Lecture 18: Antibiotics 3 Flashcards
Antibiotics used in various conditions (ear, sinus, bronchitis, sore throat, colds)
See figure
Cause of symptoms of upper respiratory tract infections
Generally symptoms are caused by toxins released by pathogens and the inflammatory response to fight the infection
Nasal congestion, runny nose, sneezing, Sore throat, cough, Fever
Utility of antibiotics in upper respiratory tract infections
Majority of infections have a viral origin
Antibiotics are only used for bacterial infections
How can antibiotics be determined as necessary in upper respiratory tract infections?
Need confirmation of significant bacterial cultures in sputum
Infections of the respiratory tract that require antibiotics
Strept Throat: Penicillin or erythromycin in allergic patients
Pneumonia: Penicillin or erythromycin
Bacterial Sinusitis: Penicillin or flouroquinolones in allergic patients
Infections of the respiratory tract that do not require antibiotics
Croup: Acetaminophen for pain/fever relief and feed warm clear fluids
Acute Bronchitis: not recommended
How quickly are resistant strains discovered after new antibiotics are created?
Within a few years we’re identifying resistant strains.
Seems that due to better screening, we’re identifying resistant strains almost as soon as the antibiotics come on to market
Diseases that pose a serious threat due to antibiotic resistance
Carbopenem Resistant Enteritis (CRE)- Enterobacter
Vancomycin Resistant Enterococci
Tuberculosis- Mycobacterium tuberculosis
Skin infections(and septicemia)- Staphylococcus aureus (MRSA)
Food poisoning- C. difficile (Generally hospital acquired)
Sexually transmitted disease- Gonorrhea
Changing treatment of gonorrhoea due to antibiotic resistance
1950s: Treated with penicillin
1970s: Bacterial resistance to penicillin so treatment with tetracycline recommended
1993: Bacterial resistance to tetracycline so treatment changed to ciprofloxacin or cephalosporins
2007: Bacterial resistance to floroquinolones so only the oral cephalosporin (cefixime) is recommended
2015: Now combination therapy is recommended: injectable cephalosporin (ceftriaxone) + oral azithromycin
Antibiotics in food
Veterinary use of antibiotics leads to production of resistant bacteria
No oversight of antibiotics in animals
Causes of antibiotic resistance
Overuse/abuse of antibiotics in humans
Overuse/abuse of antibiotics in non-humans (veterinary populations)
Developing countries (don’t require prescription)
World travel (rapid spread)
Critically ill patients (patient 0’s)
Industry advertising/promoting
What increases the risk of antibiotic resistant infections?
Patient-related factors (Increasing age, Increasing severity of underlying disease)
Hospital-related factors (Increased length of stay, Admission to ICU, Proximity to infected patients)
Treatment-related factors (Prolonged use of broad spectrum antibiotics, Contaminated devices or procedures)
Hospital related spread of antibiotic resistance
See figure
Antibiotic use in developing countries
Antibiotics available OTC
Poor patient compliance (1-2 days)
Cost (take subtherapeutic course)
Antibiotic quality is low (counterfeit, adulterated, poor quality (potency))
Why are antibiotics used in animals?
Given to healthy animals to prevent development of infections
Use of antibiotics makes animals larger = more value
Kill off bacterium in gut, more food available to animal for growth
Genetics of antibiotic resistance
Spontaneous mutation
Acquisition of new DNA
How do bacterial cells acquire new DNA?
Transformation: DNA comes from the environment after being released by another cell (plasmid DNA)
Transduction: Virus transfers DNA between bacteria
Conjugation: contact between cells as DNA crosses from
What is the mechanism of acquired antibiotic resistance
Alteration in the target site
Decreased uptake
What is the problem of beta lactamases?
Not long after the introduction of Pencillin, S. aureus developed beta- lactamases which inactivate beta-lactam drugs through cleavage of their central ring structure
How do beta lactamases work?
They form an intermediate molecule with the antibiotic, and then water cleaves the bond
B lactam ring is cleaved
How to overcome the problem with beta lactamases?
Develop inhibitors of beta lactamases (clavulanic acid)
Combine penicillin with the use of other antibiotics
Add bulkier side chains to the basic penicillin structure, hindering enzyme access to the B lactam ring beta lactam ring (second generation = methicillin)
Mechanism of synergy with B lactamases
Combine beta lactamase inhibitor with B lactic antibiotics
Mechanism of action of beta lactam + clavulanic acid
Usually, B lactamases sit on the outside of cell wall and breakdown penicillin. Allows bacteria to proliferate.
Clavulanic acid binds to the Beta lactamases, so penicillin can enter.
Antibiotic kills bacteria
Mechanisms of resistance to tetracyclines
Decreased uptake or increased extrusion
Mg2+ dependent active efflux mediated by the TetA gene (most common)
Can also be bacterial enzymes that inactivate tetracyclines, or expression of bacterial proteins that inhibit binding of tetracycline to the ribosome
Characteristics of tetracycline resistance
Widespread resistance limits clinical use
Bacteria usually have cross resistance
Mechanisms of resistance to aminoglycosides
Decreased uptake of the drug: Absence of porin channels, absence of oxygen-dependent transport system
Enzymes that inactivate aminoglycosides: Acetyltransferases, Nucleotidyltransferases, Phosphotransferases
Cross-resistance is rare
Mechanisms of resistance to macrolides
Decreased uptake of the drug
Increased efflux of the drug
Reduced affinity for the 50S ribosome subunit
Methylation of an adenine in the 23S bacterial
ribosomal RNA
Enzymes that inactivate macrolides: Erythromycin esterase
Cross-resistance is common
Mechanisms of resistance to fluoroquinolones
Alterations to DNA gyrase
Decreased uptake
Increased efflux
Problems related to resistance to fluoroquinolones
Resistance to flouroquinolones can evolve rapidly during
treatment
3-fold increase of flouroquinolone prescription in US emergency rooms
Half of these prescriptions for non-FDA approved uses such as: ear infections, acute respiratory illness, Widespread veterinary usage, Cross resistance among quinolones is common
What organisms are resistant to ciprofloxacin?
S. aureus
S. pyogenes
Enterococci,
K. penumoniae
What promoted resistance to ciprofloxacin?
Widespread use to treat minor infections and unapproved uses
Ear infections
Acute respiratory illness
Widespread veterinary usage
What bacteria are inherently resistant to sulfonamides?
Bacteria that obtain floats from the environment
What causes sulphonamide and trimethoprim resistance?
Sulfonamides: altered dihydropteroate synthase
Trimethoprim: altered dihydrofolate reductase
Reduced cellular permeability to drugs
Enhanced production of folates
Prevalence of resistance to cotrimoxazole
Rare
bacteria must have simultaneous resistance to both the sulfonamide and trimethoprim drug
Emergence of antibiotic resistant bacteria has recently renewed interest in using cotrimoxazole
What are some potential solutions to infections caused by resistant superbugs?
Knowledge about resistant infections
Infection control
Vaccination
Appropriate antibiotic use
Discover and develop new antibiotics
If treating a patient, treat as early as possible and kill the pathogen
