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Pharmacology 2. A topics > 25. Fluoroquinolones, other antibacterial agents (nitroimidazoles, nitrofurans, fosfomycin) > Flashcards

25. Fluoroquinolones, other antibacterial agents (nitroimidazoles, nitrofurans, fosfomycin) Flashcards

1
Q

Fluoroquinolone drugs that are obligatory to know

A

Gen 2: CIPROfloxacin, ENROfloxacin, MARBOfloxacin
Gen 3: LEVOfloxacin, SPARfloxacin
Gen 4: PRADOfloxacin, MOXIfloxacin

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2
Q

Fluoroquinolones drugs that are not bold in drug list:

A

Gen 1: nalidixic acid
Gen 2: flumequine, NORfloxacin, DANOfloxacin, DIfloxacin, ORBIfloxacin

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3
Q

Chemical structure of FQs and its influnce on their action

A

5 - NH2, CH3 - cardiotoxicity
6 - site of fluorine molecule

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4
Q

FQs: mechanism of action

A

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

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5
Q

Function of topoisomerase 2 (DNA gyrase)

A

Mainly removing superhelical twists so the DNA replications can proceed.

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6
Q

Function of topoisomerase 4

A

To allow 2 new interlinked chromosomes to separate so they can be segregated into 2 new daughter bacterial cells

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7
Q

FQs: mode of action

A

BACTERICIDAL, concentration-dependent
PAE: 2-5h (depends on pathogen and more pronounced ag. gram–)

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8
Q

FQs: antibacterial spectrum. 2nd generation.

A

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

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9
Q

FQs: antibacterial spectrum. 3d generation.

A

Spectrum of 2nd generation, plus:
- Streptococci
- atypical pathogens (Chamydophyla pneumoniae, Mycoplasma pneumon)

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10
Q

FQs: antibacterial spectrum. 4th generation.

A

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.)

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11
Q

FQs: resistance

A
  • significant and frequent
  • develops relatively fast
  • chromosomal resistance stays for a lonf time and frequent in E. coli, Salmonella, Campylobacter
  • Plasmid-mediated resistance significant among Enterobacteriaceae
  • cross-resistance is complete within the groups (generations)
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12
Q

FQs: mechanisms of acquired resistance:

A

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

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13
Q

FQs: PK: Absorption (except 1st gen)

A
  • 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
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14
Q

FQs: PK: Distribution (except 1st gen)

A
  • 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)
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15
Q

FQs: PK: Metabolism (except 1st gen)

A
  • partially metabolised
  • CYP450 (rare interactions)
  • metabolites also may be active
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16
Q

FQs: PK: Elimination

A
  • mainly through kidneys as active drug, partially through bile
  • in active form - UTI - E. coli, Klebsiella, Proteus, Pseudomonas, Staphylococcus)
17
Q

FQs: side effects

A

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

18
Q

FQs: interactions

A

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 **

19
Q

Indications for 2nd generation of FQs:

A

**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

20
Q

Indications for gen 3 and 4 FQs:

A
  • meningitis
  • meningoencephalitis
  • peritonitis
  • gingivitis
  • periodontitis
21
Q

Agents and species they are labeled for:

A

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)

22
Q

Nitrofuranes. Drugs

A
  • Nitrofurantoin
  • Furazolidone
23
Q

Nitrofuranes. Mechanism and mode of action

A

Bacteriacidal
Nitrofuran reductase -> toxic metabolite -> destroys DNA, ribosomes

24
Q

Nitrofurans. Spectrum

A

Relatively broad spectrum, mainly gram–, Salmonella, Mycoplasma, Coccidea spp and some protozoa

Priarily resistent are Proteus, Pseudomonas spp

25
Q

Nitrofurans. PK

A
  • 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
26
Q

Nitrofurans. Indications

A
  • UTI nitrofurantoin
  • topical application
  • enteral infections (furasolidone)
27
Q

Nitrofurans. Toxicity

A
  • low TI, toxic drugs
  • GI irritation, neurotoxicity, depression of spermatogenesis, hypersensitivity reactions
  • ## mutagenic, potentially carcinogenic (oxidative DNA damage) - not intended for food producing animals
28
Q

Nitroimidazoles. Drug list

A
  • metronidazole
  • ronidazole
  • tinidazole
29
Q

Nitroimidazoles. Mechanism of action

A

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

30
Q

Nitroimidazoles. Spectrum

A

Relatively narrow AB spectrum
Obligate anaerobic bacteria:
- Clostridium
- Bacteroides
- Fusobacterium
- Brachyspira hyodysenteriae

Protozoa:
- Trichomonas
- Histomonas
- Giardia
- Amoeba

31
Q

Nitroimidazoles. PK

A
  • 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
32
Q

Nitroimidazoles. Indications

A
  • 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
33
Q

Fosfomycin

A

-** 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)

Pharmacology 2. A topics (16 decks)

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