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

Question 1

Fluoroquinolone drugs that are obligatory to know

Answer 1

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

Question 2

Fluoroquinolones drugs that are not bold in drug list:

Answer 2

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

Question 3

Chemical structure of FQs and its influnce on their action

Answer 3

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

Question 4

FQs: mechanism of action

Answer 4

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

Question 5

Function of topoisomerase 2 (DNA gyrase)

Answer 5

Mainly removing superhelical twists so the DNA replications can proceed.

Question 6

Function of topoisomerase 4

Answer 6

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

Question 7

FQs: mode of action

Answer 7

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

Question 8

FQs: antibacterial spectrum. 2nd generation.

Answer 8

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

Question 9

FQs: antibacterial spectrum. 3d generation.

Answer 9

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

Question 10

FQs: antibacterial spectrum. 4th generation.

Answer 10

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.)

Question 11

FQs: resistance

Answer 11

• 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)

Question 12

FQs: mechanisms of acquired resistance:

Answer 12

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

Question 13

FQs: PK: Absorption (except 1st gen)

Answer 13

• 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

Question 14

FQs: PK: Distribution (except 1st gen)

Answer 14

• 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)

Question 15

FQs: PK: Metabolism (except 1st gen)

Answer 15

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

Question 16

FQs: PK: Elimination

Answer 16

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

Question 17

FQs: side effects

Answer 17

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

Question 18

FQs: interactions

Answer 18

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 **

Question 19

Indications for 2nd generation of FQs:

Answer 19

**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

Question 20

Indications for gen 3 and 4 FQs:

Answer 20

• meningitis
• meningoencephalitis
• peritonitis
• gingivitis
• periodontitis

Question 21

Agents and species they are labeled for:

Answer 21

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)

Question 22

Nitrofuranes. Drugs

Answer 22

• Nitrofurantoin
• Furazolidone

Question 23

Nitrofuranes. Mechanism and mode of action

Answer 23

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

Question 24

Nitrofurans. Spectrum

Answer 24

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

Priarily resistent are Proteus, Pseudomonas spp

Question 25

Nitrofurans. PK

Answer 25

- 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

Question 26

Nitrofurans. Indications

Answer 26

- UTI **nitrofurantoin** - topical application - enteral infections (furasolidone)

Question 27

Nitrofurans. Toxicity

Answer 27

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

Question 28

Nitroimidazoles. Drug list

Answer 28

- **metronidazole** - ronidazole - tinidazole

Question 29

Nitroimidazoles. Mechanism of action

Answer 29

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

Question 30

Nitroimidazoles. Spectrum

Answer 30

Relatively narrow AB spectrum **Obligate anaerobic bacteria:** - *Clostridium* - *Bacteroides* - *Fusobacterium* - *Brachyspira hyodysenteriae* **Protozoa:** - *Trichomonas* - *Histomonas* - *Giardia* - *Amoeba*

Question 31

Nitroimidazoles. PK

Answer 31

- 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

Question 32

Nitroimidazoles. Indications

Answer 32

- 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

Question 33

**Fosfomycin**

Answer 33

-** 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)