AfraTafreeh.

com

Other Antibiotics
Jason Ryan, MD, MPH
Sulfonamide Antibiotics
• Sulfonamide group = SO2-N
• “Sulfa” drug = contains sulfonamide group
• Sulfonamide antibiotics inhibit bacterial synthesis of folate
• Folate required for thymidine/DNA synthesis
• Mammalian cells: exogenous folate from diet
AfraTafreeh.com
• Bacterial cells: no exogenous folate - must synthesize

Sulfonamide Antibiotic Structure

 AfraTafreeh.com

Bacterial Folate Synthesis

Trimethoprim
Sulfonamides Pyrimethamine

X X
PABA Dihydropteroate Dihydrofolate
para-aminobenzoic Synthase Reductase
acid

Dihydropteroic Acid Tetrahydrofolate

Pteridine
Sulfonamides
Sulfamethoxazole (SMX), sulfisoxazole, sulfadiazine
• Mimics of PABA
• Competitively inhibit dihydropteroate synthase
• Sulfamethoxazole commonly given with trimethoprim as TMP-SMX
• Sequential block of THF synthesis
AfraTafreeh.com

Sulfamethoxazole Sulfadiazine
Sulfisoxazole
 AfraTafreeh.com

Trimethoprim-Sulfamethoxazole
TMP-SMX
• Gram positive bacteria including most MRSA strains E. Coli
• Ineffective against most anaerobes including B fragilis
• Gram negative bacteria but not pseudomonas
• Uncomplicated urinary tract infections
• Usually covers E. coli and Proteus
• Some strains of E. coli may be resistant
• Pneumocystis pneumonia (PCP)
• Treatment of choice
• Prophylaxis

Public domain
Sulfonamides
Toxicity
• Hypersensitivity reactions ~3% of patients
• Reactions linked to specific drug molecule features
• Aromatic ring attached to N4 position
• Nitrogen ring attached to N1 nitrogen
• Only sulfonamide antibiotics contain both features
AfraTafreeh.com

N1 Nitrogen
SMX

N4 Nitrogen
 AfraTafreeh.com

Other Sulfa Drugs

Furosemide Probenecid Hydrochlorothiazide

(Loop Diuretic) (Gout) (Thiazide diuretic)

Acetazolamide Sulfasalazine Sulfonylurea

(Carbonic Anhydrase) (IBD) (Diabetes)
Sulfonamides Mucosal Desquamation
Hypersensitivity (allergic) reactions
Stevens-Johnson Syndrome
• Similar to penicillin allergic reactions
• Anaphylaxis
• Maculopapular rash
• Serum sickness (fever, rash, arthritis)
• Stevens-Johnson Syndrome AfraTafreeh.com
• Toxic epidermal necrolysis
• Adverse reaction rate higher in HIV
• 25 to 50% in some studies

James Heilman, MD
 AfraTafreeh.com

Sulfonamides
Toxicity Photosensitivity

• Nephrotoxicity
• Interstitial nephritis
• Photosensitivity
• Drug interaction with UV light
• Hemolysis in G6PD deficiency
• Sulfonamides are oxidants - classic trigger for hemolysis
• Bind to albumin
• Displaces other bound substances
• Bilirubin – kernicterus in newborns (contraindicated)
• Warfarin – may increase INR

Wikipedia/Public Domain
Trimethoprim
Toxicity
• Preferentially inhibits bacterial dihydrofolate reductase
• Some inhibition of human enzyme can occur
• Inhibits DNA synthesis of rapidly dividing cells
• Bone marrow suppression
• Pancytopenia: megaloblastic anemia, leukopenia, ↓platelets
AfraTafreeh.com
• Can alleviate with folate supplementation
• Avoided in pregnancy (↑ folate demand)
 AfraTafreeh.com

Trimethoprim
Toxicity
• Hyperkalemia
• Blockade of epithelial sodium channel (ENAC)
• Blocks secretion of potassium into urine
• Similar effect to amiloride (potassium-sparing diuretic)
• May be life-threatening
• Caution if patients on other drugs
• ACE inhibitors
• Angiotensin receptor blockers
• Aldosterone antagonists
Pneumocystis Pneumonia
PCP
• Opportunistic fungal infection
• Occurs in end-stage HIV/AIDS Pneumocystis jirovecii
• Treatment of choice: TMP-SMX
• Hypersensitivity reactions more common
• Alternative therapy often neededAfraTafreeh.com
• Dapsone
• Pentamidine
• Atovaquone (malaria drug)

Yale Rosen/Wikipedia
 AfraTafreeh.com

Dapsone
• Not a sulfonamide
• Competes with PABA for dihydropteroate synthase
• PCP pneumonia
• Mycobacterium leprae (leprosy)
Fluoroquinolones
Ciprofloxacin, levofloxacin, moxifloxacin
• Inhibit enzymes for bacterial DNA synthesis
• DNA gyrase
• Topoisomerase IV
• Cover many gram positives, gram negatives and atypical bacteria
• Generally poor coverage of anaerobes except moxifloxacin
AfraTafreeh.com
• UTIs (E. Coli, other gram negatives)
• Pneumonia (S. pneumo, H. flu, atypicals)
• Abdominal infections (enteric gram negatives)
 AfraTafreeh.com

Fluoroquinolones
Ciprofloxacin
• Some gram positive coverage
• Rarely used alone for gram positive coverage due to resistance
• Very good gram negative coverage
• Most reliable fluoroquinolone pseudomonas coverage
• Gastrointestinal infections
• Enterobacteriaceae including E. coli, Klebsiella
• Often together with an anaerobic drug (metronidazole)
• Urinary tract infections
• Otitis externa (ear drops)

Shutterstock
Fluoroquinolones
Levofloxacin and moxifloxacin
• More gram positive and atypical coverage than ciprofloxacin
• Better strep pneumo coverage
• Covers most methicillin-susceptible Staph aureus
• Less effective against pseudomonas
• Commonly used in pneumonia AfraTafreeh.com
• Strep pneumonia, H. influenzae, M. catarrhalis
• Atypical bacteria
 AfraTafreeh.com

Fluoroquinolones
Adverse effects
• Tendinopathy
• Tendon rupture or tendonitis
• Most commonly Achilles
• More common in older patients (>60), people on steroids
• Cannot use in pregnancy/children
• Toxic to developing cartilage in animal studies

Wikipedia/Public Domain
Fluoroquinolones
Adverse effects
• Neurologic side effects
• Headache, dizziness, insomnia
• Rarely confusion or delirium
• QT prolongation on EKG
AfraTafreeh.com

PeaBrainC/Wikipedia
 AfraTafreeh.com

Fluoroquinolones
Antacids
• Disrupt absorption of many drugs
• Aluminum and magnesium hydroxide
• Sucralfate
• Key drugs
• Tetracycline
• Fluoroquinolones
• Isoniazid
• Iron supplements

Midnightcomm
Vancomycin
• Inhibits cell wall synthesis
• Binds D-alanyl-D-alanine peptides
• Prevents crosslinking
• Cell wall breakdown → cell death
• Only effective against gram positive bacteria
AfraTafreeh.com
• Too large to pass outer membrane gram negatives
 AfraTafreeh.com

Vancomycin C. difficile

• Methicillin resistant Staph Aureus (MRSA)

• Intravenous administration
• Often given empirically when MRSA is a concern
• Endocarditis
• Severe pneumonia/sepsis
• C. difficile pseudomembranous colitis
• Oral therapy
• Not absorbed → intestinal activity only
• Penicillin-resistant S. pneumoniae
• Empiric therapy for meningitis

Public Domain
Vancomycin
Adverse effects
• Nephrotoxicity
• Less common with modern preparations
• Increased risk if concomitant aminoglycoside therapy
• Ototoxicity
• Tinnitus, vertigo, and hearing loss reported (rare)
AfraTafreeh.com

Pixabay/Public Domain
 AfraTafreeh.com

Vancomycin
Adverse effects
• Vancomycin infusion reaction
• Flushing, erythema, itching
• Usually affects upper body, neck, face more than lower body
• Occurs 10-20 minutes after start of infusion
• Direct activation of mast cells → histamine release
• “Pseudoallergic drug reaction”
• May develop with first administration
• Infusion related → slow infusion = no symptoms

Public Domain
Metronidazole
• Causes DNA breakage/destabilization → cell death
• Prodrug that must be reduced to activate
• Only anaerobic bacteria capable of reduction
• Good coverage of anaerobes “below the diaphragm”
• Bacteroides fragilis AfraTafreeh.com
• C. difficile
• Peritonitis, abdominal abscesses, diverticulitis
• Often given with quinolone for gram negatives
• Ciprofloxacin + metronidazole often used for diverticulitis
 AfraTafreeh.com

Metronidazole
Uses
• H. Pylori
• Part of triple therapy
• Bacterial vaginosis
• Treats Gardnerella vaginalis
• Anaerobic protozoa
• Trichomonas vaginalis
• Entamoeba histolytica
• Giardia lamblia

Shutterstock
Metronidazole
Adverse Reactions
• Unpleasant metallic taste
• GI: abdominal discomfort, nausea
• Disulfiram-like reaction
• Alcohol consumption with metronidazole
• Warmth, flushing, sweating AfraTafreeh.com
• Patients should avoid alcohol

Wikipedia/Public Domain
 AfraTafreeh.com

Nitrofurantoin
• Complex, incompletely-understood mechanism
• Major use is uncomplicated urinary tract infections
• Concentrates in urine
• Safe in pregnancy (avoid TMP-SMX, quinolones)
• Can trigger hemolysis in G6PD patients

Shutterstock