Chapter 46: Sulfonamides, Trimethoprim, & Fluoroquinolones 

 
Introduction 
Sulfonamides and trimethoprim 
● Antimetabolites selectively toxic to microorganisms because they interfere with folic acid synthesis 
● Sulfonamides - used selectively as individual antimicrobial agents, although resistance is common 
● Sulfonamide + trimethoprim = sequential blockade of folic acid synthesis 
○ Resulting in a synergistic action against a wide spectrum of microorganisms 
○ Resistance occurs but slow in development 
 
Fluoroquinolones 
● Selectively inhibit microbial nucleic acid metabolism 
● Broad spectrum of antimicrobial activity that includes many common pathogens 
● Resistance has emerged to the older antibiotics in this class, but has been offset to some extent by the introduction of newer fluoroquinolones with expanded 
activity against common pathogenic organisms 
 

 
 
 
 
 
 
 
Antifolate Drugs 
 
Drug  Classification &  Mechanisms of Action  Resistance  Clinical Use  Toxicity 
Pharmacokinetics 

Sulfonamides  ● Treatment of infectious  ● Bacteriostatic  ● Common and may be  ● Active against:  ● Hypersensitivity  
diseases which inhibit  inhibitors of folic acid  plasmid-mediated  ○ Gram-positive   ○ Allergic reactions - 
microbial enzymes involved in  synthesis   ● Result from:   ○ Gram-negative  skin rashes and 
folic acid synthesis  ● Antimetabolites of  ○ decreased  ○ Chlamydia  fever 
● Weakly acidic compounds that  PABA  intracellular  ○ Nocardia  ○ Cross-allergenicity 
have a common chemical  ○ Competitive  accumulation of  1. Simple urinary tract  between the indiv 
nucleus resembling  inhibitors of  the drugs   infections   sulfonamides (oral 
p-aminobenzoic acid (PABA)  dihydropteroate  ○ increased  ○ Oral - triple sulfa,  hypoglycemics, 
● Pharmacokinetics features:   synthase  production of  sulfisoxazole  thiazides) 
○ Modest tissue penetration  ○ Sulfonamides can  PABA by bacteria  2. Ocular infections  ○ Rarely:  
○ Hepatic metabolism  also act as  ○ Decrease in the  ○ Topical -  ○ exfoliative 
○ Excretion of both intact  substrates for this  sensitivity of  sulfacetamide  dermatitis,  
drug and acetylated  enzyme resulting  dihydropteroate  3. Burn infections   ○ polyarteritis 
metabolites in  in the synthesis of  synthase to the  ○ Topical - mafenide,  nodosa 
precipitation of the drug or  nonfunctional  sulfonamides  silver sulfadiazine  ○ Stevens-Johnso
its metabolites  forms of folic acid  4. Ulcerative colitis,  n syndrome 
● Because of the solubility  ● Selective toxicity =  rheumatoid arthritis   ● Gastrointestinal 
limitation, a combination of 3  inability of mammalian  ○ Oral - sulfasalazine  ○ Commonly: 
separate sulfonamides (triple  cells to synthesize folic  5. Toxoplasmosis  ○ Nausea 
sulfa) has been used to reduce  acid  ○ Oral sulfadiazine plus  ○ Vomiting  
the likelihood that any one  ○ They must use  pyrimethamine plus  ○ Diarrhea 
drug will precipitate  preformed folic  folinic acid  ○ Mild hepatic 
● Classified as:  acid that is present  ■ Pyrimethamine -  dysfunction - 
○ Short-acting: sulfisoxazole  in the diet  dihydrofolate  may occur 
○ Intermediate-acting:    reductase inhibitor  ○ Hepatitis - 
sulfamethoxazole  uncommon 
○ Long-acting: sulfadoxine  ● Hematotoxicity  
● They bind to plasma proteins  ○ Rare 
at sites shared by bilirubin and  ○ Can cause: 
by other drugs  ○ Granulocytopen
ia 
○ Thrombocytope
nia 
○ Aplastic anemia 
○ Acute hemolysis = 
occur in persons 
with 
glucose-6-phosph
ate dehydrogenase 
deficiency 
● Nephrotoxicity 
○ Crystalluria and 
hematuria - 
sulfonamides may 
 precipitate in the 
urine at acidic pH 
● Drug interactions 
○ Competition with 
warfarin and 
methotrexate for 
plasma protein 
binding transiently 
increases the 
plasma levels of 
these drugs 
○ Sulfonamides can 
displace bilirubin 
from plasma 
proteins, with risk 
of kernicterus in 
the neonate if used 
in the third 
trimester of 
pregnancy  

Trimethoprim  ● selective inhibitor of  ● A selective inhibitor of  ● Resistance results  ● Trimethoprim-sulfameth ● Can cause predictable 
dihydrofolate reductase  bacterial dihydrofolate  from the production  oxazole (TMP-SMZ)  adverse effects of an 
● Structurally similar to folic  reductase that  of dihydrofolate  ○ Combination is  antifolate drug; these 
acid   prevents formation of  reductase that has a  effective orally in the  effects are ameliorated 
● A weak base and is trapped in  active tetrahydro form  reduced affinity for  treatment of UTI and  by supplementary 
acidic environments, reaching  of folic acid  the drug  in respiratory, ear,  folinic acid:: 
high concentrations in  ● Bacterial dihydrofolate  and sinus infections  ○ Megaloblastic 
prostatic and vaginal fluids  reductase is 4–5 orders  caused by  anemia 
● Large percentage is excreted  of magnitude more  Haemophilus  ○ Leukopenia 
unchanged in the urine  sensitive to inhibition  influenzae a​ nd  ○ Granulocytopenia 
● Half-life similar to  by trimethoprim than  Moraxella catarrhalis  ○ Combination of 
sulfamethoxazole = 10-12  the mammalian  ○ In  TMP-SMZ - may 
hours  enzyme   immunocompromised  cause any of the 
  patients, this is used  adverse effects 
for infections due to  associated with the 
Aeromonas hydrophila  sulfonamides 
and is the DOC for  ○ AIDS patients given 
prevention and  TMP-SMZ have a 
treatment of  high incidence of 
pneumocystis  adverse effects: 
pneumonia  ○ Fever 
○ IV formula is available  ○ Rashes  
○ Used for treatment of  ○ Leukopenia 
severe pneumocystis  ○ Diarrhea 
pneumonia and   
gram-negative sepsis 
○ DOC in nocardiosis 
○ Possible backup drug 
for cholera, typhoid 
 fever, and shigellosis 
○ Treatment of 
infections caused by 
methicillin-resistant 
staphylococci and 
Listeria 
monocytogenes  

Sulfonamides +    ● Antimicrobial synergy       

Trimethoprim  results from sequential 
blockade of folate 
synthesis 
● Combination is 
bactericidal against 
susceptible organisms  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fluoroquinolones 
 
 
Drugs  Classification  Pharmacokinetics  Mechanism of Action  Resistance  Clinical Use  Toxicity 
First Generation:  ● Derived from nalidixic      ● Resistance emerge  ● Fluoroquinolones in  ● Most common: 
● Norfloxacin  acid    ● Fluoroquinolones  rapidly in the case of  general are effective  Gastrointestinal 
● Has activity against  ● All have good  interfere with  second-generation  in urogenital and  distress 
the common  oral  bacterial DNA  fluoroquinolones  gastrointestinal tracts  ● Skin rashes 
pathogens that cause  bioavailability  synthesis by  especially in  caused by  ● Headache 
UTI  (antacids  inhibiting:   Campylobacter jejuni  gram-negative  ● Dizziness 
containing  o topoisomerase  and gonococci, but  organisms  ● Insomnia 
multivalent  II (DNA gyrase)  also in gram-positive  o Gonococci  ● Abnormal liver 
cations may  especially in  cocci (eg, MRSA),  o E coli  function tests 
interfere) and  gram-negative  Pseudomonas  o Klebsiella  ● Phototoxicity 
penetrate most  organisms  aeruginosa, and  pneumoniae  ● Tendinitis and 
body tissues  o topoisomerase  Serratia species.  o C jejuni  tendon rupture 
● Norfloxacin -  IV especially in  ● Mechanism of  o Enterobacter  ● Opportunistic 
does not  gram-positive  resistance include:  o P aeruginosa  infections caused 
achieve  organisms  o Decreased  o Salmonella  by C albicans and 
adequate  ● they block the  intracellular  o Shigella​ species  streptococci have 
plasma levels  relaxation of  accumulation of  ● Widely used for  occurred 
for use in most  supercoiled DNA  the drug via the  respiratory tract, skin,  ● Not recommended 
systemic  that is catalyzed by  production of  and soft tissue  for children or 
infections   DNA gyrase, a step  efflux pumps or  infections, but their  pregnant women 
● Elimination -  required for  changes in porin  effectiveness is now  because they may 
thru kidneys via  normal  structure (in  variable because of  damage growing 
active tubular  transcription and  gram-negative  the emergence of  cartilage and 
secretion,  duplication   bacteria)  resistance  cause arthropathy 
which can be  ● fluoroquinolones  o Efflux  ● Also been used in the  ● May increase 
blocked by  interferes with the  mechanisms  meningococcal carrier  plasma levels of 
probenecid  separation of  responsible for  state, in the  theophylline and 
● Dosage  replicated  resistance in  treatment of  other 
reductions are  chromosomal DNA  strains of:  tuberculosis, and in  methylxanthines, 
usually needed  during cell division  ▪ M tuberculosis  prophylactic  enhancing their 
in renal  ● bactericidal  ▪ S aureus  management of  toxicity 
dysfunction  against  ▪ S pneumoniae  neutropenic patients  ● Newer 
Second  ● Have greater activity  except for  susceptible  ● Changes in the  ● In single doses, used  fluoroquinolones 
Generation:  against  moxifloxacin  organisms  sensitivity of the  as alternatives to  (Gemifloxacin, 
● Ciprofloxacin   gram-negative  (eliminated  ● like  target enzymes via  ceftriaxone or  levofloxacin, 
● Ofloxacin   bacteria   partly by  aminoglycosides,  point mutations in the  cefixime in gonorrhea,  moxifloxacin) – 
● Also active against  hepatic  they exhibit post  antibiotic binding  but not currently  prolong QTc 
the gonococcus,  metabolism and  antibiotic effects  regions are also  recommended  interval 
many gram-positive  also by biliary  established to confer  because of resistance  o Should be 
cocci, mycobacteria,  excretion  resistance against  ● Ofloxacin – eradicates  avoided in 
and agents of  ● Moxifloxacin in  specific  Chlamydia  patients with 
atypical pneumonia:  UTI is not  fluoroquinolones.   trachomatis​, 7 day  known QTc 
o Mycoplasma  recommend   ● Mutations in the  course treatment is  prolongation 
pneumoniae  ● Half-lives: 3-8  quinolone  required  and those on 
o Chlamydophila  hours  resistance-determini antiarrhythmi
pneumoniae  ng region of the gyrA  c drugs or 
gene that encodes  drugs that 
Third Generation:  ● Slightly less active  DNA gyrase is  ● Levofloxacin – has an  increase QTc 
● Levofloxacin  than ciprofloxacin  responsible for  activity against most  interval 
● Gemifloxacin  and ofloxacin against  resistance in  organisms associated 
● Moxifloxacin   gram-negative  gonococci.  with 
bacteria but have  community-acquired 
greater activity  pneumonia including: 
against gram-positive  o Chlamydiae 
cocci including:  o Mycoplasma 
o S pneumoniae   o Legionella s​ pecies 
o Some strains of  ● Gemifloxacin and 
enterococci   moxifloxacin – have 
o Methicillin-resist widest spectrum of 
ant  activity includes: 
Staphylococcus  o Gram-positive 
aureus (​ MRSA)  o Gram-negative 
● Commonly referred to  o Atypical 
as “respiratory  pneumonia 
fluoroquinolones”   agents 
● Gemifloxacin and  o Some 
moxifloxacin  anaerobic 
o Most recently  bacteria 
introduced drugs 
o Broadest-spectru
m 
fluoroquinolones 
introduced to 
date 
o With enhanced 
activity against 
anaerobes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Summary Table: Sulfonamides, Trimethoprim, & Fluoroquinolones 
 
 
Subclass  Mechanism of Action  Activity & Clinical uses  Pharmacokinetics & interactions  Toxicities 

Trimethoprim-sulfamethoxazole  ● Synergistic inhibition of  ● Urinary tract, respiratory,  ● Oral, IV   ● Rash, fever, bone marrow 
folic acid synthesis   ear, and sinus infections  ● renal clearance, half-life ~10 h   suppression, 
● The combination is  ● P jiroveci pneumonia  hyperkalemia  
bactericidal by sequential  ● Toxoplasmosis  ● high incidence of adverse 
● nocardiosis  effects in AIDS  

Other folate antagonists  ● Sulfonamides inhibit  ● Simple urinary tract  ● Hepatic and renal clearance and  ● Oral sulfonamides cause 
Sulfisoxazole   dihydropteroate synthase   infections (oral) and topical  extensive plasma protein  GI upsets, acute 
Sulfadiazine  ● Trimethoprim and  in burn or eye infections  binding of sulfonamides  hemolysis in G6PDH 
(+/– pyrimethamine)  pyrimethamine inhibit  (sulfonamides)  (displace bilirubin,  deficiency, possible 
Trimethoprim   dihydrofolate reductase  ● toxoplasmosis (sulfadiazine +  methotrexate, and warfarin)   crystalluria and rash 
Pyrimethamine    pyrimethamine)  (assume 
(+/– sulfadoxine)   ● malaria (sulfadoxine +  cross-hypersensitivity) 
pyrimethamine) 

Ciprofloxacin  ● Inhibits DNA replication via  ● Effective in urogenital, GI  ● Oral, IV  ● GI upsets, CNS effects 
binding to DNA gyrase  tract, and some respiratory  ● mostly renal  (dizziness, headache) 
(gram-negative organisms)  infections  ● clearance, half-life 4 h Oral  ● tendinitis due to effects 
and topoisomerase IV  ● activity versus gonococci  absorption impaired by cations   on cartilage (avoid in 
(gram-positive organisms)  rapidly declining  young children and 
● Bactericidal  ● limited use in tuberculosis   pregnancy)   
● Resistance: see below  

Other fluoroquinolones  ● Mechanism identical to that  ● Norfloxacin and ofloxacin  ● Oral and IV forms of levofloxacin  ● Like ciprofloxacin (see 
Norfloxacin   of ciprofloxacin; bactericidal  used mainly for urinary tract  and moxifloxacin  above)  
Ofloxacin   ● Resistance via changes in  infections  ● mostly renal clearance  ● QTc prolongation 
Levofloxacin   target enzymes (eg DNA  ● levofloxacin and moxifloxacin  moxifloxacin—hepatic)  (levofloxacin, 
Moxifloxacin   gyrase) and possibly  are used for respiratory  ● Long half-lives of gemifloxacin  gemifloxacin, and 
Gemifloxacin   formation of inactivating  infections with enhanced  and moxifloxacin permit  moxifloxacin)  
enzymes   activity against gram-  once-daily dosing   ● Caution with use of group 
positive cocci and atypicals    1A and 3 antiarrhythmics 
  (chlamydia, mycoplasma)