ID - Abx Flashcards
What factors do you consider when you chose an antibiotic?
- The site or likely source
- Community or hospital acquired
- The diagnosis or likely organism
- Patient allergies
- Which antibiotics they have already had
- Known local resistance patterns
- Hospital prescribing policy
Why might antibiotic therapy fail?
- Wrong drug,
- Inadequate dose/Missed dose
- Wrong frequency
- Too late
- Wrong route
- Failure of penetration of the source
- Emergence of resistant organisms
- Lack of source control
- If the patient is immunosuppressed
How do Beta-lactams work?
- β-Lactam antibiotics act on enzymes called penicillin-binding proteins (PBPs) responsible for building the bacterial cell wall.
- They are active only against rapidly multiplying organisms.
- Penicillin within the cell wall interferes with production of cell wall peptidoglycans and results in cell lysis in a hypo-osmotic or iso-osmotic environment.
- There may be anywhere from 2 to 8 PBPs in a bacterium.
- Differences in the spectrum and activity of β-lactam antibiotics are due to their relative affinity for different PBPs. To bind to the PBPs, the β-lactam antibiotic must first diffuse through the bacterial cell wall. Gram-negative organisms have an additional lipopolysaccharide layer that decreases antibiotic penetration. Therefore gram-positive bacteria are usually more susceptible to the action of β-lactams than gram-negative bacteria.
- Penicillins poorly penetrate mammalian cells and are ineffective in the treatment of intracellular pathogens
How does the presence of a toxin producing Group A streptococci, affect your choice of treatment?
- Use of clindamycin to reduce toxin production.
- This is combined with other antibiotics to reduce the development of clindamycin resistance.
- Consider adjuvant therapy such as immunoglobulins
- Debridement is likely to be necessary if the organism produces necrotising fasciitis.
Which antibiotic levels in common use are monitored routinely and why?
- Gentamicin: efficacy and ototoxicity and nephrotoxicity
- Vancomycin: ototoxicity and nephrotoxicity.
- Needs to maintain an effective level in the blood for a period of time to have its bacteriocidal effect on bacterial cell walls.
- Easy to get high levels with organ failure especially renal failure
- These are drugs with a low volume of distribution and a narrow therapeutic index
- Vancomycin levels may be even more difficult to judge when patient on CVVH
What do you know about the Penicillin group of antibiotics
This is the oldest group of drugs, obtained from a mould, penicillium notatum. They inhibit the enzyme transpeptidase which forms the lattice cross links. Their action is bacteriosidal, because defects in the murein wall allows the bacteria to swell and burst. The penicillin molecule contains a beta-lactam ring, which confers its anti transpeptidase activity. In this original form it has a narrow antibacterial spectrum, confined to gram-positive bacteria, gram negative cocci and spirochetes. Many gram negative bacteria are unaffected by penicillin
Some bacterial produce penicillinase which cleaves the beta lactam ring and confers penicillin resistance on the organism.
Penicillins are well tolerated, but at high doses are neurotoxic and convulsions may be seen with sudden high concentrations in the brain. This is due to GABA antagonism and can occur after intrathecal or high dose intravenous administration.
Chemical manipulation of the penicillin molecule to give better bioavailability, penicllinase resistance and a wider spectrum has been performed.
Flucloxacillin is penicillinase resistant and orally absorbed.
The aminopenicillin amoxicillin has a wider spectrum being active against many gram negative organisms, it is combined with clavulanic acid which prevents the action of penicillinase.
Carboxypenicillins such as carbicillin, ticacillin, and acylaminopenicillins such as mezclocillin azlocillin and piperacillin have a very broad spectrum but are not acid stable, or penicillinase resistant.
They are active against Pseudomonas species
What do you know about cephalosporin antibiotics?
These drugs also come from fungi and contain the beta lactam group in their molecules. These are classified in generations, the earliest first generation cephalosporin was cephalexin, which is a wide spectrum oral cephalosporin with a spectrum of activity largely in gram positive bacteria. It is bacteriosidal. The subsequent developments have been to produce wider spectrum of activity. The second generation includes cefuroxime wich has a broader spectrum including many gram negative species. Resistance to second generation cephalosporins is increasing. The 4th generation consists of one drug cefepime, which is active against Pseudomonus aeroginosa the 5th generation soon to be launched called ceftobiprol is active agains Methacillin resistant Staph Aureus. (MRSA)
What do you know about glycopeptide antibiotics?
A glycopeptide structurally unlike any other antibacterial drug. It inhibits cell wall production but also affect cell synthesis.
Vancomycin and Teicoplanin are the commonest used
Vancomycin is highly polar and not absorbed from the gut as a result it has been used to treat pseudomembranous enteroclitis caused by clostridium difficile. Reistance to this drug appears to be stable.
How does Trimethoprim and Co-trimoxazole work?
These two drugs inhibit the conversion of dihydrofolate to Tetrahydrofolic acid by blocking dihydrofolate reducatase. Tetrahydrofolic acid is a co-enzyme in the synthesis of purine bases and thmidine. These are required for the synthesis of DNA and RNA. The effect is to limit cell growth. They are therefore basteriostatic.
Trimethoprin has a selectivity for bacterial dihrdrofolate reductase, but can affect human folate metabolism and rarely causes bone marrow depression. It is usually combined with a sulphonamide sulfamethoxazole, which also affects folate metabolism but at a different step in the pathway. The combined preparation is more effective than either alone, and example of pharmacological synergy.
Resistance to these drugs is rare.
Dapsone, acts by the same mechanism and is used prophylactically and as chemotherapeutic agent in leprosy, toxoplasmosis and acinomycosis.These two drugs inhibit the conversion of dihydrofolate to Tetrahydrofolic acid by blocking dihydrofolate reducatase. Tetrahydrofolic acid is a co-enzyme in the synthesis of purine bases and thmidine. These are required for the synthesis of DNA and RNA. The effect is to limit cell growth. They are therefore basteriostatic.
Trimethoprin has a selectivity for bacterial dihrdrofolate reductase, but can affect human folate metabolism and rarely causes bone marrow depression. It is usually combined with a sulphonamide sulfamethoxazole, which also affects folate metabolism but at a different step in the pathway. The combined preparation is more effective than either alone, and example of pharmacological synergy.
Resistance to these drugs is rare.
Dapsone, acts by the same mechanism and is used prophylactically and as chemotherapeutic agent in leprosy, toxoplasmosis and acinomycosis.
How do metronidazole and Rifampicin work?
They both inhibit DNA function.
Metronidazole damages DNA by complex formation with the DNA molecule and strand breakage. In anerobic organisms it is converted to a reactive metabolite which attacks the DNA. It bacteriocidal and also anti protozoal and anti amoebic. The drug is potentially mutagenic and tetratogenic and should be avoided in pregnancy and lactation.
Rifampin prevents RNA transcription and is bactericidal against mycobacteria species as well as gram positive and gram negative organisms. Resistance develops and it is reserved for the treatment of TB and leprosy.
How do Tetracyclines and Aminoglycosides work?
Tetracyclines and aminoglycoside drugs both alter transcription of RNA and creation of proteins. They bind to ribosomes and prevent the initiation of protein synthesis. Tetracyclines are broad spectrum and bacteriostatic. The aminoglycosides induce the production of ‘false proteins’ and are bacteriocidal. They are active against gram negative orgamisms. Gentamycin is not active against anaerobes because oxygen is needed for its uptake into the bacterial cell. It is synergistic with the beta lactam containing antibiotics. The aminoglycosides are taken up in the tubular cells of the kidney and can cause renal tubular damage. They are also concentrated in the endolymph of the inner ear and can cause damage to the 8th cranial nerve. The toxic effects are associated with high peaks of serum concentration. Gentamicin levels may need to be monitored in renal impairment. If bolus doses are given they should be injected slowly over 5 minutes to prevent the peak concnetraion rising into the toxic range.
How do chloramphenicol and erythromycin?
Chloramphenicol inhibits peptide sythetase, it has a bacteriostatic effect. It is toxic to bone marrow, particularly in babies. It is used in bacterial meningitis.
Erythromycin inhibits transfer RNA preventing the assembly of proteins. It is active against gram positives but most gram negative organisms are resistant to it. Clarithromycin is a derivative with better acid resistance and bioavailability, clindomycin is a semisynthetic analogue that is well absorbed orally. These drugs are bacteristatic.
Name some antibiotics that inhibit nucleic acid synthesis?
- Metronidazole
- Nitrofurantoin
- Quinolones/ fluroquinolones (ciprofloxancin/levofloxacin)
- Rifampicin
- Sulphonamides (trimethoprim/Co-trimoxazole)
Name some antibiotics that inhibit bacterial protein synthesis?
- Aminoglycosides
- Chloramphenicol
- Clindamycin
- Fusidic Acid
- Macrolides (azithro, clarithro, erythro)
Name some antibiotics that inhibit wall synthesis?
- Beta lactams
- Glycopeptides
