Deck 1 Flashcards
Name 3 fluroquinolones
Ciprofloxacin
Levofloxacin
Moxifloxacin
Name 3 folic acid inhibitors
Sulfonamides
Trimethoprim
Cotrimoxazole
Name a Urinary Antiseptic
Nitrofurantoin
Name 2 Polymyxins
Polymyxin B
Colistin
Describe MOA of fluroquinolones
Target DNA gyrase, primarily in G(-) bacteria & topoisomerase IV in G(+) bacteria to inhibit DNA replication
- DNA gyrase: Introduces negative supercoils into DNA to prevent excessive positive supercoiling
- Topoisomerase IV: Promotes separation of chromosomal DNA into daughter cells (more common with G(+) bacteria e.g. Streptococci)
Describe MOA of sulfonamides
- Competitive inhibitors of dihydropteroate synthase, the bacterial enzyme responsible for incorporation of para-aminobenzoic acid into dihydropteroic acid, the immediate precursor of folic acid
- Sensitive microorganisms are those that must synthesize their own folic acid; bacteria that can use preformed folate are not affected
- Bacteriostasis induced by sulfonamides is counteracted by PABA competitively
- Mammalian cells require preformed folic acid, cannot synthesize it, are insensitive to drugs acting by this mechanism
Describe MOA of trimethoprim
- Inhibits reduction of dihydrofolic acid by dihydrofolate reductase to its active form
- Leads to decreased availability of tetrahydrofolate cofactors required for purine, pyrimidine, aa synthesis
Describe MOA of Cotrimoxazole
- Synergistic antimicrobial activity of cotrimoxazole results from inhibition of two sequential steps in synthesis of tetrahydrofolic acid
- Sulfamethoxazole inhibits incorporation of PABA into dihydrofolic acid precursors; Trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate
Describe MOA of urinary antiseptics (Nitrofuratonin)
- Sensitive bacteria reduce the drug to a highly active intermediate that inhibits various enzymes & disrupt the synthesis of proteins, DNA, RNA & metabolic processes
Describe MOA of Polymyxins
- Bactericidal, cationic, surface-active agents that disrupt the structure of cell membrane phospholipids & increase cell permeability by a detergent like action
- G(-) much more sensitive than G(+) because they contain more phospholipid in their cytoplasm & outer membranes
Describe MOA of Fosfomycin
- Bactericidal
- Interferes with cell wall synthesis in both G(+) & G(-) by inhibiting initial step involving phosphoenolpyruvate synthetase
- Enters cells of Fosfomycin-susceptible bacteria by means of two different transport uptake systems & inhibits synthesis of peptidoglycan by blocking formation of N-acetylmuramic acid from N-acetylglucosamine and phosphoenolpyruvate
ROA of Fluroquinolones
- Oral
- IV
- Ophthalmic
ROA of sulfonamides
Oral
ROA of trimethoprim
Oral
ROA of cotrimoxazole
- Oral (common; full cup water)
- IV (severe pneumonia, UTI caused by susceptible organism where pt unable to take orally)
ROA of Nitrofurantonin
Oral
ROA of Polymyxin B
IV
Prodrug of Colistin
CMS (Colistimethate)
ROA of Colistin
- Inhalation
- IV
ROA of Fosfomycin
Oral
List drug(s)/ drug class(es) best taken on empty stomach
Fluroquinolones
Fosfomycin
Fluroquinolones should not be taken with
with Ca or other divalent cations e.g. Al/Mg containing antacids, or dietary supplements containing Fe/Zn
Name the drug which has the following property: Not absorbed orally or suppository, thus reserved for tx of chronic inflammatory bowel disease (e.g. ulcerative colitis)
Sulfasalazine
Distribution of fluroquinolones
- High levels in bone, urine (except moxi), kidney, prostatic tissue
- Concentrations in lungs exceed serum
Distribution of sulfonamides
- Bound to serum albumin
- Distribute throughout bodily fluids & penetrate well into CSF fluid (even in absence of inflammation)
- Pass placental barrier & enter fetal tissues
Name the drug(s)/ drug class(es) which penetrate well into CSF fluid
Folic acid inhibitors (sulfonamide, trimethoprim, cotrimoxazole)
Fosfomycin
Anti-Protozoal Agent (Metronidazole)
Name the drug class(es) & drug(s) which satisfy the following:
- Achieves very high urinary conc while limiting systemic exposure (due to rapid clearance), ideal targeted medication for UTI
Urinary antiseptics (Nitrofuratoin)
Distribution of trimethoprim
- Weak base, so higher conc of trimethoprim achieved in relatively acidic prostatic & vaginal fluids
- Widely distributed into body tissues & fluids, incl penetration into CSF
List the drugs which are excreted renally
Fluroquinolones (cipro, levo, NOT moxi) Folic Acid Inhibitors (all three) Urinary antiseptics (Nitrofuratonin) Polymyxins (ONLY CMS, NOT Colistin & Polymycin B) Fosfomycin Anti-Protozoal Agent (Metronidazole)
Name the drug(s) metabolized by liver
Moxifloxacin
Sulfonamides
Metronidazole
Drug(s) which causes crystalluria & potential damage to kidney
Sulfonamides
Describe MOA of Metronidazole
- Amoebas possess electron transport proteins that participate in metabolic electron removal reactions
- Metronidazole is a nitroimidazole
- Nitro group of metronidazole is able to serve as an electron acceptor, forming cytotoxic free radicals that results in protein & DNA damage, and death of the E. histolytica trophozoites
- Reduction in metronidazole requires strong reducing conditions & anaerobic organisms have more reducing potential than aerobic organisms
ROA of Metronidazole
Oral
Describe absorption of metronidazole
Completely & rapidly absorbed after oral administration
Drug(s) that crosses placenta
Sulfonamides
Fosfomycin
Drug(s) that are found in breast milk
Fosfomycin
Metronidazole
Drug(s)/ Drug Class(es) which require dose adjustment in renal failure
Fluroquinolones (cipro, levo)
Folic acid inhibitors (Sulfonamides, Trimethoprim)
Drug which turns urine brown
Nitrofurantoin
Name an inactive prodrug
CMS (Colistimethate)
Describe the indications & spectrum of activity of ciprofloxacin
1) Active agst G(-) strains & enteric coliform incl penicillin, cephalosporin, aminoglycoside-resistant strains
2) Highly active agst P. aeruginosa
- Commonly used in cystic fibrosis pts for this indication
3) Skin, bone & joint infections
4) Traveler’s diarrhea caused by e. coli, food poisoning caused by all Enterobacteriaceae (E. Coli, Salmonella, Shigella), and Campylobacter jejuni
5) Typhoid fever caused by Salmonella typhi
6) UTI (not first line for simple UTI due to increasing resistance & adverse effects)
7) Used agst anthrax caused by Bacillus anthracis
8) Prostatitis
AVOIDED in MRSA due to resistance
INEFFECTIVE agst anaerobes
NOT VERY EFFECTIVE agst streptococci & enterococci
Can ciprofloxacin be used against MRSA? Why?
Avoided in MRSA infections
- Associated with high incidence of staphylococcal resistance
- Ineffective against anaerobes
- Not very effective against streptococci & enterococci
Name 2 3rd generation furoquinolones
Levofloxacin
Moxifloxacin
Which drug(s) are known as respiratory fluroquinolones?
Levofloxacin
Moxifloxacin
Describe spectrum of activity of 3rd generation fluroquinolones as compared to ciprofloxacin
- Better coverage agst G(+), esp S. pneumoniae
- Increased coverage agst atypical pathogens e.g. Mycoplasma pneumoniae & chlamydia pneumoniae (vs cipro)
- Useful agst respi infections due to a/m organisms & Mycobacterium tuberculosis
What drugs can sulfonamides be combined with, what are they used for in their respective combinations?
- Combi with trimethoprim (co-trimoxazole): for Pneumocystis carinii (now known as P. jirovecii)
- Combi with pyrimethamine: for drug-resistant malaria & for toxoplasmosis
Name an intermediate acting sulfonamide drug
Sulfamethoxazole
Describe the indications of sulfonamides
- Inflammatory bowel disease: sulfasalazine (sulfapyridine-aminosalicylate combination)
- Infected burns: silver sulfadiazine; topically
- Some STIs: e.g. trachoma, chalmydia, chancroid
- Respi infections: use confined to a few special problems e.g. infection with Nocardia
- Acute UTI: now seldom used
What strains are now resistant to sulfonamides?
Many strains of formerly susceptible species incl meningococci, pneumococci, streptococci, staphylococci, gonococci are now resistant
What drug has a similar spectrum of activity to sulfamethoxazole? List 3 species that are sensitive to both drugs.
Drug: Trimethoprim
Species: Enterobacter spp, E. coli, Klebsiella pneumoniae
Describe the uses of Trimethoprim
May be used alone in tx of UTIs & in tx of bacterial prostatitis (although fluroquinolones are preferred)
Is the spectrum of Cotrimoxazole broader, narrower, or the same as compared to sulfa drugs?
Broader
What is Cotrimoxazole effective in treating? (5 points)
1) UTIs, E. coli
- Low dose can be given to women for recurrent UTI as prophylaxis or those with penicillin allergies
2) RTI caused by Haemophilus sp, Moraxella catarrhalis & Klebsiella pneumonia
3) Toxoplasmosis
4) MRSA & community-acquired skin & sort tissue infections caused by this organism
5) Pneumocystis pneumonia cause by Pneumocystis jiroveci
- (more common in immunocompromised patients, e.g. those with HIV/AIDS)
- (These pts also present with more adverse reactions e.g. fever, rashes, hyperkalemia, hyponatremia & diarrhea)
Indication of Nitrofurantonin
Used in prevention & tx of lower UTIs (acute lower UTI, prophylaxis of lower UTI)
Nitrofurantonin is effective against strains of (name 2)
- E. coli
- Enterococci
What species are resistant to nitrofurantonin?
most species of Proteus & Pseudomonas & many species of Enterobacter & Klebsiella
Antibacterial activity of nitrofurantoin is ___ in acidic urine
higher
Poymyxins have a ___ antibacterial spectrum, mainly Gram ___
Narrow; Negative
Describe uses & spectrum of activity of polymyxins
Used for serious infections with multidrug-resistant G(-) bacteria
- Especially those caused by Enterobacteriaceae family, including E. coli, Enterobacter spp, Klebsiella spp., Salmonella spp., Shingella spp.
- Also have significant activity against Acinetobacter baumannii & P. aeruginosa
What is polymyxins not active against?
- Proteus spp. Legionella, Campylobacter, Vibrio cholera, G(-) cocci (Neisseria spp.), G(+) & anaerobic bacteria
Describe uses of Inhaled CMS
- Pseudomonas is a major cause of lung infections in people with cystic fibrosis (less so in Singapore)
- Useful in respi infections & severe pneumonia due to MDR G(-) microbes
Describe uses of Polymyxin B
- Acute infections due to MDR G(-) microbes with no alternatives (E. coli, UTI, Klebsiella pneumoniae bacteremia)
- UTI & bloodstream infections due to P. aeruginosa
Fosfomycin has a ___ spectrum of activity against a ___ range of Gram ___ bacteria
broad; wide; positive & negative
Name 2 Gram positive & 2 gram negative pathogens fosfomycin is active against
S. aureus & enterococcus
P. aeruginosa & Klebsiella pneumoniae
Describe the uses of fosfomycin
- Mainly in tx of UTIs, particularly caused by E. coli & Enterococcus faecalis
- In combi with other abx in tx of nosocomial infections due to resistant G(+) & G(-) bacteria
- Can have synergistic effects with beta lactam abx
- Not suitable for pyelonephritis or severe urinary sepsis due to poor systemic absorption
Describe the uses & spectrum of metronidazole (describe 4)
1) Amebic infections caused by Protozoa including:
- Entamoeba histolytica, Trichomonas vaginalis (vaginitis), Giardia lamblia (Giardiasis)
2) Anaerobes such as:
- Bacteroides species & Clostridium difficile
3) Helicobacter pylori (part of triple therapy for H. pylori infection)
4) Surgical prophylaxis (30-60 mins before incision)
State & describe use of fluroquinolones in pregnancy
Cat C
- Arthropathy observed in immature animals
- Cipro detected in breast milk; Not recommended during breastfeeding
State & describe use of sulfonamides in pregnancy
Avoid in pregnant women at term
State the pregnancy classification of trimethoprim
Cat C
State & describe use of cotrimoxazole in pregnancy
Use with caution
- Can cause folate deficiency
State & describe use of nitrofurantoin in pregnancy
Contraindicated: (38-42 wks gestation) - During labor or delivery - When start of labor is imminent - Reason: Possibility of hemolytic anemia
State pregnancy category of fosfomycin
B
State & describe pregnancy category of metronidazole
Cat B
- But avoid use in first trimester
- Only use if clearly needed (carcinogen in rodents)
8 adverse events of fluroquinolones
1) N/V/D (most common)
2) C. diff colitis (especially cipro)
3) HA/dizziness/light HA
- Caution in pts with CNS disorders e.g. epilepsy
4) Phototoxicity
- Use sunscreen, avoid excess exposure to light
5) Tendinitis or tendon rupture
- Increased risk with systemic use
6) Joint problems (arthropathy)
- In young animals
- Not recommended in infants/children < 18yo
7) Prolong QTc interval (more common with 3rd gen)
- Should not be used in pts who are predisposed to arrhythmias or those who are taking other medications that cause QT prolongation
8) Peripheral Neuropathy
- With systemic use
- May occur any time during tx, may persist for months to years (even permanent) after drug stopped
5 Adverse events of sulfonamides
1) Crystalluria
- Can result in development of nephrotoxicity
- Prevention by hydration & alkalization of urine; reduces concentration of drug & promotes its ionization
2) Hypersensitivity
- E.g. rashes, angioedema, SJS
- Previous sulfa allergies (note description)
3) Hematopoietic disturbances
- Hemolytic anemia encountered in patients with G6PD deficiency (lower ability to counter oxidative stress)
- Can also cause thrombocytopenia
4) Kernicterus
- May occur in newborns if taken by mums in late pregnancy
- Sulfa drugs displace bilirubin from binding sites on serum albumin
- Bilirubin is then free to pass into CNS, as BBB not fully developed
5) Drug potentiation
- Transient potentiation of anticoagulant effect of warfarin results from displacement from binding sites on serum albumin
- Reported in pts receiving both sulfamethoxazole & warfarin; increased monitoring recommended
Name an adverse effect of trimethoprim & its effects
Effects of folic acid deficiency:
- Megaloblastic anemia, leukopenia, granulocytopenia
- Especially in pregnant pts & those having very poor diets
In management of folic acid deficiency with trimethoprim, ___ administration of ___ is given
Simultaneous; folinic acid
___ is a 5-formyl derivative of ___ which is readily converted to ___, which is then utilized for important cellular metabolic functions
Folinic acid; tetrahydrofolic acid; tetrahydrofolic acid
List & describe 6 adverse events involving cotrimoxazole
1) Skin reactions e.g. rash (common)
2) Photosensitivity
3) GI effects e.g. N/V (most common)
4) Glossitis & stomatitis
5) Hemolytic anemia
- In pts with G6PD deficiency due to sulfamethoxazole component
6) Megaloblastic anemia, leukopenia, thrombocytopenia
- Can be fatal
- Hematologic effects reversed by concurrent administration of folinic acid, which protect pt & does not enter microorganism
List & describe 7 common adverse effects of nitrofurantoin
1) N/V/D (common)
- Macrocrystalline preparation better tolerated
2) Hypersensitivity reactions (occasionally)
- Chills, fever
3) Leukopenia, hemolytic anemia (associated with G6PD deficiency)
4) Cholestatic jaundice & hepatocellular damage (rare)
- Nitro-reductive metabolism produces injurious oxidative free radicals which can damage hepatocytes
5) Pulmonary toxicity
- Elderly patients especially susceptible
6) Peripheral neuropathies (rare)
- Most likely to occur in pts with impaired renal function & persons on long-continued tx
7) Prolonged incubation period to onset of liver injury due to nitrofurantoin
- Frequently leads to mistaken or delayed dx
List & describe 3 adverse events related to polymyxins
1) Nephrotoxicity (toxic to renal tubule cells)
- Avoid use with other nephrotoxic agents
2) Neurotoxicity (visual disturbances, vertigo, confusion, hallucinations, seizures)
- Usually associated with high serum levels in patients with renal impairment or nephrotoxicity
- DO NOT use in neuromuscular blockade agents & in pt with myasthenia gravis
3) Adverse events related to aerosolized CMS:
- Sore throat, cough, bronchoconstriction, chest tightness
- Bronchoconstriction can occur due to direct chemical stimulation, liberation of histamine, allergy in airway, irritation from chemicals
- Bronchoconstriction usually requires discontinuation of medication, administration of bronchodilators & supplemental oxygen
List 3 adverse events of foscfomycin
1) GI disturbances (e.g. N/D)
2) HA
3) Vaginitis
List 4 adverse events of metronidazole
1) GI
- N/V, epigastric distress, abdominal cramps
2) Unpleasant, metallic taste (common)
3) Oral moniliasis (yeast infection of mouth)
4) CNT & PNS Effects
- Convulsive seizures, optic & peripheral neuropathy
- Rare, but discontinue drug if happens
Avoid alcohol
Contraindication of fluroquinolones
Avoid in pts with myasthenia gravis
- May exacerbate muscle weakness
List 2 contraindication of sulfonamides
- Newborns & infants < 2/12 age
- Pregnant women at term
List 3 contraindications of urinary antiseptics
1) Impaired renal function (CrCl < 40 mL/min)
2) Pregnant women (38-42 wks gestation)
- During labor or delivery
- When start of labor is imminent
- Reason: Possibility of hemolytic anemia
3) Infants < 1 month of age
- Reason: Possibility of hemolytic anemia
Quinolones may ___ serum levels of ___ & ___
raise; warfarin; cyclosporine
Ciprofloxacin can ___ serum levels of ___ by ___
increase; theophylline; inhibiting its metabolism
Cotrimoxazole can:
1) ___ half-life of ___
2) ___ effect of ___
increase; phenytoin;
enhance; warfarin
metronidazole may ___ effects of ___
potentiate; warfarin
Describe two mechanisms of resistance against trimethoprim
Resistance in G(-) bacteria due to:
- Presence of altered dihydrofolate reductase that has lower affinity for trimethoprim
- Efflux pumps & decreased permeability to the drug
Describe resistance of bacterial against nitrofurantoin
- Approved only for tx of UTI caused by microorganisms known to be susceptible to drug
- Bacterial resistance to nitrofurantoin more frequent than resistance to fluroquinolones or trimethoprim-sulfamethoxazole
Resistance to metronidazole ___(is/is not)___ a therapeutic problem for ___, although strains of ___ resistant to drug ___(have/have not)___ been reported
is not; amebiasis; trichomonads; have
