1. QUINOLONES, FOLIC ACID ANTAGONISTS, AND URINARY TRACT ANTISEPTICS
(according to Lippincott´s
Pharmacology, 2009)
Summary of drugs described in this chapter.
QUINOLONES, FOLIC ACID ANTAGONISTS, AND URINARY TRACT ANTISEPTICS
Fluoroquinolones
Inhibitors of folate reduction
FIRST GENERATION
Nalidixic acid
SECOND GENERATION
Ciprofloxacin
Norfloxacin
Ofloxacin
THIRD GENERATION
Levofloxacin
FOURTH GENERATION
Moxifloxacin
Pyrimethamine
Trimethoprim
Combination of inhibitors of folate synthesis and reduction
Cotrimoxazole
Urinary tract antiseptics
Methenamine
Nitrofurantoin
Inhibitor of folate synthesis
Mafenide
Silver sufadiazine
Succinylsulfathiazole
Sulfacetamide
Sulfadiazine
Sulfamethoxazole
Sulfasalazine
Sulfisoxazole

2. FLUORQUINOLONS A. Mechanism of action
They enter the bacterium by passive diffusion through water-filled protein channels (porins) in the outer membrane.
They inhibit the replication of bacterial DNA by interfering with the action of DNA gyrase (topoisomerase II) and topoisomerase IV during bacterial growth and reproduction.
Binding to both enzyme and the DNA forms a ternary complex that inhibits the resealing step, and can cause cell death by inducing cleavage of the DNA.

3. B. Spectrum All are bactericidal.
They exhibit concentration-dependent bacterial killing. Bactericidal activity becomes more pronounced as the serum drug concentration increases to cca thirty-fold the MIC.
They exhibit also - PAE !!!! -they act even though the concentrations are below detection
Effective against G- (e.g., Enterobacteriaceae, Pseudomonas sp., H. influenzae, Moraxella catarrhalis, Legionellaceae, chlamydia, mycobacteria - except for M. avium intracellulare complex).
Effective in the treatment of gonorrhea but not syphilis.
Newer agents (levofloxacin, gatifloxacin, sparfloxacin, clinafloxacin, moxifloxacin) - also good activity against some G+ organisms (e.g., Streptococcus pneumoniae).
Activity against some anaerobes - sparfloxacin, gatifloxacin, moxifloxacin.
If used prophylactically before surgery -  incidence of postsurgical UTIs.

4. C. Examples of clinically useful fluoroquinolones
1. Ciprofloxacin [sip row FLOX a sin] - frequently used.
Effective against many systemic infections (excepting serious infections by MR S. aureus, enterococci, and pneumococci).
Particularly useful in infections caused by many Enterobacteriaceae and other G- bacilli. E.g., traveler's diarrhea caused by E. coli.
Drug of choice for prophylaxis and treatment of anthrax.
The most potent of the fluoroquinolones for P. aeruginosa infections and -  used in the treatment of pseudomonal infections in cystic fibrosis.
An alternative to more toxic drugs (e.g.,aminoglycosides).
It may act synergistically with b-Iactams; also of benefit in treating resistant tuberculosis.

5. 2. Norfloxacin: [nor FlOX a sin]
It is not effective in systemic infections.
- more potent than nalidixic acid, effective against both G- (incl. P. aeruginosa) and G+ organisms. Useful in treating complicated and uncomplicated UTIs and prostatitis.
3. Levofloxacin: [leave oh FlOX a sin]
Primarily used in the treatment of prostatitis due to E. coli and of sexually transmitted diseases (excepting syphilis).
An alternative therapy in patients with gonorrhea.
Some benefit in skin and lower respiratory tract infections.
Broad spectrum  skin infections, sinusitis, exacerbation of chronic bronchitis, community-acquired and nosocomial pneumonia
Excellent activity against respiratory infections due to S. Pneumoniae.

6. Pharmacokinetics
Absorption: 85 to 95 %
- except norfloxacin ( % after p.o. administration)
I.v. preparations of ciprofloxacin, levofloxacin, gatifloxacin, and ofloxacin are available.
Ingestion with antacids (with Al or Mg), or dietary supplements (with Zn or Fe) - interfere with the absorption.
Calcium and other divalent cations - also interfere with the
absorption.
Levofloxacin, moxifloxacin - the longest T0.5  it permit once-daily dosing.

7. Distribition, elimination
Binding to plasma proteins is variabile (10 – 40 %)
All distribute well into all tissues and body fluids.
Levels high in bone, urine, kidney, lung and prostatic tissue
Low penetration into CSF (except for ofloxacin).
second-generation fluoroquinolone
is a racemic mixture of 50% levofloxacin and
50% of dextrofloxacin
Fluorquinolons accumulate in macrophages and polymorphonuclear leukocytes - effective against intracellular organisms (e.g., Legionella pneumophila).
They are excreted by kidney.

8. Generally - very well tolerated.
Adverse reactions
Generally - very well tolerated.
1. GIT: the most common - nausea, vomiting, diarrhea (3 – 6 % of patients).
2. CNS: headache and dizziness or light-headedness.
Patients with CNS disorders (epilepsy) should be treated cautiously.
Ciprofloxacin interferes in the metabolism of theophylline - may evoke seizures.
3. Phototoxicity: They should be discontinued at the first sign of phototoxicity.

9. SULFONAMIDES Structurally related to p-aminobenzoic acid (PABA).
The sulfa drugs - seldom use alone
(except some regions, where are still employed because of their low cost and their efficacy in certain infections - e.g., trachoma, UTIs). Because of the emergence of resistant bacteria and the availability of penicillin, their use had diminished.
The introduction of trimethoprim in combination with sulfamethoxazole in the mid-1970s led to a renewed interest in sulfonamides.

10. Pteridine is
composed of fused pyrimidine and pyrazine rings

11. Administration:
Mostly well absorbed after oral administration via the small intestine.
An exception - SULFASALAZINE [sui fa SAL a zeen] - not absorbed - reserved for treatment of chronic inflammatory bowel disease (e.g., Crohn disease or ulcerative colitis).
I.v. sulfonamides - reserved for patients who are unable to take them orally.
Sulfa drugs distribute throughout the body's water and penetrate well into CSF - even in the absence of inflammation. They can also pass the placental barrier and enter fetal tissues.

12. 2. Elimination
The product of its metabolism is devoid of antimicrobial activity but retains the toxic potential to precipitate at neutral or acidic pH. This causes crystalluria ("stone formation") and potential damage to the kidney.
Elimination by glomerular filtration
»» depressed kidney function causes accumulation of the both the parent compounds and their metabolites.
The sulfonamides may also be eliminated in breast milk.

13. Individual sulfonamides:
Well absorbed orally, short-acting: Sulfadiazine, Sulfisoxazole, Sulfamethoxazole
2) Well absorbed orally, long-acting: Sulfamethopyrazine
3) Poorly absorbed in GIT: Sulfasalazine
Use in inflammatory bowel disease
metabolite of sulfasalazine aminosalicylic acid (5-ASA)
is credited with causing the drug's therapeutic antiinflammatory effect.
4) Used topically: Silver sulfadiazine
- treatment of burns

14. E. Adverse effects 1. Nephrotoxicity: - a result of crystalluria
Adequate hydration and alkalization of urine is necessary
and prevent the crystalluria.
Note: It is contraindicated to use acidic drugs (salicylates) or food
(oranges etc.) which may lead to acidic pH of urine .
2. Hypersensitivity: rashes, fever,
angioedema, anaphylactoidreactions,
Stevens-Johnson syndrom -
toxic epidermal necrolysis
serious life-threatening condition

15. 3. Hemopoietic disturbances: Hemolytic anemia in patients with
glucose 6-phosphate dehydrogenase deficiency. Granulocytopenia
and thrombocytopenia can also occur.
4. Kernicterus: In newborns because of the displacement of bilirubin from its binding site on serum albumin and its penetration into CNS (because the baby's blood-brain barrier is not fully developed). The effects range from clinically unobservable to severe brain damage and even death
5. Nausea, vomiting, headache
6. Hepatitis.

16. Summary of drugs described in this chapter.
(according to Lippincott´s
Pharmacology, 2009)
Summary of drugs described in this chapter.
QUINOLONES, FOLIC ACID ANTAGONISTS
Fluoroquinolones
Inhibitors of folate reduction
FIRST GENERATION
Nalidixic acid
SECOND GENERATION
Ciprofloxacin
Norfloxacin
Ofloxacin
THIRD GENERATION
Levofloxacin
FOURTH GENERATION
Moxifloxacin
Pyrimethamine
Trimethoprim
Combination of inhibitors of folate synthesis and reduction
Cotrimoxazole
Inhibitor of folate synthesis
Mafenide
Silver sufadiazine
Succinylsulfathiazole
Sulfacetamide
Sulfadiazine
Sulfamethoxazole
Sulfasalazine
Sulfisoxazole

17. TRIMETHOPRIM [trye METH oh prim]
inhibitor of bacterial dihydrofolate reductase;
antibacterial spectrum similar to SA.
It is most often compounded with sulfamethoxazole, producing the combination called co-trimoxazole.
May be used alone in the treatment of acute UTIs, and in the treatment of bacterial prostatitis (fluoroquinolones are preferred) and vaginitis.
It also penetrates the CSF.
Mostly excreted unchanged through the kidney
Adverse effects
efects of folic acid deficiency
(megaloblastic anemia, leukopenia, granulocytopenia - esp. in pregnant patients and those with poor diets).
- nausea, vomiting, skin rashes

18. Inhibition of tetrahydrofolate synthesis by sulfonamides and trimethoprim
Microorganisms
Humans and microorganisms
2 NADPH
+ 2 H+
2 NADPH
Amino acid
synthesis
Dihydro-
pteroate
synthetase
Dihydro-
folate
reductase
H2N
COOH
Folic acid
Tetrahydrofolic
acid
Purine
synthesis
Pteridine precursor + p-Aminobenzoic acid
(PABA)
Glutamate O
Thymidine
synthesis
H2N S
NHR
Sulfanilamide
(and other
sulfonamides)
Trimethoprim O
(according to Lippincott´s Pharmacology, 2006)

19. Summary of drugs described in this chapter.
(according to Lippincott´s
Pharmacology, 2009)
Summary of drugs described in this chapter.
QUINOLONES, FOLIC ACID ANTAGONISTS
Fluoroquinolones
Inhibitors of folate reduction
FIRST GENERATION
Nalidixic acid
SECOND GENERATION
Ciprofloxacin
Norfloxacin
Ofloxacin
THIRD GENERATION
Levofloxacin
FOURTH GENERATION
Moxifloxacin
Pyrimethamine
Trimethoprim
Combination of inhibitors of folate synthesis and reduction
Cotrimoxazole
Inhibitor of folate synthesis
Mafenide
Silver sufadiazine
Succinylsulfathiazole
Sulfacetamide
Sulfadiazine
Sulfamethoxazole
Sulfasalazine
Sulfisoxazole

20. CO-TRIMOXAZOLE (co trye MOX a zole)
Trimethoprim – mostly compounded with sulfamethoxazole.
The synergistic antimicrobial activity of co-trimoxazole –
inhibition of 2 sequential steps in the synthesis of tetrahydrofolic acid.
Sulfamethoxazole inhibits the incorporation of PABA into folic acid,
trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate.
More potent activity than sulfamethoxazole or trimethoprim alone.
Broader spectrum than SA.
Treating UTls and respiratory tract infections, Pneumocystis pneumonia and ampicillin- or chloramphenicol-resistant systemic salmonella infections.
Co-trimoxazole is generally administered orally.

21. E. Adverse effects
- Dermatological: Reactions involving the skin are very common and
may be severe in the elderly.
- GIT: Nausea, vomiting, glossitis, stomatitis - not unusual.
Hematological:
megaloblastic anemia, leukopenia, thrombocytopenia
may be reserved by the concurrent administration of folinic acid
Hemolytic anemia - in patients with glucose 6-phosphate
dehydrogenase deficiency due to the sulfamethoxazole.
Immunocompromised patients with P. jeroveci pneumonia,
pneumocystis pneumonia frequently show drug-induced fever,
rashes, diarrhea, and/or pancytopenia.

22. Treatment of urinary tract infections
Few Comments on clinical treatment of urethritis

23. Upper urinary tract Infections:
Pyelonephritis
Lower urinary tract infections
Cystitis (“traditional” UTI)
Urethritis (often sexually-transmitted)
Prostatitis

24. Choice of antibiotic depends on:
Whether infection is complicated or uncomplicated.
Whether infection is primary or recurrent.
Type of patient : pregnant women ,children ,
hospitalized patients , diabetic patients
Bacterial count.
Presence of symptoms.

25. Choice of antibiotic depend on susceptibility pattern
Amoxicillin ( with or without clavulanate)
Cephlosporins ( first or second generation)
TMP-SMX
Nitrofurantoin ( long term use)
Fluoroquinolone ( ciprofloxacin or norfloxacin)-
(not for pregnant women or children); first choice if other ATB are resistant.
Fosfomycine

26. Fosfomycin
is indicated in the treatment of urinary tract infections
as a single oral megadose
The drug is well tolerated and has a low incidence of harmful side-effects
However, development of bacterial resistance under therapy is a frequent occurrence and makes fosfomycin unsuitable for sustained therapy of severe infections.
It is not recommended for children and those over 75 years old

27. Mechanism of action
-bactericidal
-inhibits bacterial cell wall synthesis by inactivating pyruvyltransferase
(enzyme which catalyzes the committed step in peptidoglycan biosynthesis
- Fosfomycin enters the bacterial cell through the glycerophosphate transporter.
Fosfomycin has broad antibacterial activity against both Gram-positive and Gram-negative pathogens, with useful activity against E. faecalis, E. coli, and various Gram-negatives like Citrobacter and Proteus.
Given a greater activity in a low pH milieu, and predominant excretion in active form into the urine

28. Recurrent infections need preventive therapy
patients with two or more symptomatic UTIs within 6 months or thrice or more over a year.
need preventive therapy
antibiotic taken as soon as symptoms develop

29. Prophylactic antibiotics
Reduces recurrence by up to 95%
Low dose antibiotic taken continuously for 6 months or longer
it includes :
TMP-SMX, Nitrofurantoin, or Cephalexin
Antibiotic taken at bed time more effective
-prolonged antibiotic residence time in the bladder

30. Uncomplicated pyelonephritis
Patients with fever, chills and flank pain , but they are healthy non-pregnant not nauseous or vomiting with no signs of kidney involvement. Can be treated at home with oral antibiotics for days with one of the followings: Ciprofloxacin, Ceftriaxone , Aminoglycosides or TMP-SMX. First dose may be given by injection Nirofurantoin - is not effective for kidney infections

31. Moderate to sever pyelonephritis
Patients need hospitalization Antibiotic given by IV route for 3-5 days until symptoms relieved for hrs. Ciprofloxacin or ceftriaxone for days If fever and back pain continue after 72 hrs of antibiotic, imaging tests indicated to exclude abscesses, obstruction or other abnormality.

32. Chronic pyelonephritis
Those patients need long-term antibiotic treatment even during periods when they have no symptoms.

33. Treatment of specific populations
Pregnant women High risk for UTI and complications Should be screened for UTI Antibiotics during pregnancy include: Amoxicillin, ampicillin, cephalosporins Pregnant women should NOT take quinolones.