MICR:3164 Antimicrobial Therapies and Drug Resistance

antimicrobial chemotherapy

deliver a drug to an infected person and kill the microbial cells without harming the host cells

types of drug activity for antimicrobials

• broad-spectrum

• narrow-spectrum

• antibiotics/antibacterial

• antimicrobial

• prophylaxis

broad-spectrum

effective against a wide variety of microbial types

narrow-spectrum

effective against a limited array of microbial types

antibiotics/antibacterial

substances that can inhibit or destroy microbes; generally bacteria

antimicrobial

inclusive term for any antimicrobial drug

prophylaxis

used to prevent infection of a person at risk

before starting antimicrobial treatment, one needs to?

• identify the microbe(s) causing disease

• determine the susceptibility of the microbe to antimicrobials

• examine the condition and history of the patient

tests for susceptibility

• kirby-bauer

• e-test

kirby-bauer

• bacteria of interest are spread on plate

• discs with antimicrobial drugs are placed on top

• incubate, then measure zone of inhibition around the discs and compared to a standard

E-test

• bacteria of interest are spread on plate

• strip of plastic with a gradient of antimicrobial concentrations is placed on top

• after 48 hours of incubation, look for susceptibility

• MIC

minimum inhibitory concentration (MIC)

the smallest concentration of drug that visibly inhibits growth

therapeutic index

• compares the toxic dose to the minimum effective dose

• toxic dose / MIC

• bigger TI, better and safer

why might treatment not work?

• drug cannot reach infected area (eg joints, brain)

• resistant microbes were missed during testing

• more than one pathogen is responsible for the disease

• patient didn’t take antimicrobials as prescribed

impact of patient history

• pre-existing conditions

• allergies to antimicrobials

• disease of kidneys or liver

• age, pregnancy

• reactions with other medications

how can we target microbes without damaging host cells?

• attack structure and pathways specific to microbial cells

• disrupt the structure of function to the point where the microbe can no longer survive

drug action mechanisms

1. inhibit cell wall synthesis

2. inhibit nucleic acid structure and function

3. inhibit protein synthesis

4. interfere with cytoplasmic membrane

5. inhibit folic acid synthesis

drugs that target cell wall

• beta-lactam antibiotics

• vancomycin

beta-lactam antibiotics

• ex. penicillins, cephalosporins, carbapenems

• block the last stage of cross-linking peptides in peptidoglycan synthesis

• more effective on gram-positive bacteria

vancomycin

• prevents proper peptidoglycan production

• important for role in treating methicillin-resistant Staphylococcus aureus (MRSA)

drugs that target nucleic acids

quinolone antibioticsq

quinolone antibiotics

• ex. ciprofloxacin

• inhibit DNA transcription, replication, necessary enzymes

drugs that target protein synthesis

• ex. tetracyclines, clindamycin

• block successful translation at the ribosome/mRNA level

drugs that target cytoplasm membrane

• ex. polymyxin, daptomycin

• interact with phospholipids, causing distortion and leakage of cell contents

• more effective on gram-negative bacteria

drugs that target folic acid synthesis

sulfonamides

sulfonamides

• ex. sulfamethoxazole, silver sulfadiazene

• inhibit enzymes required for folic acid synthesis

what is folic acid?

• an essential vitamin required for DNA synthesis and cell replication

• bacteria synthesize folic acid, humans require it in diet

why is treatment for fungal infections more complicated?

• most antimicrobials were designed for prokaryotic cells

• similarities between fungal and human cells makes treatments more toxic

how do we treat fungal infections?

• target fungal membranes, sterols, cell wall, and enzymes

• ex. amphotericin B, fluconazole

treating protozoal infections

• diversity of these microbes = diversity of treatment

• quinine

• metronidazole (Flagyl)

quinine

antimalarial compound, now replaced with chloroquine and primaquine (less toxic)

metronidazole (Flagyl)

• an amoebicide with many uses

• giardiasis, trichomoniasis, some anaerobic bacterial infections

treating helminth infections

• most difficult to treat because most similar to humans

• blocking reproduction doesn’t eliminate adult worms

• goal to immobilize, disintegrate, or inhibit metabolism of all life cycle stages

• ex. ivermectin, albendazole

treating viral infections

• viruses use our cellular pathways to replicate, so treatments often include inhibiting host cell pathways

• vaccines are the best defense against viral infections

what does inhibition of viral cycles cause?

prevent viral entry, production of viral proteins/genome replication, virion maturation

how do we treat biofilms?

• antimicrobials may not be able to penetrate the sticky layers of biofilms

• when microbes in biofilm, they express different genes and have different susceptibility profiles

• workarounds include treatment with additional molecules to enhance the effects of antimicrobials

how do microbes develop antimicrobial resistance?

they may acquire mutations or share genetic information

microbial mechanisms of drug resistance

• synthesis of new enzymes which inactivate the drug

• microbial cell doesn’t let drug in

• drug is eliminated

• binding sites for drug are deceased

• microbe uses an alternate pathway

drug resistance: new enzyme synthesis

• new enzymes synthesized which inactivate the drug

• occurs when new genes are acquired

drug resistance: exclude drug from cell

permeability or uptake of the drug into the bacterium is decreased (occurs via mutation)

drug resistance: eliminate drug

• drug immediately eliminated

• occurs thru acquisition of new genes

• many bacteria possess multidrug-resistant (MDR) pumps that actively transport drugs out of cells

drug resistance: binding sites decreased

• binding sites for drugs are decreased in number and/or affinity

• occurs via mutation or thru acquisition of new genes

• erthromycin and clindamycin resistance associated with alteration on 50S ribosomal binding site

drug resistance: alternate pathways

• an affected metabolic pathway is shut down

• OR an alternate pathway is used

• occurs via mutation of original enzymes

• sulfonamide and trimethoprim resistance occurs when microbes deviate from the usual pattern of folic acid synthesis

how antibiotic resistance occurs?

1. high number of bacteria. few of them are resistant to antibiotics

2. antibiotics kill bacteria causing the illness as well as good bacteria protecting the body from infection

3. the resistant bacteria now have preferred conditions to grow and take over

4. bacteria can even transfer their drug-resistance to other bacteria, causing more problems

serious adverse reactions that are possible with beginning an antimicrobial treatment

• toxicity to organs

• allergic reactions

• microbiome disruption

toxicity to organs

drug damages human organsall

allergic reactions

drug triggers the immune system

microbiome disruption

helpful microbes are killed

superinfection

• microbiome disruption

• after destruction, microbes which are usually present in small numbers overgrow and cause disease

• ex. patient treated for UTI may develop yeast infection