Antimicrobials Flashcards
Static antimicrobials
slow or inhibit growth
Slower onset of axn
Require a functional immune system– not used in imcp’d
or life threatening situations
Cidal
kills the microbes
Does not require a functional immune system– used in imcp’d and life-threatening situation.
Fast onset of axn
Situations to use broad-spectrums
1- Wide differential
2- waiting for identification would be dangerous
3- Tx of resistant pathogens to narrow spectrum compounds
4- polymicrobial infections
Natural sources for antibiotics
Actinomycetes
Filamentous fungi
Soil bacteria
Sulfonamides
Inhibitors of metabolism/Blocks NA synthesis
Synthetic antimicrobials
Block folic acid synthesis- they’re structural analogs of PABA (component of folic acid)
Used against bacteria bc humans don’t synthesize their own folic acid.
TMP-SMX synergy
TMP (trimethoprim) blocks dihydrofolate reductase- inhibits nucleic acid synthesis
SMX (sulfamethoxazole) block dihydropteroate synthetase
Together they are v effective at inhibiting folic acid synthesis in bacteria.
Cyclines
ex: Doxycycline
inhibit protein synthesis
Bind aminoacyl site of 30S– inhibits aminoacyl tRNA from binding
Aminoglycosides
ex: Streptomycin
Interferes with formation of 30S initiation complex
Macrolides
ex: Erythromycin
binds 23S component of 50S rRNA and blocks the exit of the peptide chain.
B-lactams
Inhibit PDG/cell wall synthesis
Includes: Penicillins, cephalosporins, monobactams, and carbapenems
All are only active on growing cells
No cross-linking of PDG– weakened cell wall– increased pressure with no support– lysis.
Does not work on mycoplasma bc they don’t have cell wall, or fungi, bc they don’t have PDG.
Mechanism of B-lactams
Antibiotic binds to PBPs involved in cross-linking the cells wall.
Blocks transpeptidation
Activates bacterial autolytic enzymes/removes autolysis inhibitor–> bacterial cell lyses
Quinolones and Fluoroquinolones
Inhibit nucleic acid synthesis
They are nalidixic acid analogs.
Ex: Ciprofloxacin (fluoroquinolone)
VRE
vancomycin resistant enterococci
KPC
Klebsiella pneumoniae carbapenemases
ESBL
Extended spectrum B-lactamases
Confer resistance to all B-lactam antibiotics (except cephamycins and carbapenems), and frequently many others like ahminoglycosides and fluoroquinolones
Why are enterococci resistant to SMX-TMP?
bc they lack folic acid synthesis pathway.
Amino glycosides are ineffective against what?
Anaerobes, bc they lack oxidative phosphorylation.
Glycopeptides are ineffective against what?
G-, bc they are too large to penetrate outer membrane
Nitroimidazoles are ineffective against what?
Aerobes, bc they lack flavodoxin which is required to activate nitroimidazoles.
Mechanisms of resistance
Altered uptake
Altered target
Drug inactivation
Altered uptake
prevents antibiotic intracellular accumulation to therapeutic level.
Often involves efflux pumps norm encoded by transposons, or membrane location transport proteins
Seen in G+ and G-
Altered target
mecA gene- encodes for PBP2a (modified transpeptidase) lowers binding affinity for B-lactam antibiotics. Transpeptidation still occurs.
Seen in S. aureus and S. pneumoniae spp.
Antibiotic inactivation
Hydrolytic enzymes cleave the antibiotic, making them inactive.
common in B-lactamase bacteria.
Solution: antibiotic with B-lactamase inhibitor (Clavulanic acid)
Main ESBL producers
Enterobacteriacae:
E. coli (CTX-M enzymes)
Klebsiella spp.
B-lactam antibiotics that ESBL aren’t resistant to
Cephamycins (cefoxitin and cefotetant)
Carbapenems
Risks for ESBL exposure
long-term antibiotics prolonged ICU stay Nursing homes Severe illness Residence in institution with high use of 3rd-gen cephalosporins Instrumentation or catheterization
Why is AST performed?
To give reliable estimate of activity of 2+ antimicrobial agents against a pathogen
Predict likely outcome of therapy
Survey development of resistance among a normally susceptible population of organisms
Predict therapeutic potential
Why use antibiograms?
To guide treatment in advance of individual susceptibility results
Helps institutions determine and track their susceptibility trends
Mechanisms of resistance for a plasmid or transposom
1- Transformation (DNA binding proteins)
2- Conjugation (plasmid)
3- Transduction (bacteriophage)
What happens to newly acquired DNA?
1- destruction by bacterial endonucleases
2- Circularization and maintenance as a plasmid
3- Recombination and integration
Types of recombination
1- Homologous (general)
2- Non-homologous (site-specific): “cut and paste” mechanism. Transposition
Homologous recombination
between similar/identical DNA
For integration of DNA acquire by: conjugation, transduction or transformation
Transformation
Uptake of free-floating DNA.
Facilitated by DNA binding proteins on the bacterial cell membrane.
Requires Ca2+
Conjugation
Only in G- bacteria
Reliant of sex pilus encoded by F factor (tra) plasmid.
Pilus brings F+ and F- cells into contact, F+ gives F- some DNA and then they’re both F+
MDR bacteria are normally plasmid encoded
Transduction
Bacteriophage injects DNA into host bacterial cell.
Transposition
Mobile genetic elements Tn or IS are transferred between bacteria– helps confer resistance.
Fluoropyrimidine analogs
Target nucleic acid synthesis in fungi.
Flucytosin= artificial pyrimidine.
Causes intracellular deamination by fingal cytosine deaminase to 5-fluorouracil– inhibits NA synthesis
Works against: Candid, cryptococcus fungi
anti-protozoal against” Leishmania, and acanthamoebae
Polyenes
Target ergosterol synthesis
Lipophilic
Ex: amphotericin B
Binds ergosterol in fungal cell membrane– disrupts osmotic integrity–> ion leakage and membrane destabilization –> lyses the cell.
Fungicidal against most yeasts and filamentous fungi
Anti-protozoal against amoebas
Azoles
Target ergosterol synthesis by inhibiting 14a-demethylase (converts lanosterol to ergosterol)
Most widely used antifungal
Imidazole’s (2Ns): Ketoconazole
Triazoles (3Ns): Fluconazole, Voriconazole
have reduced toxicity and higher efficacy to imidazoles
Can be fungicidal or fungistatic
Terbinafine
an Allylamine anti fungal often in topical creams
Inhibits squalene epoxidase–> squalene can’t be converted to lanosterol–> can’t form ergosterol
Echinocandins
Inhibit chitin synthesis
ex: Caspofungin
Block (1,3)-B-D-glucan synthetase involved in chitin formation
Resistance to azoles
due to:
Efflux mediated by multi drug transporters
Mutations that decrease affinity to the fungi
Upregulation of demthylase
Alteration in the ergosterol biosynthetic pathway
Neuraminidase inhibitors
Target viral release (influenza virus)
Ex: Osteltamivir
Blocks neuraminidase –> virus forms aggregates at cell surface and their release is blocked
IFNs as anti-virals
Both Type I and type II IFNs stimulate uninfected cells to produce antiviral proteins.
Produced in response to:
- live virus
- inactivated virus
- viral nucleic acids
IFN-a2b used for chronic Hep C
IFN-a used against Hep B
IFN-a-n3 used against genital and perianal HPV warts.
Adamantanes
Antivirals that inhibit uncoating
Ex: Amantadine
Blocks M2 ion channel– viral RNAs then remain bound to M1 and can’t enter the nucleus. Viral replication is halted.
Integrase strand transfer inhibitors (INSTIs)
Antiretrovirals, target viral synthesis
Ex: Raltegravir, Elvitegravir
Inhibits viral DNA from combining to integrase which blocks it from bonding with the host DNA.
NRTIs and NtRTIs
anti-virals. Reverse transcriptase inhibitors
Both lack 3-hydroxyl group (have N3 instead). Incorporation into DNA results in chain termination. Aka inhibits DNA synthesis.
Acyclovir
NRTI (nucleoside analog reverse transcriptase inhibitor)
Requires intracellular phosphorylation to a triphosphate form.
Selective toxicity against viral thymidine kinase. Causes chain termination
Activity against: HSV-1 and HSV-2
Viral load
measures treatment efficacy
Most frequently used to monitor antiretroviral therapy
Nitazoxanide
Thiazolide. Interferes with pyruvate ferredoxin oxidoreductase.
Activity against: Helminths - nematodes - cestodes - trematodes Protozoa (guardia, cryptosporidium) - interferes w anaerobic metabolism
Nitroimidazoles
Anti-protozoal and anti-bacterial for anaerobes.
Ex: Metronidazole
Causes DNA damage and strand breakage– loss of helical structure, impaired ability to act as template.
Pentamidine
Interferes w NA and protein synthesis
Anti-fungal (P. jirovecii)
Antiprotozoa (giardiasis, cryptospoirodsis)
Toxic with lots of side effects
Antimalarials
Quinines: interferes with parasite’s hematin detoxification. Targets blood schizontocides
- chloroquine, mefloquine, quinine
Protein synth inhibitors: Inhibits 70S ribosomes and apicoplast. Targets blood and liver stages.
- Doxycycline
Sesquiterpenes: Artemisinin. Release free-radicals into parasite vacuoles and damage membranes. Inhibits metab processes (glycolysis)
Ivermectin
Anti-helminthic
Interferes with glutamate gated Cl- channel–> disrupts neural and neuromuscular transmission.
Acts against: nematodes, cestodes and trematodes.
For: onchocerciasis and lymphatic filariasis
Benzimidazoles
Anti-helminthic.
Binds Beta-tubulin, and inhibits polymerization, glucose transport and fumarate reductase
Exs: Albendazole, Mebendazole
Activity against intestinal nematodes and cestode spp.
Praziquantel
Anti-helminthic
Interferes with calcium transport (tegument). Causes worm paralysis –> detachment, breakdown and expulsion.
Activity against: trematodes and cestodes.
Tx for: schistosomiasis, liver flukes and cysticercosis.
