Ch 31: Quinolones, Folic acid antagonists, urinary tract antiseptics

Fluoroquinolone resistance

1. Chromosomal mutations of target enzymes leads to decrease affinity at site of action. Responsible for high levels of resistance to gram + and -

2. Degradation and inactivation by aminoglycoside acetyltransferase

3. Reduced intracellular concentration due to decreased number of porin channels and increased number of efflux pumps.

A 21 y/o marathon runner reports to the clinic with acute achilles tendon rupture. The pt recently took an antibiotic for CAP. Which antibiotic could have caused this?

Levofloxacin

How do folate synthesis inhibitors work?

Inhibit bacterial de novo folate synthesis

HOw do folate reduction inhibitors work?

Prevent microorganisms from converting dihydrofolic acid to tetrahydrofolic acid.

Sulfonamides resistance

-Bacteria that can obtain folate from environment are naturally resistant

Acquired:

-Altered dihydropeteroate synthetase

-decreased permeability of bacterial cell to sulfa

-enhanced bacterial production of PABA

Cross resistance exists among drugs in the class

Trimethoprim resistance

-resistance in gram neg bacteria d/t altered dihydrofolate reductase that has lower affinity for trimethoprim

-efflux pumps

-decreased permeability to trimethoprim

A 55y/o presents with erythematous and tender abscess on thigh. Hx of MRSA skin infections. Which is an appropriate antibiotic for empiric tx?

Cotrimoxazole

What is the most causative organism in UTis?

E. Coli

What are commonly used to tx UTIs?

Antiseptics

Floroquinolones (MOA)

Inhibition of two bacterial enzymes to increase chromosomal breaks in DNA and trigger cell lysis.

Bactericidal

Floroquinolones BBW

Tendonitis, peripheral pneuopathy, and CNS effects

Fluoroquinoloines Spectrum of activity

Gram (+): Strep, bacillus anthracis

Gram (-): E. Coli, p. Aeruginosa, H.influenzae, Enterobacter sp., klebsiella, proteus mirabilis, cerratia marcescens, shigella

Atypical: Legionellaceae, chlamydiaceae

Mycobacteria: M. tuberculosis

Ciprofloxacin (class)

Second gen fluoroquinolone

Cipro (use)

Cystic fibrosis (p. Aeruginosa)

drug of choice for post exposure prophylaxis and tx of anthrax

UTI

Traveller’s diarrhea (e. Coli)

Typhoid fever (salmonella typhi)

Second line for tuberculosis

Cipro (spectrum of activity)

Aerobic gram (-): P. Aeruginosa, e. Coli, h. Influenzae

Atypical: Chlamydia, legionella, mycoplasma sp.

Levofloxacin (class)

Third gen Fluoroquinolone

Levofloxacin (use)

Prostatitis, skin infections, CAP, HAP

S. Pneumoniae resp infections

UTI

Second line for MDR-TB

Levofloxacin (spectrum)

Improved gram (+)

Improved activity against s. Pneumoniae

MOxifloxacin (class)

Fourth gen Fluoroquinolone

Moxifloxacin (use)

S. Pneumo anaerobes, mycobacterium

CAP (not HAP)

Mild-mod intra-abdominal infections

Second line TB

Moxifloxacin (spectrum)

Enhanced gram (+), s. Pneumoniae, mycobacteria, B. Fragilis, anaerobes

Delafloxacin (class)

Fourth gen fluoroquinolone)

Delafloxacin (use)

MRSA and enterococcus

Acute bacterial skin infections

Delafloxacin (spectrum)

Enhanced gram (+)

-S. Pneumoniae, mycobacteria, b. Fragilis, anaerobe, MRSA, E. Faecalis, p. Aeruginosa

Sulfonamides (class)

Folate synthesis inhibitor

Folic acid antagonist

Sulfonamides (MOA)

Synthetic analogs of PABA.Compete with PABA for binding sites of dihydropteroate synthetase and inhibits snythesis of dihydrofolic acid

Bacteriostatic

Sulfas (use)

Toxoplasmosis when given in combo with dihydrofolate reductase inhibitor pyrimethamine.

Used with other ABX for nocardiosis, UTI, and chloroquine resistant falciparum malaria.

Burns

Sulfa (spectrum of activity)

Select enterobacter in urinary tract, H. Influenzae, strep sp., staph, nocardia.

Sulfa (contraindications)

Avoid in newborns and infants <2 mos

Avoid in pregnant women at term or during breastfeeding

Trimethoprim (class)

Folate reduction inhibitor

Trimethoprim (MOA)

Inhibits the bacterial enzyme dihydrofolate reductase. Decreases amt of tetrahydrofolic acid available for synthesis of purines, pyrimidines, and AAs. Preference for bacterial enzyme over human.

Trimethoprim (Use)

Pneumocystitis jirovecii pneumonia

Chronic bacterial prostatitis

Prophylactic and tx of UTI in pts with sulfa allergy

Acne vulgaris

Often used in combo with sulfamethoxazole

Trimethoprim (spectrum)

Gram + and - coverage

Protozoans: Cystoispora and cyclospora sp.

Fungus: Pneumocystis jirovecii

Cotrimoxazole (Trimethoprim + Sulfamethoxazole) (MOA)

Sulfamethoxazole inhibits incorporation of PABA into dihydrofolic acid precursors.

Trimethoprim prevents reduction of dihydrofolate to tetrahydrofolate.

Cotrimoxazole (use)

Bacterial prostatitis as alt to FQ

Uncomplicated cystitis in women

UTI prophylaxsis

TX and ppx of pneumocystis pneumonia in immunocompromised pts

Infection caused by nocardia and L. Monocytogenes

Community associated MRSA

Cotrimoxazole (spectrum)

Gram (+): Straph aureus, nocadia, listeria

Gram (-): E. Coli, h. Influenzae, salmonella, legionella, proteus mirabilis, s. Typhi, shigella

Methenamine (class)

Urinary tract antiseptic

Methenamine (MOA)

Produces formaldehyde upon decomposition in acidic pH of urine. Acts locally and is toxic to bacteria.

Methenamine (use)

Chronic suppressive therapy to reduce frequency of UTIs.

Methenamine (contraindication)

Liver insufficiency

Nitrofurantoin (class)

Urinary tract antiseptic

Nitrofurantoin (MOA)

Inhibits DNA and RNA synthesis

Nitrofurantoin (use)

First line for uncomplicated cystitis

Nitrofurantoin (contra)

Renal impairment

Age <1 month

Pregnancy at term

G6PD deficiency

Nitrofurantoin (spectrum)

E. Coli, enterococci, s. Sapropphyticus, s. Aureus, klebsiella and enterobacter sp.