MG - infectious diseases and oncology 4

Lecture 5 - Antibiotics 3: nucleic acid synthesis inhibitors

folic acid

turns into folate, which is needed in bacteria

sulfonamides

folate synthesis inhibitors

sulfamethoxazole, sulfametrol, sulfadiazine

MOA: analogs of PABA inhibiting the folate synthesis, bacteriostatic effect

combined with DHF reductase inhibitor trimethoprim(synergistic)

spectrum:gram positive and negative, bacteriostatic, antiprotozoal effects

resistance: common

• PABA synthesis

• DHFR overproduction

• the binding affinity of the enzyme changes

• decreased cell penetration

CI: pregnancy and newborns

PK: weak acids, good oral absorption/distribution, plasma protein binding, metabolism in the liver, excretion via kidney

SE: overall safe, UT disturbances, allergy, bone marrow suppression, GI disturbances, photosensitivity, hemolysis

cotrimoxazol

sulfamethoxazole + trimethoprim

bactericide effect

indications

• airway infections(acute exacerbations of chronic bronchitis

• urinary infections(acute uncomplicated urinary tract infections

• GI tract infections

• otitis media

• acute brucellosis, in combination with other antibiotics

sulfadiazine

used against toxoplasmosis

• in combination with folic acid and pyrimethamine(antimalaria)

silver sulfadiazine: prevention of infections in burn wounds

• topical cream

• wide spectrum bactericide effect

trimethoprim/sulfametrol

parental administration

GI infections, skin infections(incl. MRSA), respiratory, Granuloma inguinale

sulfasalzine

(aminosalicylate) sulfonamide

non-absorbable oral administration

indications

• ulcerative collitis

• enteritis

• inflammatory bowel diseases

fluoroquinolones

(quinolones) topoisomerase inhibitors

MOA: prevention of bacterial DNA from unwinding and duplicating, inhibiting the ligase activity of type II topoisomerases, DNA gyrase and topoisomerase IV

• concentration dependent bactericide effect

• prominent PAE effect

norfloxacin

fluoroquinolone 2A generation

spectrum: a few intestinal bacteria

indicated: non-complicated urinary or GI infections

fast excretion urine

ciprofloxacin, ofloxacin, pefloxacin

fluoroquinolone 2B generation

spectrum: gram negative

• intestinal bacteria

• H. influenzae

• P. aeruginosa

• Gonococcus

• Chlamydia

modest activity from gram positive

ciprofolxacin has the added that it is first choice in B. antracis and mycobacteria

indications:

• urinary(not 1st)

• GI

• nosocomial Gr- infections

• osteomyelitis

• gr- induced skin and soft tissue infections

• atypical TBC

good oral absorption, good tissue penetration, metabolized then excreted kidney

levofloxacin

fluoroquinolone 3rd gen

also gram negative but with the addition of gram positive

indication:

• respiratory infections!!

• noncomplicated cystitis

• complicated urethritis

moxifloxacin

fluoroquinolones 4rd gen

same spectrum as III with the addition of anaerobes

indications:

• lung infections

• complicated skin and soft tissue infections

• generally not a first choice

CI: arrythmias

what are the mechanisms of resistance in fluoroquinolones

change in DNA gyrase binding

decreased permeability

active efflux

side effects fluoroquinolones

generally minor but there are some rare serious ones

• GI disturbances

• photosensitivity

• QT interval prolongation(moxifloxacin)

• hypersensitivity

• tendon pain(tendinopathy)

• arthralgia, cartilage malformation

• aortic aneurysm and aortic dissection

PK interactions fluoroquinolones

antacids, iron, food products(incl Ca) decrease the absorption

CYP1A2 inhibitors(pefloxacin, ofloxacin, ciprofloxacin)

main side effects sulfonamides

GI disturbances, UT disturbances, allergy

what is the main mechanism of action of sulfamethoxazole

PABA analogue and therefore inhibits the DNA synthesis

what is the main mechanism of action of the fluoroquinolones

topoisomerase inhibition

which of the following fluoroquinolones might be effective against anaerobe infection

moxifloxacin

choose the drug indicated for ulcerative colitis or enteritis

sulfalazine

metronidazole

imidazole derivative

MOA: reduction within the microbe > DNA damaginf metabolite bactericide effect

Spectrum: obligate anaerobe bacteria and antiprotozoal effect

resistance: relatively uncommon but growing

indications:

oral

• urethritis and vaginitis

• giardiasis

• respiratory

• gynecological infections

• anaerobe infections

• part of H. pylori eradication

• prophylactic treatment to avoid post-op infections

iv

• CNS infections

• respiratory, GI, gynecology

• bone and joint infections

• gas gangrene

cutaneous: acne rosacea, smelly wounds

local(vaginal): urethritis and vaginitis

PK: good oral absorption, good tissue penetration, metabolized in the liver. ezyme inhibitor(CYP2C9)

SE: generally considerable side effects but some rare severe ones

• headache, interaction with alcohol(disulfiram reactions!), flu-like symptoms, GI disturbances, metal taste in mouth, might discolor urine

nitrofurantoin

MOA is unknown there is an effect on ribosomes and damages the DNA, bactericide effect

• activity is pH dependent(especially effective in acidic urine)

spectrum: gram positive cocci and E. coli

resistance:

• natural resistance for Pseudomonas and Proteus ssp

• relatively rare but growing

indications:

• acute lower respiratory tract infection

• short-term prophylaxis during transurethral procedures

• long term treatment of lower UTI infections

PK:

• only proper therapeutic conc in urine

SE:

• generally safe also during pregnancy and children

• some rare but serious SE(C. difficile associated diarrhea and colitis, liver injury peripheral neuropathy, pulmonary toxicity)

• GI disturbances

• headaches

rifampicin, rifabutin

RNA synthesis inhibitors

MOA: inhibitor of the RNA polymerase, bactericide effect, log PAE

spectrum: broad : mycobacteria, staphylococcus, neisseria, haemophylus influenzae, legionella, pox virus

indications: (rifampicin): all forms of tuberculosis, lepra, brucellosis, prophylaxis of meningococcal meningitis

PK: good oral absorption and tissue penetration, metabolism in the liver, (rifampicin: strong enzyme inductor

SE: liver damage, abdominal pain, GI disturbances, orange-colored secretions(warn patient), fever, flu-like symptoms

rifaximin

RNA polymerase inhibitor

PK: no oral absorption, but local GI effect

spectrum: wide(gram positive and negative, both aerobe and anaerobe

indication: prevention of recurrent episodes of manifest hepatic encephalopathy and GI infections(not in kompas but is used)

protozoa

heterogenous group of unicellular eukaryotic organisms

typically 2 life stages: trophozoites actively feeds and is the proliferative stage, cysts are the dormant phase and can resist harsh conditions

classification is based on the means of locomotion: amoeboids, ciliates, sporozoa, flagellates

malaria

most common protozoan disease

there are four species of human malaria

• plasmodium falciparum

• P. vivax

• P. malariae

• P. ovale

diagnosis is typically done by observation of the blood sample under the microscope

the mechanism of disease is not fully understood, but the hard part is that the common disease symptoms only later become visible and by then it is already too late

choloroquine

antimalarial drug

MOA: blood schizonticide

used for both chemoprophylaxis and treatment

effective against all P. forms, but falciparum developed resistance

PK: oral administration with rapid absorption, good distribution, excreted via the urine

SE: usually well tolerated but there is the nausea, vomiting, abdominal pain and headache

resistance: transporter mutation

quinine and quinidine

antimalarial drugs

MOA: very effective blood schizonticide

used in chloroquine resistant cases

SE: strong cardiac toxicity, cinchonism

mefloquine

anti-malarial

MOA: strong blood schizonticide against falciparum and vivax, used in lower concentrations for chemoprophylaxis of chloroquine resistant arears

PK: only oral administration, good absorption

SE: toxic: nausea, dizziness, vomiting, sleep disturbance, diarrhea, abdominal pain, leukocytosis

primaquine

only drug against the dormant liver forms

generally well tolerated

good oral absorption with wide distribution, rapid metabolism and excretion via the urine

sulfadoxine - pyrimethamine

antimalarial drug: folate antagonist

acts slowely against all 4 malaria species

used for: combination regimes for treatment and prophylaxis of chloroquine resistant falciparum malaria

not used anymore as resistance is too frequent

artemisinin

antimalarial drug

MOA: iron catalyzes the reductive cleavage of the endoperoxide in parasite food vacuoles increasing the free radicals

toxoplasmosis

common treatment: pyrimehtamine and sulfadiazine

most people in the population are infected with this but it is only lethal for fetuses

amebiasis

water borne pathogen transmitted by the fecal oral route

treatment: luminal amebicides, metronidazole