Hoicyzk L14 Flashcards
What is a resistant organism?
One that will not be inhibited or killed by an antibacterial agent at concentrations of the drug achievable in the body after normal dosage.
What are the causes of resistance?
Over prescription through no diagnostic or misdiagnosis. Over the counter prescription. Improper use by patients.
What are the two types of resistance?
Innate and Acquired
What is innate resistance?
Natural resistance due to lack of target such as Mycoplasma have no peptidoglycan and are resistant to penicillin.
What is acquired resistance?
Reduced uptake. Outer membrane porins are non-specific channels Single mutation can increase resistance 5-10 fold for many drugs. Efflux Multidrug resistance (MDR) exporter (AcrB – E. coli) Tetracycline eg. tetA and tetG (Gram negative bacteria).
Inactivation of drug b-lactamase hydrolyses lactam ring of penicillin. Common in Gram negatives and S. aureus. Also chloramphenicol acetyl transferase, streptogramin acetyl transferase, tetracycline oxidation, aminoglycoside modification all inactivate various drugs through chemical modification by enzymes.
Alteration of target b-lactams – Alteration in Penicillin binding proteins (low affinity for drug)
How are glycopeptides and tetracyclines involved in resistance to antibiotics?
Glycopeptides – Vancomycin binds to terminal D-ala-D-ala on muramyl peptide. Resistance involves incorporation of D-ala-D-lac. Due to van genes in Enterococcus Vancomycin used as drug of last resort for MRSA BUT VRSA (Vancomycin Resistant Staphylococcus aureus).
Tetracyclines – resistance due to ribosome protection by another protein preventing Tet binding (Neisseria, Haemophilus etc.). Macrolides, streptogramins and lincosamides – due to RNA methylase. Methylates adenine residue within binding site for all the drugs. Quinolones and rifampin – due to point mutations in DNA gyrase and RNA polymerase, respectively.
What are the genetic properties that cause antibiotic resistance?
Point mutations in for example DNA gyrase. New genetic material. Transduction (phage) that has a narrow range due to phage receptor or require homologous recombination. Transformation (linear DNA) again having narrow range for same reason.
What are current problems involving antibiotic resistance?
MRSA (VRSA) Mycobacterium tuberculosis Multidrug resistance cost 1 billion dollars ($) to bring under control in New York alone. NDM-1 (New Delhi metallo-beta-lactamase 1) E. coli etc. carbapenem - plasmid mediated (2008).
The latest threat - colistin resistance is a last resort for multidrug resistant Enterobacteriaceae. Mcr1 - alters outer membrane plasmid mediated.
What is the future for preventing antibiotic resistance?
Cost >$1 billion per drug Takes 10-12 years Identification > pharmacokinetics > trials. There are several methods to decrease resistance: Empirical screening, Alter existing drugs: Combinatorial chemistry, Alter biosynthetic genes, Rational drug design: Use crystal structure of target molecule and design inhibitor (saquinavir (HIV)).
What are the three main properties of diagnostics?
Rapid, point of care and cheap
