety Information.

Important Side-effects:

• QT inteveral Prolongation
• Tendon damage
• Hypersensivity reactions (SCARs - severe cutaneous adverse reactions)
• Gastrointestinal — diarrhoea, nausea (common), vomiting, dyspepsia, flatulence, gastrointestinal and abdominal pains (uncommon).
  
  • Rarely: pseudomembranous colitis (for more information, see the CKS topic on Diarrhoea - antibiotic associated).
• Musculoskeletal — pain, arthralgia (uncommon).
  
  • Rarely: myalgia, arthritis.
  • Very rarely: muscle weakness, tendonitis, tendon damage — this may occur within 48 hours of starting treatment, or months after stopping. Risk of tendon rupture is increased by co-administration of corticosteroids and in people aged over 60 years. If tendonitis is suspected, ciprofloxacin should be discontinued immediately.
• Nervous system — headache, dizziness, sleep disorders, taste disorders (uncommon).
  
  • Rarely: tremor, vertigo, lowering of the seizure threshold – this may trigger seizures.
• Psychiatric — hyperactivity, agitation (uncommon).
  
  • Rarely: confusion, anxiety, depression, hallucinations.
• Skin — rash, pruritus, urticaria.
  
  • Rarely: Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis anaphylaxis, drug rash with eosinophilia, systemic symptoms (DRESS), acute generalised exanthematous pustulosis (AGEP).
• Cardiovascular system — there is an increased risk of aortic aneurysm and dissection with fluoroquinolones, particularly in the older population. Fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in people with positive family history of aneurysm disease, or in people diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (for example, Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, known atherosclerosis).
• Other adverse effects include:
  
  • Anaphylaxis.
  • Hepatic impairment, hepatitis.
  • Renal impairment.
  • Tachycardia.
  • Tinnitus.
  • Visual disturbances.
• NOTE: fluoroquinolones can very rarely cause long-lasting (up to months or years), disabling, and potentially irreversible side effects, sometimes affecting multiple systems, organ classes, and senses. People should be advised to stop treatment at the first signs of a serious adverse reaction, such as tendonitis or tendon rupture, muscle pain, muscle weakness, joint pain, joint swelling, peripheral neuropathy, and central nervous system effects, and to contact their doctor immediately for further advice

Question 44

What are contraindications to quinolone antibiotics?

Answer 44

• History of tendon disorders related to quinolone use

Question 45

What are cautions to quinolone antibiotics?

Answer 45

• Prolong QT interval
  
  • Risk factors for QT intevral - bradycardia, electrolyte disturbance)
• Conditions that predispose to seizures
• diabetes (may affect glucose)
• Expose to excessive sunlight/UV radiation should be avoided during and 48h after treatment
• G6PD deficiency
• history of epilepsy
• myasthenia gravis (Risk of exacerbation)
• psychiatric disorders

NICE:

• • Positive family history of aneurysm disease or congenital heart valve disease.
    
    • Pre-existing aortic aneurysm and/or dissection or heart valve disease, or in presence of other risk factors or conditions predisposing for:
      
      • Both aortic aneurysm and dissection and heart valve regurgitation/incompetence (e.g. connective tissue disorders such as Marfan syndrome or Ehlers-Danlos syndrome, Turner syndrome, Behcet’s disease, hypertension, rheumatoid arthritis) or additionally
      • Aortic aneurysm and dissection (such as vascular disorders including Takayasu arteritis or giant cell arteritis, or known atherosclerosis, or Sjögren’s syndrome) or additionally
      • Heart valve regurgitation/incompetence (such as infective endocarditis).
    • Epilepsy, or conditions that predispose to seizures, and in people taking other medication that may predispose to seizures, as quinolones can lower the seizure threshold.
      
      • Quinolones may induce convulsions in patients with or without a history of convulsions, and taking NSAIDs at the same time may also induce them.
    • Diabetes mellitus — may affect blood glucose. Blood glucose should be monitored closely.
    • Glucose-6-phosphate dehydrogenase deficiency —haemolytic reactions have been reported.
    • A history of tendonitis — quinolones can very rarely cause tendon damage, and the risk of tendon rupture is increased by co-administration of corticosteroid.
    • Conditions which predispose to QT interval prolongation:
      
      • Congenital long QT syndrome.
      • Concomitant use of drugs that are known to prolong the QT interval (for example Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics).
      • Uncorrected electrolyte imbalance (for example hypokalaemia, or hypomagnesaemia).
      • Cardiac disease (for example, heart failure, myocardial infarction, or bradycardia).
      • Electrolyte disturbances.
    • History of a psychotic disorder — there have been reports of suicidal thoughts or self-endangering behaviour after use quinolones.
    • Myasthenia gravis — symptoms can be exacerbated.
• Also prescribe with caution in people aged over 60 years, people with renal impairment or solid-organ transplants, as they are at a higher risk of tendon injury.

Question 46

What type of bacteria are quinolone antibiotics effective against?

Answer 46

Quinolones are broad-spectrum antibiotics that are active against both Gram-positive and Gram-negative bacteria, including mycobacteria (can cause leprosy and TB), and anaerobes.

Question 47

What types of infections are quinolone antibiotics used for?

Question 48

What are drug interactions with quinolone anitbiotics?

Answer 48

• Antacids (containing aluminium, calcium, or magnesium) and other medications containing iron or zinc — these reduce the absorption of ciprofloxacin if taken concurrently.
  
  • Ciprofloxacin should be taken at least 2 hours before these preparations, and not less than 4 to 6 hours after them.
• Ciclosporin — increased concentrations and nephrotoxicity might occur in a small number of patients.
• Corticosteroids — the risk of tendonitis and tendon rupture is increased in people taking a fluoroquinolone and a corticosteroid. The MHRA advises that concurrent should be avoided.
• Domperidone — the manufacturer advises that concurrent use with ciprofloxacin should be avoided as it may lead to QT interval prolongation.
• Ergometrine — levels may be increased, leading to ergotism. Concurrent use is contraindicated.
• Mizolastine — the manufacturer advises that concurrent use should be avoided. Mizolastine has a weak potential to cause QT interval prolongation in some people and this may be additive to the effects of ciprofloxacin.
• Methotrexate — plasma levels of methotrexate may be increased. The manufacturer recommends that concurrent use is avoided.
  
  • If concurrent use is necessary, monitor methotrexate levels.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) — possible increased risk of seizures when quinolones are given with NSAIDs. Avoid concurrent use in people with epilepsy or people predisposed to seizures, or monitor them very closely.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of ciprofloxacin.
  
  • However, women should be advised about the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the sections on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.
• Phenytoin — concurrent administration of ciprofloxacin can cause an increase or decrease in serum phenytoin levels. Monitor phenytoin levels.
• Strontium ranelate — the absorption of quinolones is reduced by strontium ranelate so they should not be given together.
• Theophylline — ciprofloxacin increases the plasma concentration of theophylline, leading to possible increased risk of convulsions. Monitor theophylline concentration closely.
• Tizanidine — ciprofloxacin increases the plasma concentration of tizanidine (increased risk of toxicity). Avoid conccurrent use.
• Warfarin — rarely, ciprofloxacin may enhance the anticoagulant effect, increasing the risk of bleeding. Monitor the international normalised ratio (INR) within 3 to 5 days of starting ciprofloxacin, frequently during and shortly after administration.
• Zolmitriptan — quinolones increase the plasma concentration of zolmitriptan by inhibiting its metabolism. Manufacturer recommends a maximum dose of 5 mg in 24 hours in people taking a quinolone.
• Drugs that prolong the QT interval (such as Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, and antipsychotics) — very rare cases of QT interval prolongation have been reported in people taking quinolones and they should therefore be prescribed with caution alongside drugs known to prolong the QT interval.

Question 49

What advice should be given to patients on quinolones?

Answer 49

https://assets.publishing.service.gov.uk/media/5c9364c6e5274a48edb9a9fa/FQ-patient-sheet-final.pdf

Question 50

What are examples of tetracycline antibiotics?

Answer 50

lymecycline, methacycline, minocycline, rolitetracycline, and doxycycline

Question 51

What type of bacteria are tetracyclines effective against?

Answer 51

Tetracyclines are broad-spectrum agents, exhibiting activity against a wide range of gram-positive and gram-negative bacteria, atypical organisms such as chlamydiae, mycoplasmas, and rickettsiae, and protozoan parasites.

Effective against aerobic and anaerobic bacteria

Question 52

What infections are tetracyclines used for?

Question 53

What are contraindications to tetracyclines?

Answer 53

• Women who are pregnant or breastfeeding. Tetracyclines are deposited in growing bone and teeth which can result in discolouration of teeth and occasionally dental hypoplasia.

Question 54

What are cautions to tetracyclines?

Answer 54

• Hepatic impairment and those receiving potentially hepatotoxic drugs.
• Myasthenia gravis — tetracyclines may increase muscle weakness in people with myasthenia gravis.
• Systemic lupus erythematosus (SLE) — tetracyclines may exacerbate SLE symptoms.
• Renal impairment — avoid excessive doses.

Question 55

What are side-effects of tetracyclines?

Answer 55

Common or very common

Angioedema; diarrhoea; headache; Henoch-Schönlein purpura; hypersensitivity; nausea; pericarditis; photosensitivity reaction; skin reactions; systemic lupus erythematosus exacerbated; vomiting

• Tooth decolouration
• Headache and visual disturbances may indicate benign intracranial hypertension (discontinue treatment if raised intracranial pressure develops).

NICE:

• Blood disorders — haemolytic anaemia, thrombocytopenia, neutropenia, eosinophilia, porphyria.
• Gastrointestinal — usually mild symptoms, but may include nausea, vomiting, dyspepsia, abdominal discomfort, diarrhoea, tooth discolouration and dental hypoplasia in children.
  
  • Rarely: dysphagia, oesophagitis, oesophageal irritation, For more information, see the CKS topic on Diarrhoea - antibiotic associated.
• Hepatic disorders – hepatitis, jaundice, hepatic failure (rare).
• Renal disorders — blood urea increased.
• Skin — photosensitivity, rash, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme, exfoliative dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS).
• Other rare adverse effects include:
  
  • Anaphylaxis.
  • Arthralgia, myalgia.
  • Flushing.
  • Severe headache and/or visual disturbances — may be an early symptom of benign intracranial hypertension.
  • Tinnitus.
  • Porphyria.

Question 56

What is the mechanism of action of tetracyclines?

Answer 56

Tetracycline antibiotics are protein synthesis inhibitors. They inhibit the initiation of translation in variety of ways by binding to the 30S ribosomal subunit, which is made up of 16S rRNA and 21 proteins. They inhibit the binding of aminoacyl-tRNA to the mRNA translation complex.44

Question 57

What are drug interactions with tetracyclines?

Answer 57

• Antacids (containing aluminium, calcium, or magnesium) and other medications containing iron, zinc, or bismuth — these may reduce the absorption of doxycycline if taken concurrently.
• Barbiturates, carbamazepine, phenytoin, primidone — these may reduce the exposure to doxycycline. Monitor and adjust the dose if necessary.
• Methotrexate — doxycycline increases the risk of methotrexate toxicity.
• Oral hormonal contraception — additional contraceptive precautions are not required during or after courses of doxycycline.
  
  • However, women should be advised about the importance of correct contraceptive practice if they experience vomiting or diarrhoea. For further information, see the sections on vomiting or diarrhoea in the CKS topics on Contraception - combined hormonal methods and Contraception - progestogen-only methods.
• Retinoids — there is a possible increased risk of benign intracranial pressure if tetracyclines are used concurrently with retinoids (such as isotretinoin).
  
  • Avoid the concurrent use of tetracyclines and retinoids.
• Rifampicin — rifampicin decreases exposure to doxycycline. Monitor the effects and increase doxycycline dose if necessary.
• Warfarin — the concurrent use of warfarin with doxycycline may increase the anticoagulant effect.
  
  • Monitor the person’s international normalized ratio (INR) and adjust the warfarin dose accordingly.

Question 58

Advice to patients on tetracyclines?

Answer 58

Patients should be advised to avoid exposure to sunlight or sun lamps.

Question 59

What antibiotics are more likely to have allergy risks associtated?

Answer 59

• Penicillins
• Cephalosporins
• Sulphonamides (part of co-trimoxazole)

Patients with a history of atopic allergy (e.g. asthma, hay fever, eczema) are more likely to be allergic to penicillins. If allergic to 1 penicillin you are allergic to all.

If allergic to penicillin, may be allergic to cephalosporins.

Common hypersensitivty reaction in elderly patients e.g. skin reactions when using sulphonamides

Question 60

How does renal function affect choice of antibiotics?

What antibiotics are affected by renal function?

Answer 60

Many drugs are renally excreted and may also affect renal function themselves.

Renal Function

• Aminoglycosides e.g. gentamycin
• Tetracycline
• Nitrofurantoin
• Amoxicillin
• Vancomycin

Gentamycin and Vancomycin need to have TDM. These drugs both rely on renal function to calculate intial dose.

Question 61

What antibiotics are affected by liver function?

Answer 61

Liver Failure

• Choramphenicol
• Co-amoxiclav
• Co-trimoxazole
• Tetracyclines

Choramphenicol is metabolised by liver enzymes therefore hepatic monitoring is required.

Co-amoxiclav = amoxicillian and clavulanic acid. Clavulanic acid component means hepatic monitoring required

Co-trimoxazole - the sulphonamide component is metbolised by hepatic enzymes so hepatic monitoring required

Tetracyclines - caution in liver impairment. High doses of intravenous tetracycline can induce fatty liver disease and may result in severe hepatic dysfunction, acute liver failure and death

Question 62

What conditions can affect the ability to take antibiotics orally?

Answer 62

• Concomitant disease states e.g. Crohn’s, UC
• Vomiting & diarrhoea
• Dysphagia

Question 63

How does being a female affect selection of antibiotics?

Answer 63

1. Pregnancy
   
   • Aminoglycosides e.g. gentamycine (toxic to feotus)
   • Tetracycilnes (prevent skeletal development therefore not used in children)
   • Quinolones e.g. ciprofloxacin (Contraindicated in children. Special cases may use in child)
   • Trimethoprim (terotogenic in trimester 1)
   • Nitrofurantion (terotogenic in trimester 3)
2. Breast feeding:
   
   • Rule of thumb - safe in pregn = safe in breast feeding
   • Avoid ciprofloxacin and tetracyclines
3. Oral contraception

Question 64

How does dehydration affect selection?

Answer 64

Dehydration/inadequate fluid intake

• Can lead to crystalluria - crystals in urine
• Specifically with ciprofloxacin Sulphonamides
• Counsel on importance of fluid intake

Question 65

How does glucose-6-phosphate dehydrogenase deficiency affect selection?

Answer 65

Glucose 6-phosphate dehydrogenase (G6PD) deficiency

• Haemolytic anaemia can develop in those defieceny of enzyme. Without this enzyme some drugs are impossoble to metabolise
• caution with sulphonamides, ciprofloxacin and nitrofurantoin
• Susceptibility to the haemolytic risks from drugs varies
• Risk & severity of haemolysis is almost dose-related
• Need to avoid certain foods - check chap 9 anaemia bnf

Question 66

How does cardiac failure affect selection

Answer 66

Parental borad spectrum penicillins have high Na+ content

Question 67

How does epilepsy affect selection?

Answer 67

A

Some drugs lower epileptic threshold

Question 68

What are unwanted side effects of ABs

Answer 68

• Nausea
  
  • Particularly with erythromycin, doxocycline and nitrofurantion
• Diarrohea
• Oral/anogenital thrush/ pruritis (rash)
  
  • especially with sulphonamides and penicillins
  • Caused by broad spec see below
• Broad spectrum AB can cause fungal infections. AB associated collitis, other problems associated with suprainfections e.g. vagitis and pruritis
  
  • This is due to AB killing goof and bad bacteria leading to overgrowht of other bacteria

Question 69

Treatment of unwanted effects:

• Vaginitis
• Candidosis
• AB associated colitis

Answer 69

• Vaginitis - metronidazole
• Candidosis - topical or oral anti-fungal

Antibiotic associated colitis likely to be due to a C.difficile infection - oral metronidazole, oral vancomycin, Fidaxomicin (Dificlir™) [Latter for management of recurrent C.difficile infection]

Vancomycin not absorbed from GI tract therefore useful

Fidaxomicin licenced for reccurent C.diff infections

Question 70

What are specific side effects of:

1. Aminoglycosides
2. Vancomycin
3. Doxycycline
4. Trimethoprim
5. Sulphonamides
6. Penicillins
7. Cephalsporins

Answer 70

Penicillins Allergy

• (5-10%)urticarial rash(5%)
• Joint pain,malaise,local oedema,anaphylaxis

​Cephalosporins

• up to 6.5% patients cross-allergic with penicillins

Trimethoprim

• bone marrow depression in folate deficient patients, potentially teratogenic

Aminoglycosides & vancomycin

• ototoxicity, nephrotoxicity

Sulphonamides

• Stevens-Johnson syndrome & hypersensitivity, blood dyscrasias due to bone marrow depression and agranulocytosis

Doxycycline

• Photosensitivity

Question 71

What should be adviced to patients taking doxycycline

Answer 71

avoid sunbathing or sun beds

Question 72

Q

How does tissue level affect choice?

Answer 72

Want high level of drug in tissue where infection is

• CSF - chloramphenicol, cefotaxime (meningitis)
• Bones - flucloxacillin, fusidic acid
• Prostate - Trimethoprim, ciprofloxacin
• Urinary exretion - all excreted bar chloramphenicol

Question 73

Drug interactions

Answer 73

• Food - Decreases plasma levels of many antibacterials
• Exception – Nitrofurantoin
• Combined OC’s (decreased effect) - with rifampicin
• Progesterone-only OC’s (decreased effect) – rifampicin
• Alcohol - with Metronidazole leads to disulfuram reaction - nausea & vomiting
• Antacids/iron/zinc - decrease effect of tetracyclines, doxycycline & ciprofloxacin
• Warfarin
• Antiepileptics
  
  • Rifampicin decreases efficitivty
• Theophylline

Question 74

Rifampicin METABOLISES ALL DRUGS

MACROCYCLIC AB

Answer 74

Note

Question 75

What are the safest classes of antibiotics to use in pregnancy?

Answer 75

Penicillins, erythromycin and Cephalosporins (cefalexin (1st gen cefalexin, 2nd gen ceftriaxone, 1st gen cefadroxil)- all but Cefopime a 4th generation cephalosporin

Question 76

What type of bacteria is metronidazole effect against?

Answer 76

Metronidazole is an antimicrobial drug with high activity against anaerobic bacteria and protozoa.

It is effective against both gram positive and negative bacteria.

Question 77

What is the mechanism of action of metronidazole?

Answer 77

Metronidazole itself is ineffective. It is a stable compound able to penetrate into microorganisms.

Under anaerobic conditions nitroso radicals acting on DNA are formed from metronidazole by the microbial pyruvate-ferredoxin-oxidoreductase, with oxidation of ferredoxin and flavodoxin. Nitroso radicals form adducts with base pairs of the DNA, thus leading to breaking of the DNA chain and consecutively to cell death.

Question 78

What types of infections can metronidazole be used for?

Answer 78

Metronidazole is indicated in the prophylaxis and treatment of infections in which anaerobic bacteria have been identified or are suspected to be the cause (see sections 4.4 and 5.1).

Metronidazole is indicated in adults and children for the following indications:

1) Prevention of post-operative infections due to anaerobic bacteria (gynecological and intra-abdominal operations)
2) Urogenital trichomoniasis in the female and in man.
3) Bacterial vaginosis (also known as non-specific vaginitis)
4) The treatment of septicaemia, bacteraemia, peritonitis, brain abscess, necrotising pneumonia, osteomyelitis, puerperal sepsis, pelvic abscess, pelvic cellulitis and post- operative wound infections from which pathogenic anaerobes have been isolated.
5) All forms of amoebiasis (intestinal and extra-intestinal disease and asymptomatic cyst passers).
6) Acute ulcerative gingivitis.
7) Giardiasis.
8) Acute dental infections (e.g. acute pericoronitis and acute apical infections)
9) Anaerobically-infected leg ulcers and pressure sores
10) Treatment of Helicobacter pylori infection associated with peptic ulcer as part of triple therapy

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Question 79

What are important side-effects of metronidazole?

Answer 79

NICE:

• Adverse effects of metronidazole include gastrointestinal disturbances (including nausea and vomiting), taste disturbances, furred tongue, oral mucositis, and anorexia.
• Very rarely, the following may occur: hepatitis, jaundice, pancreatitis, drowsiness, dizziness, headache, convulsion, ataxia, psychotic disorders (including confusion and hallucinations), darkening of urine, thrombocytopenia, pancytopenia, myalgia, arthralgia, visual disturbances, rash, pruritus, and erythema multiforme.
  
  • Advise the person not to drive or operate machinery if drowsiness, dizziness, confusion, hallucinations, convulsions, or transient visual disturbances occur.
• Severe bullous skin reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) or acute generalised exanthematous pustulosis (AGEP) have been reported. If symptoms/signs are present, treatment must be immediately discontinued.

BNF:

Common/very common:

With topical use

Skin reactions

With vaginal use

Pelvic discomfort; vulvovaginal candidiasis; vulvovaginal disorders

Question 80

What are cautions to metronidazole?

Answer 80

With topical use

Avoid exposure to strong sunlight or UV light

With vaginal use

Avoid intravaginal preparations (particularly those that require the use of an applicator) in young girls who are not sexually active, unless there is no alternative (in children); not recommended during menstruation; some systemic absorption may occur with vaginal gel

• Active or chronic severe peripheral and central nervous system disease (due to the risk of neurological aggravation).
• Severe liver disease and hepatic encephalopathy (due to substantial impairment of metronidazole clearance) — reduce the total daily dose to one-third, and give once daily.

Question 81

What are contraindications to metronidazole?

Answer 81

None - bnf

NICE:

• Known metronidazole or nitroimidazole hypersensitivity.
• Cockayne syndrome. Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome have been reported

Question 82

In what age group is the use of metronidazole vaginal gel unlicensed?

Answer 82

not licensed for use in children under 18 years

Question 83

What are potential interactions with metronidazole?

Answer 83

• Alcohol — some people taking oral metronidazole experience a disulfiram-like reaction (flushing, increased respiratory rate, increased pulse rate, nausea, headache, and dizziness) with alcohol.
  
  • Although there is no conclusive evidence to support this interaction, warn the person that they might experience this reaction if they drink alcohol whilst taking metronidazole. Alcohol should be avoided during treatment with metronidazole and for at least 48 hours afterwards.
• Anticoagulants — the anticoagulant effects of warfarin can be markedly increased by metronidazole.
  
  • Monitor the international normalized ratio (INR) if metronidazole is given with warfarin, and adjust the warfarin dose accordingly.
  • Warn the person of the possible risk of increased bruising and bleeding, and advise them on when to seek medical help.
• Ciclosporin — people receiving ciclosporin are at risk of elevated serum ciclosporin levels.
  
  • When co-administration of metronidazole and ciclosporin is necessary, monitor serum ciclosporin and creatinine levels closely.
• Lithium — raised lithium levels accompanied by evidence of possible renal damage has been reported in people treated concurrently with lithium and metronidazole.
  
  • Before starting metronidazole in a person taking lithium, seek specialist advice regarding tapering or stopping lithium treatment. If concurrent treatment is unavoidable, plasma concentrations of lithium, creatinine, and electrolytes should be monitored closely.
  • Lithium treatment should be tapered or withdrawn before administering metronidazole.
  • Plasma concentrations of lithium, creatinine and electrolytes should be monitored in patients under treatment with lithium while they receive metronidazole.

Question 84

What advice should be given to patients on metronidazole?

Answer 84

Patients should be advised not to take alcohol during metronidazole therapy and for at least 48 hours afterwards because of the possibility of a disulfiram-like (antabuse effect) reaction.

Question 85

What advice should be given to patients on metronidazole?

Answer 85

Patients should be advised not to take alcohol during metronidazole therapy and for at least 48 hours afterwards because of the possibility of a disulfiram-like (antabuse effect) reaction.

Question 86

What type of bacteria is clindamycin effective against?

Answer 86

Clindamycin is active against Gram-positive cocci, including streptococci and penicillin-resistant staphylococci, and also against many anaerobes, especially Bacteroides fragilis.

Question 87

Pharmacokinetics of clindamycin

Answer 87

It is well concentrated in bone and excreted in bile and urine.

Question 88

What types of infections can clindamycin be used for?

Answer 88

• Acne vulgaris
• Bacterial vaginosis
• Treatment of falciparum malaria (to be given with or following quinine)
• Cellulitis,Erysipelas
• Diabetic foot

Staphylococcal bone and joint infections,Chronic sinusitis,Lower respiratory-tract infections,Complicated intra-abdominal infections,Pelvic and female genital infections,Skin and soft-tissue infections

Staphylococcal bone and joint infections such as osteomyelitis,Peritonitis,Intra-abdominal sepsis,Meticillin-resistant Staphylococcus aureus (MRSA) in bronchiectasis, bone and joint infections, and skin and soft-tissue infections

Treatment of mild to moderate pneumocystis pneumonia (in combination with primaquine)

Question 89

What are contraindications to clindamycin?

Answer 89

• Sensitive to Clindamycin, lincomycin, or to any excipients
• should not be used in patients with existing diarrhoea

Question 90

What is the mechanism of action of clindamycin?

Answer 90

Clindamycin binds to the 50S subunit of the bacterial ribosome and inhibits the early stages of protein synthesis. The action of clindamycin is predominately bacteriostatic, though high concentrations may be slowly bactericidal against sensitive strains.

Question 91

What are important side-effects of clindamycin?

Answer 91

General side-effects:

Common or very common

Skin reactions

Specific side-effects:

Common or very commonWith oral use

Abdominal pain; antibiotic associated colitis; diarrhoea (discontinue)

Uncommon

With oral use

Nausea; vomiting

Frequency not known

With oral use

Agranulocytosis; angioedema; eosinophilia; gastrointestinal disorders; jaundice; leucopenia; neutropenia; severe cutaneous adverse reactions (SCARs); taste altered; thrombocytopenia; vulvovaginal infection

With parenteral use

Abdominal pain; agranulocytosis; antibiotic associated colitis; cardiac arrest; diarrhoea (discontinue); eosinophilia; hypotension; jaundice; leucopenia; nausea; neutropenia; severe cutaneous adverse reactions (SCARs); taste altered; thrombocytopenia; thrombophlebitis; vomiting; vulvovaginal infection

With topical use

Abdominal pain; antibiotic associated colitis; folliculitis gram-negative; gastrointestinal disorder

With vaginal use

Constipation; diarrhoea (discontinue); dizziness; gastrointestinal discomfort; headache; increased risk of infection; nausea; vertigo; vomiting; vulvovaginal irritation

Side-effects, further information

Antibiotic-associated colitis:

• Clindamycin has been associated with antibiotic-associated colitis, which may be fatal. Although antibiotic-associated colitis can occur with most antibacterials, it occurs more frequently with clindamycin. If C. difficile infection is suspected or confirmed, discontinue the antibiotic if appropriate. Seek specialist advice if the antibiotic cannot be stopped and the diarrhoea is severe.

Systemic side-effects (with vaginal use):

• Clindamycin 2% cream is poorly absorbed into the blood—low risk of systemic effects.

Question 92

What are cautions with clindamycin?

Answer 92

With systemic use

• Avoid in Acute porphyrias

CautionsFor Dalacin® 2% cream

• Avoid intravaginal preparations (particularly those that require the use of an applicator) in young girls who are not sexually active, unless there is no alternative (in children)

Question 93

What are important interactions with clindamycin?

Answer 93

Muscle relaxants:

Clindamycin has been shown to have neuromuscular blocking properties that may enhance the action of other neuromuscular blocking agents. Therefore, it should be used with caution in patients receiving such agents.

Antibacterial agents:

Antagonism has been demonstrated between clindamycin and erythromycin in vitro. Due to possible clinical significance, the two drugs should not be administered concurrently and therefore clindamycin should not be given in combination with macrolides or streptogramin antibacterial agents.

Neostigmine and pyridostigmine:

Clindamycin antagonises the effects of the above anticholinesterases.

Vaccines:

Oral typhoid vaccine is inactivated by concomitant administration of antibacterial. Thus, clindamycin should be avoided for 3 days before and after oral typhoid vaccination.

Vitamin K antagonists:

Increased coagulation tests (PT/INR) and/or bleeding, have been reported in patients treated with clindamycin in combination with a vitamin K antagonist (e.g. warfarin, acenocoumarol and fluindione). Coagulation tests, therefore, should be frequently monitored in patients treated with vitamin K antagonists

Question 94

What is important contraception advice to give to patients on Dalacin® (clindamycin) 2% cream?

Answer 94

Damages latex condoms and diaphragms.

Question 95

What are monitoring requirements for clindamycin?

Answer 95

With systemic use

Monitor liver and renal function if treatment exceeds 10 days.

With systemic use in children

Monitor liver and renal function in neonates and infants.

Question 96

What advice should be given to patients on metronidazole?

Answer 96

Patients and their carers should be advised to discontinue and contact a doctor immediately if severe, prolonged or bloody diarrhoea develops.

With oral use:

Capsules should be swallowed with a glass of water.