Antibiotics inhibiting Nucleic acid synthesis (11&14&18&19)) Flashcards
Antifolate drugs
Antimetabolite (anti-folate) antibiotics
Antimetabolite – a substance inhibiting cell growth by competing with, or substituting for, a natural substrate in an enzymatic process
Sequential blockade – the combined effect of 2 different drugs that inhibit sequential steps in a pathway of bacterial metabolism; enables synergistic enhancement
Sulfonamides → Bacteriostatic effect; competitive inhibitors of dihydropteroate synthase (not expressed in eukaryotes)
Trimethoprim → Bacteriostatic effect; selective inhibitor of bacterial dihydrofolate reductase
Trimethoprim + Sulfamethoxazole → Bactericidal effect
Mechanism of action: inhibition of folate synthesis → purine and nucleic acid synthesis ↓
why eukariotic cells are not sensitive: differnece in folic acid sources, bacteria are not able to take it up but have to synthesize folic acid. eukaryotic cells have other machanism plus take it up by environment
“Folate” refers to the many forms of folic acid and its related compounds, including
tetrahydrofolic acid (the active form),
methyltetrahydrofolate (the primary form found in blood).
Tetrahydrofolic acid is the active form which is a cofactor in many reactions
Sulfonamides
Antimetabolite – a substance inhibiting cell growth by competing with, or substituting for, a natural substrate in an enzymatic process
Sequential blockade – the combined effect of 2 different drugs that inhibit sequential steps in a pathway of bacterial metabolism; enables synergistic enhancement
Sulfonamides → Bacteriostatic effect; competitive inhibitors of dihydropteroate synthase (not expressed in eukaryotes)
Trimethoprim → Bacteriostatic effect; selective inhibitor of bacterial dihydrofolate reductase
Trimethoprim + Sulfamethoxazole → Bactericidal effect
kinetics: - Weak acid - Hepatic metabolism, excreted in urine both intact and metabolised - Extensive binding to plasma proteins (may displace bilirubin, warfarin, methotrexate)
- orally absorbable
- ((short acting (T1/2 ~ 6-9 h) - e.g. sulfisoxazole (not relevant group))
medium acting (T1/2 ~ 10-17 h) - e.g. SULFAMETHOXAZOLE!!!!
(sulfadiazine)
( long acting (T1/2 ~ 1 week) - e.g. sulfadoxine )
good absorption, wide distribution (incl. CSF, placenta)
various protein binding, metabolism in the liver, renal excretion
(sulfapyridine) - used in IBDs (as sulfasalazine)
- topical agents
(sodium sulfacetamide, sulfadimidine) (bacterial conjunctivitis, burn wounds)
Effect :
bacteriostatic, competitive inhibition of dihydrofolic acid synthesis
Spectrum :
originally broad,
G (+) and (-), but many of them became resistant
- some enterobacteria (E. coli, salmonella, shigella, klebsiella)
- chlamydia, yersinia, nocardia
- atypical mycobacteria (M. kansasii, M. scrofulaceum)
- some protozoa (toxoplasma, plasmodium, pneumocystis)
Ø effect against anaerobes
monotherapy - very rare because of rapid resistance
(e.g. nocardiasis or topical use in trachoma, burn wounds)
used in comb. with dihydrofolate reductase inhibitors for non-complicated cystits
intracellular active
+protozoal action
- Antibiotic use not as a single agent; only in combination with trimethoprim (TMP-SMX)
- Burn infections (silver-sulfadiazine; topical)
- Sulfasalazine (oral) is used to treat rheumatoid arthritis and ulcerative colitis
Mechanisms of resistance:
- overproduction of PABA
- modified folic acid-synthesizing enzyme
- decreased permeability
- Decreased intracellular accumulation of the drug
- Increased production of PABA by bacteria
- Decreased sensitivity of bacterial dihydropteroate synthase to the drug
Side effects:
- allergic reactions
- rash 35 %, fever, exfoliative dermatitis, rarely Stevens-Johnson syndrome
Lyell’s syndrome – esp. with long-acting agents - potential cross-allergy with other sulfonamides (e.g. diuretics, antidiabetics) !!!!!
- gastrointestinal (nausea, vomiting, loss of appetite, gastrointestinal pain, diarrhea)
- photosensitivity
- nephrotoxicity (precipitation in urine – crystalluria, hematuria),
- rarely hematotoxicity (anemia, granulocytopenia, thrombocytopenia, risk of kernicterus in newborns), hepatotoxicity, CNS
- Sulfonamide hypersensitivity
- GI symptoms
- Bone marrow suppression
- Precipitate acute hemolysis
in G6PD deficient patients - Nephrotoxicity (crystalluria)
- Photosensitivity
- Teratogenic (neural tube
defects)
Sulfonamide hypersensitivity – presentation:
- Skin rash (potentially painful) - Urticaria
- Fever - Stevens-Johnson syn. (exfoliative dermatitis)
Sulfonamide hypersensitivity – non-antibiotics:
- Loop, thiazide, CAI diuretics - Celecoxib (selective COX-2 inhibitor)
- Sulfonylurea - Probenecid
prevention: adequate hydration (> 1 L/d),
treatment:
urine alkalinization
Dihydrofolate reductase inhibitors
diaminopyrimidine structure
Agents:
trimethoprim!!!!
- mainly combined with sulfamethoxazole
- Weak base
- Reaches high concentrations in
prostatic and vaginal fluids - Renal excretion
- T1/2 10-12 h’
- similar pharmacokinetics, even better CNS penetration, high concentration in prostatic and vaginal fluid
- monotherapy
- only in case of uncomplicated acute urinary infections (rapid resistance)
(pyrimethamine)
- combined with sulfadiazine (leishmaniosis and toxoplasmosis) or sulfadoxine (malaria)
Effect :
- bacteriostatic (in some case bactericidal)
- selective inhibition of bacterial (and/or protozoal) dihydrofolate reductase
- 20-100 x stronger action compared to sulfonamides
Spectrum :
- G (+) cocci (staphylococci, pneumococci)
- G (-) bacteria
- enterobacteria (e.g. E. coli, salmonella, Yersinia enterocolitica)
- H. influenzae
- some protozoa (toxoplasma, plasmodium - pyrimethamine)
- Gram-negative infections
(E. coli, Salmonella, Shigella, H. influenzae, M. catarrhalis)
- Gram-positive infections (community-acquired MRSA, Strep., Staph., Nocardia)
- Pneumocystis jirovecii (PJP), treatment and prophylaxis in HIV patients (CD4 < 200/μL)
- UTI empiric treatment
Mechanisms of resistance:
- Production of dihydrofolate reductase that has a reduced affinity for the drug
- overproduction or modification of dihydrofolate reductase
- decreased permeability
Side effect:
- hematotoxicity
- megaloblastic anemia, granulocytopenia (folic acid ↓)
- Bone marrow suppression (megaloblastic anemia, leukopenia, granulocytopenia)
- Enterocolitis
trimethoprim not really used without
sulfamethoxazole+trimethoprim
trimethoprim + sulfamethoxazole (co-trimoxazole)
Antimetabolite – a substance inhibiting cell growth by competing with, or substituting for, a natural substrate in an enzymatic process
Sequential blockade – the combined effect of 2 different drugs that inhibit sequential steps in a pathway of bacterial metabolism; enables synergistic enhancement
Sulfonamides → Bacteriostatic effect; competitive inhibitors of dihydropteroate synthase (not expressed in eukaryotes)
Trimethoprim → Bacteriostatic effect; selective inhibitor of bacterial dihydrofolate reductase
Trimethoprim + Sulfamethoxazole → Bactericidal effect
Effect :
bactericidal
1:5 combination, synergistic effect
Clinical use :
- urogenital infections (cystitis, prostatitis, prophylaxis of recurrent infections in women)
- salmonella infections (fluoroquinolones are preferred)
- pneumocystis pneumonia (prophylaxis or therapy, latter requires very high doses, in severe cases i.v.)
- nocardia, S. maltophila, Burkholderia cepacia infections (high doses)
for empirical treatment of respiratory infections not recommended (increasing prevalence of res.)
- Gram-negative infections
(E. coli, Salmonella, Shigella, H. influenzae, M. catarrhalis) - Gram-positive infections (community-acquired MRSA, Strep., Staph., Nocardia)
- Pneumocystis jirovecii (PJP), treatment and prophylaxis in HIV patients (CD4 < 200/μL)
- UTI empiric treatment
- Weak base
- Reaches high concentrations in
prostatic and vaginal fluids - Renal excretion
- T1/2 10-12 h’
- Production of dihydrofolate reductase that has a reduced affinity for the drug
- Bone marrow suppression (megaloblastic anemia, leukopenia, granulocytopenia)
- Enterocolitis
DNA GYRASE INHIBITORS
Mechanism of action:
- Interfere with bacterial DNA synthesis: inhibition of topoisomerase II (DNA gyrase) in gram-negative organisms, and topoisomerase IV in gram-positive organisms
- Bactericidal effect
- Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
Pharmacokinetic/dynamic properties:
- Orally active (may be altered by food, antacids, multivalent cations Ca2+, Mg2+, Fe2+)
- Renal excretion, blocked by probenecid; dose adjustment required in renal impairment
- T1/2 3-8 h’
Mechanisms of resistance:
- Efflux pump, changes in porin structure (gram-negative) – decreased intracellular accumulation of the drug
- Changes in the sensitivity of target enzymes via point mutations
FLOUROQUINOLONES
Effect:
bactericidal, concentration (+ time)-dependent
G (-) AUC/MIC > 125
G (+) AUC/MIC > 30
long postantibiotic effect
Mechanism of action: - topoisomerase II (DNA gyrase) ↓ → formation of negative supercoils (required for normal DNA replication) ↓
main effect:
Gram (-) bacteria (eg. E. coli)
- topoisomerase IV ↓ → separation of interlinked
(catenated) chromosomal DNA into the respective
daughter cells during cell division ↓
main effect in staphylococci, streptococci
flouroqinolones and quinolones?
Quinolones
not really in the list?
(nalidixic acid, oxolinic acid)
- weak effect
- narrow spectrum: some enterobacteria (E. coli, klebsiella, proteus)
- Gram-negative coverage (Proteus, Shigella, Salmonella, Campylobacter, E. coli)
- UTI’s, prostatitis, GI tract infections
- rapid development of resistance (mutation of topoisomerase or decreased perm.)
- rapid excretion into the urine (low systemic antibacterial levels)
Side effects:
- GI distress (nausea, vomiting, diarrhea)
- Skin rash
- Phototoxicity
- CNS effects (insomnia, dizziness, headaches)
- Hepatotoxicity
- Tendinitis, tendon rupture
- QT prolongation (mainly 3rd and 4th gen’)
- Teratogenic (cartilage and joint deformities)
- Not recommended for children < 10 y’
Clinical use: only in lower urinary tract infections (p. os)
Fluoroquinolones
- greatly improved antibacterial activity
- broader spectrum, less resistance
- better pharmacokinetics - high, bactericidal levels in blood and tissues
- divided into four groups (generations)
1st gen: gram -
Norfloxacin? or quinolones??
2nd gen: gram- &gram+
- Norfloxacin
- Ciprofloxacin
- Ofloxacin
3rd gen: equal gram- and gram+
- Levofloxacin
4th gen: gram- & gram+ and anaerobes
- Moxifloxacin
2nd gen flouroqinolones
norfloxacin
1st or 2nd gen?? differnet sources say differently
Mechanism of action:
- Interfere with bacterial DNA synthesis: inhibition of topoisomerase II (DNA gyrase) in gram-negative organisms, and topoisomerase IV in gram-positive organisms
- Bactericidal effect
- Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
Pharmacokinetic/dynamic properties:
- Orally active (may be altered by food, antacids, multivalent cations Ca2+, Mg2+, Fe2+)
- Renal excretion, blocked by probenecid; dose adjustment required in renal impairment
- T1/2 3-8 h’
Mechanisms of resistance:
- Efflux pump, changes in porin structure (gram-negative) – decreased intracellular accumulation of the drug
- Changes in the sensitivity of target enzymes via point mutations
Spectrum:
- G (-) bacteria (E. coli, klebsiella, proteus, shigella, neisseria, H. inf.)
(((- Gram-negative coverage (including Pseudomonas)
- Gram-positive cocci
- Mycobacteria (2nd line agents for TB)
- Atypical agents (Chlamydophila, Mycoplasma)
- N. gonorrhoea (oral, single dose)
- B. anthracis
- Otitis externa (ciprofloxacin topical))))
- weaker effect (4-8 x higher MIC than ciprofloxacin)
- lower bioavailability (~ 35%), rapid renal excretion (low systemic level)
→ used only in urinary tract infections (incl. prostatitis, gonorrhea) or in enteritis
- dose reduction in renal failure
Side effects:
- GI distress (nausea, vomiting, diarrhea)
- Skin rash
- Phototoxicity
- CNS effects (insomnia, dizziness, headaches)
- Hepatotoxicity
- Tendinitis, tendon rupture
- QT prolongation (mainly 3rd and 4th gen’)
- Teratogenic (cartilage and joint deformities)
- Not recommended for children < 10 y’
2nd gen flouroqinolones
ciprofloxacin!!!, ofloxacin!!! ((pefloxacin, enoxacin, lomefloxacin))
Mechanism of action:
- Interfere with bacterial DNA synthesis: inhibition of topoisomerase II (DNA gyrase) in gram-negative organisms, and topoisomerase IV in gram-positive organisms
- Bactericidal effect
- Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
Pharmacokinetic/dynamic properties:
- Orally active (may be altered by food, antacids, multivalent cations Ca2+, Mg2+, Fe2+)
- Renal excretion, blocked by probenecid; dose adjustment required in renal impairment
- T1/2 3-8 h’
Mechanisms of resistance:
- Efflux pump, changes in porin structure (gram-negative) – decreased intracellular accumulation of the drug
- Changes in the sensitivity of target enzymes via point mutations
Spectrum: stronger effect against G (-) bacteria
+ pseudomonas (esp. ciprofloxacin)
+ some Gr (+) cocci (staphylococci, pneumococci, but not S. pyogenes)
+ atypical bacteria (e.g. mycoplasma, chlamydia, legionella - esp. ofloxacin)
Ø effect against anaerobes
(((- Gram-negative coverage (including Pseudomonas)
- Gram-positive cocci
- Mycobacteria (2nd line agents for TB)
- Atypical agents (Chlamydophila, Mycoplasma)
- N. gonorrhoea (oral, single dose)
- B. anthracis
- Otitis externa (ciprofloxacin topical))))
Kinetics:
- high oral bioavailability (70-95 %)
- good tissue penetration (intracellular space, bones, prostate)
- half-life 3 - 5 h, elimination renally (dose adjustment in renal failure, esp. by ofloxacin)
- pefloxacin: mainly biliary elimination (main metabolite: norfloxacin)
Clinical use:
- urinary infections (drugs of choice)
- bacterial diarrhea (shigella, salmonella, E. coli, campylobacter)
- meningococcus contact prophylaxis
- soft tissue, bone, joint infections
- respiratory tract infections (but increasing res. of pneumococci)
- systemic infections (incl. sepsis, but usually in combination)
- intra-abdominal infections
- ciprofloxacin is an alternative for legionellosis and tuberculosis
Side effects:
- GI distress (nausea, vomiting, diarrhea)
- Skin rash
- Phototoxicity
- CNS effects (insomnia, dizziness, headaches)
- Hepatotoxicity
- Tendinitis, tendon rupture
- QT prolongation (mainly 3rd and 4th gen’)
- Teratogenic (cartilage and joint deformities)
- Not recommended for children < 10 y’
3rd gen flouroquinolones
levofloxacin!!! , ((sparfloxacin, gatifloxacin ))
Mechanism of action:
- Interfere with bacterial DNA synthesis: inhibition of topoisomerase II (DNA gyrase) in gram-negative organisms, and topoisomerase IV in gram-positive organisms
- Bactericidal effect
- Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
Pharmacokinetic/dynamic properties:
- Orally active (may be altered by food, antacids, multivalent cations Ca2+, Mg2+, Fe2+)
- Renal excretion, blocked by probenecid; dose adjustment required in renal impairment
- T1/2 3-8 h’
Mechanisms of resistance:
- Efflux pump, changes in porin structure (gram-negative) – decreased intracellular accumulation of the drug
- Changes in the sensitivity of target enzymes via point mutations
(“respiratory fluoroquinolones”)
Spectrum:
- slightly less effective against G (-) bacteria
- better activity against S. pneumoniae, mycoplasma,
- mycobacteria (M. tuberculosis, M. avium)
Ø effect against anaerobes
- Less active against gram-negative organisms
- Extended activity against gram-positive
(including S. pneumoniae, enterococci, MRSA) - Active against most pathogens responsible for
community-acquired pneumonia (typical + atypical) → ‘Respiratory fluoroquinolone’
Kinetics:
- similar to 2. generation
- longer half-life (5 - 8 h), given 1-2 x daily p. os / i.v.
- elimination renally (except: sparfloxacin)
Clinical use:
- respiratory infections: pneumonia, exacerbation of chronic bronchitis (pneumococci, mycoplasma, chlamydia, legionella)
- urinary infections, soft tissue infections
- tuberculosis
adverse effect:
- GI distress (nausea, vomiting, diarrhea)
- Skin rash
- Phototoxicity
- CNS effects (insomnia, dizziness, headaches)
- Hepatotoxicity
- Tendinitis, tendon rupture
- QT prolongation (mainly 3rd and 4th gen’)
- Teratogenic (cartilage and joint deformities)
- Not recommended for children < 10 y’
4th gen flouroquinolones
moxifloxacin!!, (trovafloxacin)
Mechanism of action:
- Interfere with bacterial DNA synthesis: inhibition of topoisomerase II (DNA gyrase) in gram-negative organisms, and topoisomerase IV in gram-positive organisms
- Bactericidal effect
- Capable of exerting post-antibiotic effect (PAE) – killing action continues after plasma levels have declined below the MIC
Pharmacokinetic/dynamic properties:
- Orally active (may be altered by food, antacids, multivalent cations Ca2+, Mg2+, Fe2+)
- Renal excretion, blocked by probenecid; dose adjustment required in renal impairment
- T1/2 3-8 h’
Mechanisms of resistance:
- Efflux pump, changes in porin structure (gram-negative) – decreased intracellular accumulation of the drug
- Changes in the sensitivity of target enzymes via point mutations
- Activity similar to 3rd gen’ with extended anaerobic coverage (broadest spectrum)
Spectrum:
- even better activity against S. pneumoniae, mycoplasma, ureaplasma
+ anaerobes (B. fragilis, peptostreptococcus)
Kinetics:
- similar to 2. and 3. generation
- longer half-life (9 - 10 h), given 1 x daily p. os / i.v.
- hepatic elimination
Clinical use:
- respiratory infections (pneumococci, mycoplasma, chlamydia, legionella)
- soft tissue infections
- tuberculosis
Side effects:
- GI distress (nausea, vomiting, diarrhea)
- Skin rash
- Phototoxicity
- CNS effects (insomnia, dizziness, headaches)
- Hepatotoxicity
- Tendinitis, tendon rupture
- QT prolongation (mainly 3rd and 4th gen’)
- Teratogenic (cartilage and joint deformities)
- Not recommended for children < 10 y’
side effects flouroquinolones
Side effects: well tolerated antibiotics
- GI (nausea, vomiting, diarrhea)
- CNS (headache, sleep disturbances, dizziness, rarely hallucinations, seizures, psychosis - interaction with GABA or NMDA receptors?)
- chelation (with di- and trivalent cations, Ca2+, Mg2+, Al3+, Fe3+) - antacids, laxatives reduce absorption
- inhibition of CYP1A2 (toxicity of theophylline ↑)
- photosensitivity (esp. pefloxacin, lomefloxacin)
- chondrotoxicity, arthropathy, tendinitis (→→ tendon rupture, esp. with pefloxacin and with concomitant use of steroids)
- QT-prolongation (sparfloxacin > gatifloxacin, levofloxacin, moxifloxacin)
- allergy, hematotoxicity (rarely)
- hypo/hyperglycemia (gatifloxacin), hepatotoxicity (trovafloxacin)
- GI distress (nausea, vomiting, diarrhea)
- Skin rash
- Phototoxicity
- CNS effects (insomnia, dizziness, headaches)
- Hepatotoxicity
- Tendinitis, tendon rupture
- QT prolongation (mainly 3rd and 4th gen’)
- Teratogenic (cartilage and joint deformities)
- Not recommended for children < 10 y’
Contraindications :
- pregnancy, patients under 18 (relative), epilepsy, allergy
FURTHER ANTIBIOTICS
DAMAGING THE DNA
Nitroimidazoles
Nitroimidazoles
metronidazole, (tinidazole)
metronidazole
Effect:
bactericidal
Mechanism of action:
- intracellular reduction of the NO2 group (mainly under anaerobic conditions)
→ toxic metabolites damage the DNA
- The drug undergoes a reductive bioactivation of its nitro group by ferredoxin (present in anaerobes) → form reactive cytotoxic products (free radicals) → interfere with nucleic acid synthesis
- Bactericidal effect
Spectrum: - protozoa (trichomonas, G. lamblia, amoeba) - anaerobes (bacteroides, clostridium, fusobact.), H. pylori (microaerophilic) - Anaerobic gram-negatives - Clostridium species (pseudomembranous colitis) - Gardnerella vaginalis - H. pylori eradication regimen - Intra-abdominal infections - Brain abscesses - Antiprotozoal: Giardia, Trichomonas, Entamoeba
Pharmacokinetics:
- good absorption, wide distribution (incl. CNS, abscesses)
- hepatic metabolism, biliary excretion,
- T1/2 ~ 6 h
- Oral, parenteral
- Achieves high CSF conc.
- Hepatic metabolism
(dose reduction may be required in liver dysfunction)
- Inhibitor of CYP450 enzymes
Indications:
- anaerobic infections
- pseudomembranous colitis – first choice
- abscesses
- H. pylori eradication
Antiprotozoal:
Giardia lamblia
Trichomonas vaginalis
Entamoeba histolytica
- mixed intra-abdominal infections (usually in combination with aminoglycosides, fluoroquinolones or cephalosporines)
Adverse effects: - GI (nausea, metallic taste, diarrhea, stomatitis) - neurotoxicity (headache, dizziness, paresthesia, peripheral neuropathy) - alcohol intolerance - allergy, hematologic problems (rare), - (teratogenic in animals) - GI distress - Leukopenia - CNS effects (neuropathy) - Dark urine discoloration - Metallic taste - Disulfiram-like reaction with ethanol (nausea, vomiting, headache, hypotension)
*Tinidazole share many common properties and indications as metronidazole; provides longer serum T1/2 (allows once daily dosing)
