25. Fluoroquinolones, other antibacterial agents (nitroimidazoles, nitrofurans, fosfomycin) Flashcards
Fluoroquinolone drugs that are obligatory to know
Gen 2: CIPROfloxacin, ENROfloxacin, MARBOfloxacin
Gen 3: LEVOfloxacin, SPARfloxacin
Gen 4: PRADOfloxacin, MOXIfloxacin
Fluoroquinolones drugs that are not bold in drug list:
Gen 1: nalidixic acid
Gen 2: flumequine, NORfloxacin, DANOfloxacin, DIfloxacin, ORBIfloxacin
Chemical structure of FQs and its influnce on their action
5 - NH2, CH3 - cardiotoxicity
6 - site of fluorine molecule
FQs: mechanism of action
Inhibition of DNA synthesis by promoting cleavage of bacterial DNA in the DNA-enzyme complexes of type 2 topoisomerase (a.k.a. DNA gyrase) and topoisomerase type 4 -> rapid bacterial death
topoisomerase 2 (DNA gyrase) is primary target of FQs in gram– bacteria
topoisomerase 4 is primary target of FQs in gram+ bacteria
Function of topoisomerase 2 (DNA gyrase)
Mainly removing superhelical twists so the DNA replications can proceed.
Function of topoisomerase 4
To allow 2 new interlinked chromosomes to separate so they can be segregated into 2 new daughter bacterial cells
FQs: mode of action
BACTERICIDAL, concentration-dependent
PAE: 2-5h (depends on pathogen and more pronounced ag. gram–)
FQs: antibacterial spectrum. 2nd generation.
GRAM —
- Enterobacteriaceae family: E. coli, Salmonella spp
- Klebsiella spp
- Bordetella bronchiseptica and Actinobacillus pleuropneuoniae
- Histophilus somni
- Pasteurella spp
- Mycoplasma, Ureaplasma
- Chlamydia spp and Chlamydophilia spp
- Pseudomonas sp (P. aeruginosa <-> ciprofloxacin)
- Brucella spp
GRAM+
- Staphylococcus spp (S. aureus, S. pseudintermedius)
- Mycobacterium spp
Primarily resistent are obligate anaerobic bacteria, streptococci, enterococi
FQs: antibacterial spectrum. 3d generation.
Spectrum of 2nd generation, plus:
- Streptococci
- atypical pathogens (Chamydophyla pneumoniae, Mycoplasma pneumon)
FQs: antibacterial spectrum. 4th generation.
Spectrum of 3d generation with improved Gram+ coverage and added anaerobic coverage (intra-abdominal infections)
- Methicillin-susceptible and resistent Staphylococcus aureus
- Streptococci, anaerobes (Porphyroonas and Prevotella spp.)
FQs: resistance
- significant and frequent
- develops relatively fast
- chromosomal resistance stays for a long time and frequent in E. coli, Salmonella, Campylobacter
- Plasmid-mediated resistance significant among Enterobacteriaceae
- cross-resistance is complete within the groups (generations)
FQs: mechanisms of acquired resistance:
CHROMOSOMAL
- chromosomal mutation in coding genes (changed structure of target enzymes)
- overexpression of efflux pumps
- reduction of the membrane permeability
PLASMID:
- proteins that protect target enzymes
- acetylation of quinolones
- increase outflow through efflux pumps
FQs: PK: Absorption (except 1st gen)
- excelent after PO, good bioavailability in monogastric species (very poor in adult cattle)
- food delays time to peak
- divalent or trivalent cations reduce absorption (chelation), incompatibility with antacids!
- SC, IM good absorption
FQs: PK: Distribution (except 1st gen)
- excellent, very high Vd
- high conc. in bile, urine, prostate, appear in the milk
- good penetration through special barriers (CSF, ocular fluids)
- FQs are concentrated within phagocytic cells (reduction of survival of IC pathogens)
FQs: PK: Metabolism (except 1st gen)
- partially metabolised
- CYP450 (rare interactions)
- metabolites also may be active
FQs: PK: Elimination
- mainly through kidneys as active drug, partially through bile
- in active form - UTI - E. coli, Klebsiella, Proteus, Pseudomonas, Staphylococcus)
FQs: side effects
usually when theraupetic doses are applied SE are not common
- retinopathy in cats leading to blindness (deficiency of efflux protein in cats -> distribution to retina is not restricted at the blood-retinal barrier)
- inhibition of cartilage development
- CNS signs (may predispose the seizure activity)
- dysbacteriosis
FQs: interactions
1.** synergistic effect with: beta-lactams, AGs, vancomycin**. E.g.:
- Staphylococcus aureus - (ciprofloxacin + azlocillin, levofloxacin + oxacillin)
- Pseudomonas aeruginosa - (ciprofloxacin + imipenem/azlocillin/ amikacin)
- Enterococci - (ciprofloxacin + imipenem/ampicillin/vancomycin)
2. Expended AB spectrum with metronidazole
3. **Antagonistic interactions with:
- chloramphenicol
- rifampin/rifampicin **
Indications for 2nd generation of FQs:
**ONLY IF THERE IS NO OTHER AB AVAILABLE (AMEG CATEGORY B) **
- UTI
- GIT infections (resistance is frequent)
- Respiratory infections
- Mycoplasmosis (now resistance is frequent)
- Soft tissue infections, pyoderma
- osteomyelitis
- prostatitis
- eye infections
Indications for gen 3 and 4 FQs:
- meningitis
- meningoencephalitis
- peritonitis
- gingivitis
- periodontitis
Agents and species they are labeled for:
ENROfloxacin - lactating cows, swine, poultry, small animals (extralabel - horses)
CIPROfloxacin - human (small animals)
MARBOfloxacin - large animals (only inj), pets (horses)
PRADOfloacin - small animals (only orally)
Nitrofuranes. Drugs
- Nitrofurantoin
- Furazolidone
Nitrofuranes. Mechanism and mode of action
Bacteriacidal
Nitrofuran reductase -> toxic metabolite -> destroys DNA, ribosomes
Nitrofurans. Spectrum
Relatively broad spectrum, mainly gram–, Salmonella, Mycoplasma, Coccidea spp and some protozoa
Priarily resistent are Proteus, Pseudomonas spp
Nitrofurans. PK
- PO absorption is very good
- furasolidone is inactivated by liver rapidly
- quick excretion with urine, nitrofurantoin in active form
- blood and tissue levels are usually too low
- not active against systemic infections
Nitrofurans. Indications
- UTI nitrofurantoin
- topical application
- enteral infections (furasolidone)
Nitrofurans. Toxicity
- low TI, toxic drugs
- GI irritation, neurotoxicity, depression of spermatogenesis, hypersensitivity reactions
- ## mutagenic, potentially carcinogenic (oxidative DNA damage) - not intended for food producing animals
Nitroimidazoles. Drug list
- metronidazole
- ronidazole
- tinidazole
Nitroimidazoles. Mechanism of action
Nitroimidazoles are reduced by ferrodoxin (found in anaerobic bacteria and protozoans but NOT in animals and aerobic bacteria). Ferrodoxin can donate electron to nitroimidazoles -> free radicals -> DNA damage -> fragmentation -> organism can’t anymore synthesize nuclein acids as RNA or DNA -> cell death
Nitroimidazoles. Spectrum
Relatively narrow AB spectrum
Obligate anaerobic bacteria:
- Clostridium
- Bacteroides
- Fusobacterium
- Brachyspira hyodysenteriae
Protozoa:
- Trichomonas
- Histomonas
- Giardia
- Amoeba
Nitroimidazoles. PK
- excellent absorption and tissue penetration to abscesses, bone marrow, CSF, prostate, etc
- metabolism in liver (30%) oxidation (active metabolites) + glucuronid conjugates (inactive metabolites)
- eliination via kidney
Nitroimidazoles. Indications
- gingivitis, paradontitis, periodontitis, oral cavity infections
- anal saculitis
- pseudomembranous colitis (Clostridium)
- trichomonosis
- giardiosis
- histomonosis (tratment of clackhead, not anymore in turkeys)
- banned for swine dysentery prevention
Fosfomycin
-** inhibition of the synthesis of peptidoglycan,** bacteriacidal (conc. and/or time-dependent)
- spectrum relatively wide Gram+ and Gram– including VRE, MRSA
- acquired resistence develops rapidly during treatment
- PK: F (p.o.) = 0,35 (in dog 0,7); elimination half-life is 5-6h, no metabolism, moderate distribution, excretion via feces and kidney -> use in UTI
- mainly UTI (PO)
