Week 6 Flashcards
Define the terms bactericidal and bacteriostatic:
Bactericidal: achieve sterilisation of the infected site by directly killing bacteria; lysis of bacteria can lead to release of toxins and inflammatory material
Bacteriostatic: suppresses growth but does not directly sterilise infected site; requires additional factors to clear bacteria- immune mediated killing
What are the different antibiotic uses?
Guided therapy: depends on identifying cases of infection and selecting agent based on sensitivity testing
Empirical therapy: best (educated) guess therapy based on clinical/epidemiological acumen, used when therapy cannot wait for culture
Prophylactic therapy: preventing infection before it begins
How can antibiotics cause harm?
Disruption of bacterial flora leads to: overgrowth with yeasts (thrush), overgrowth of bowel (diarrhoea)
Antibiotic use associated with development of C. diff colitis; future colonisation and infection with resistant organisms
What are the main categories of beta-lactams?
Penicillins, cephalosporins carbapenems, monobactams
What is the mechanism of action of beta-lactams?
Beta-lactam motif inhibits cross linking of cell wall peptidoglycan, causing lysis of bacteria (bacteriocidal)
What are beta-lactamases?
Enzymes that lyse and inactivate beta-lactam drugs commonly secreted by gram -ves and S. aureus, which confer high level resistance to antibiotic resulting in total antibiotic failure
What are the adverse effects of beta-lactams?
GI toxicity: - nausea and vomiting - diarrhoea - cholestasis Hypersensitivity: - Type 1; urticaria and anaphylaxis - Type 4; mild to severe dermatology - Interstitial nephritis Infection: - candidiasis; oral or vulvovaginal - clostridium difficile infection - selection of resistant bacteria
Describe benzylpenicillin, amoxicillin and flucloxacillin:
Benzylpenicillin
- administered IV
- remains first choice for antibiotic for serious streotococcal infection
- narrow spectrum
Amoxicillin
- broad spectrum
- greatly increased activity against gram -ve, and much more orally bioavailable than natural penicillins
Flucloxacillin
- developed to be resistant to beta-lactamase produced by staphylococci
- highly active against staph aureus (not MRSA) and streptococci
- no activity at all against gram -ve
- can be given orally but nausea limits dose
Describe cephalosporins:
Multiple generations, gram -ve spectrum increases with each generation and recent introduction of MRSA activity
Example: ceftriaxone
Describe carbapenems:
- Ultra-broad-spectrum beta-lactam antibiotics
- Spectrum of activity against gram +ves and gram -ves
- No activity against MRSA
- Meropenem is an example
Describe monobactams:
- Aztreonam the only member of the class
- Beta-lactam antibiotic but no cross reactivity to penicillins so can be given to those with penicillin allergy (except anaphylaxis)
- Only given IV- no oral absorption
Describe vancomycin:
- Inhibits cell wall formation in gram +ves
- Not dependent on PBP binding so effective against resistant organisms
- Always given IV, oral route only used for treatment of C. diff
- Long half-life so loading doses usually given
- Nephrotoxicity- more likely with higher doses
- Red-man syndrome if injected too rapidly
- Main issue in clinical use is under-dosing
Other than beta-lactams, what are other classes of antibiotics?
- Protein biosynthesis inhibitors
- DNA/RNA replication inhibitors
- Folate synthesis inhibitors
What antibiotics are protein synthesis inhibitors:
Inhibit 50S ribosomal subunit or 30S ribosomal subunit 50S - Macrolides - erythromycin - clarithromycin - azithromycin - Cindamycin - Cholaramphenicol 30S - Aminoglycosides - Gentamicin - Tetracyclines - Doxycycline
Describe macrolides:
- Good spectrum of activity against G+ves and respiratory G-ves
- Have activity against atypicals
- Legionella
- Mycoplasma
- Chlamydia
- Excellent oral absorption
Adverse effects:
- D+V
- QT prolongation
- Hearing loss with long term use
Drug interactions
- over 400
- Simvastatin, atorvastatin and warfarin
What is the difference between clindamycin and macrolides?
Clindamycin has no action against aerobic G-ves or atypicals, but excellent activity against anaerobes
Also highly effective at stopping exotoxin production
Added to patients with G+ve toxin mediated disease: toxic shock syndrome, necrotising fasciitis
Notorious for causing C. diff as its anaerobic activity disrupts colonic flora, now understood all abs cause CDI
What antibiotics mostly cause CDI?
4Cs: - clindamycin - co-amoxiclav - cephalosporins - ciprofloxacin All abs cause CDI, even those that treat it: keep to as narrow a spectrum as possible
Describe chloramphenicol:
- Very broad spectrum of activity
- Very toxic: bone marrow suppression, aplastic anaemia and optic neuritis
- Modern uses: topical therapy to eyes and bacterial meningitis with beta-lactam allergy
Describe aminoglycosides:
Gentamicin:
Reversibly binds to 30S ribosome: bacterio static action that results in prolonged post-antibiotic effect
Poorly understood action on the cell membrane: bactericidal action that is prominent at high concentrations, results in rapid killing early in dosing interval
Toxicity:
- nephrotoxicity
- ototoxicity: hearing loss, loss of balance, oscillopsia
- neuromuscular blockade (only in M.G.)
Describe tetracyclines:
- Similar spectrum of activity to macrolides
- Also active against atypical organisms
- Relatively non-toxic
- in pregnant women and children can cause bone abnormalities and tooth discolouration
What antibiotics target DNA repair and replication?
- Quinolones
- ciprofloxacin
- levofloxacin
- Rifampicin
Describe quinolones:
- Broad spectrum, bactericidal antibiotics
- Ciprofloxacin; good against G-ves, not G+ves, used in UTI/abdominal tract infection
- Levofloxacin; sacrifices some G-ve activity for stronger G+ve, used in treating respiratory tract infections
- Orally bioavailable
- Active against many atypical pathogens, inc. legionella
Toxicity: - GI - QT prolongation - tendonitis Resistance also emerging and can cause CDI
Describe rifampicin:
Used in UK for two indications:
- TB
- slow growing with high bacterial burden as well as limited access of drugs to granuloma
- rifampicin is bactericidal against slowly replicating organisms in necrotic foci
- prolonged therapy (usually 6 months) in combination with other drugs (see summaries)
- In addition to another antibiotic in serious G+ve infection (esp. staph aureus)
Interactions are important:
- CYP450 enzyme induced, so affects most drugs that undergo hepatic metabolism
Describe inhibitors of folate synthesis:
Inhibition of folate metabolism pathway leads to impaired nucleotide synthesis and therefore impaired DNA replication
Trimethoprim:
- orally administered
- good range of action against G+ves and -ves
- resistances major problem and use is limited to uncomplicated UTI
Toxicity:
- elevation of serum creatinine and K+
Describe metronidazole:
- Enters by passive diffusion and produces free radicals
- Effective against most anaerobic bacteria
- Often added to therapy in intra-abdominal infections (abscess)
- Causes reaction with alcohol
- Peripheral neuropathy with long term use
Describe an uncomplicated UTI:
Lower urinary tract symptoms with absence of sepsis or evidence of upper tract involvement (pyelonephritis)
Treatment only needs to sterilise urine, and low risk infection so can often wait for culture results
What is the treatment for lower UTI?
Trimethoprim
- first line
- avoid in 1st trimester of pregnancy
- penetrates well into prostate so good choice for men
Nitrofuratoin
- broad spectrum
- concentrated in urine so no effect on other tissues
- failure to concentrate in urine in renal failure
- relatively non-toxic in short courses
- pulmonary fibrosis with long term use
What antibiotics would be used in complicated UTI?
- Ciprofloxacin first line
- Amoxicillin, trimethoprim or gentamicin could be considered
What abs would be used in a severely unwell patient with a UTI?
- Amoxicillin ot gentamicin
- Trimethoprim or ciprofloxacin could be considered
What abs are safe in pregnancy?
Most beta-lactams, macrolides and anti-tuberculants Not considered safe: - tetracyclines - trimethoprim - nitrofurantoin - aminoglycosides - quionolones
How do bacteria develop resistance to antibiotics?
- Drug inactivation (usually through enzymes)
- Target change
- Decreased entry
- Increased exit
Describe enzyme inactivation of abs:
Bacteria mutates to produce enzymes, such as beta-lactamases, ESBLs and carbapenemases in coil-forms
Describe modification of drug target:
Target change occurs in streptococcus pneumonia and MRSA where the penicillin binding protein is altered such that is has a decreased affinity for the drug, so peptidoglycan cross linking is not prevented
Describe decreasing permeability of the cell to abs:
Decreased entry occurs in coil-forms which can be carbapenem resistant through a combination of AMPC and porin loss
Describe drug export from cell:
Multi-drug resistant efflux pumps can be produced by pseudomonas aeruginosa as a mechanism of increased drug exit
Describe the relationship between fitness cost and selection pressure:
As antibiotics attack biological functions of cell, mutations to avoid abs may also result in changes to normal functioning of the cell- FITNESS COST
In an environment without a selection pressure, slower growing mutants will be outgrown by “wild type” bacteria and will slowly die away
In hospital environment or livestock production there is selection pressure that outweighs fitness cost
What is primary immunodeficiency?
Inherited or exposure in utero to environmental factors
What is secondary immunodeficiency?
Caused by underlying disease state or treatment for disease
What is the most important risk factor for infection?
Deficiency or absence of neutrophils
What are the most common causes of travellers diarrhoea?
Bacterial
- enterotoxigenic E coli
- enteroaggregative E coli
- campylobacter
- salmonella
- shigella
- c. diff
Viral (as common as bacterial causes)
- norovirus
- rotavirus
- enteric adenovirus
Parasitic (3 weeks after contact)
- giardia
- cryptosporidium
- cyclospora
- microsporidia
- isospora
- entamoeba histolytica
What are the clinical manifestations and management of travellers diarrhoea?
- Often happens in day 4-14 of travel
- Self limiting (1-5 days)
- Symptoms: anorexia, malaise and abdominal cramps, watery diarrhoea (no blood), fever, nausea and vomiting
- Colitic symptoms (blood in stool and tenesmus) are indicative of salmonella/shigella
- Fluid replacement
- Abx only if significant co-morbiditiy
- quinolone
- azithromycin
What are the clinical features of malaria and how is it treated?
CFs:
- fever, malaise, headache, myalgia, diarrhoea
- anaemia
- jaundice
- renal impairment
Severe Malaria:
- parasitaemia
- cerebral malaria
- severe anaemia
- renal failure
- shock
- DIC
- acidosis
- pulmonary oedema
Treatment:
- Artemether compounds (riamet)
- Quinine and doxycycline
Describe enteric fever:
- Typhoid or paratyphoid caused by S. typhi or S paratyphi INFECTION OF BLOOD
- No animal reservoir (only human), transmission human-human or contaminated food/water
- Incubation period 5-21 days (affected by age, gastric acidity, immune status, infectious load)
Symptoms: fever, myalgia, headache, cough, abdominal pain, constipation, diarrhoea developing to septic shock and death
Other symptoms:
- 50:50 diarrhoea: constipation
- Rectal bleeding and bowel perforation
- Neurological (headache, enteric encephalopathy)
- Bacteraemia
- Relative bradycardia
- Rose spots
How is enteric fever diagnosed and treated?
Diagnosis
- travel history
- blood culture
- 60-80% positive
Treatment
- quinolone
- most effective, but resistance developing
- cephalosporins
- empiric therapy, longer courses (14 days)
- azithromycin
- oral option
Describe dengue fever:
- Day biting mosquitoes
- Incubation 5-14 days
CFs:
breakbone fever; headache, fever, retro-orbital pain, arthralgia/myalgia, rash
Lab: leucopenia, thrombocytopenia, transaminitis
Management: symptomatic
Can cause dengue haemorrhagic fever:
- <1% infections
- increased vascular permeability, thrombocytopenia, fever and bleeding
Describe viral haemorrhagic fever:
Several different causes:
Lassa (rats), ebola/marbug (bats), Crimean Congo haemorrhagic fever (CCHF), SAVHFs, RVF, DHF, yellow fever
Clinical presentation:
Exposure (up to 21 days after)»_space; non specific febrile illness»_space; haemorrhagic manifestations»_space; sepsis syndrome/shock»_space; death
Treatment is supportive, correct coagulopathy/anaemia
