68. Sulfonamides, trimethoprim, pyrimethamine. Fluoroquinolones

Sulphonamides and diaminopyrimidines

Sulphonamides and diaminopyrimidines both act on the folic acid metabolism of bacteria and parasites. They potentiate each other’s actions and are therefore almost always sold in fixed combinations. Here are the most important combinations:

Sulphonamide	Diaminopyrimidines	Name of combination	Effective against
Sulfamethoxazole (SMX)	Trimethoprim (TMP)	Co-trimoxazole or Bactrim® or TMP/SMX	Bacteria, pneumocystis
Sulfadiazine	Pyrimethamine	–	Toxoplasmosis
Sulfadoxine	Pyrimethamine	SP	Malaria

Silver-sulfadiazine is used topically to prevent wound infections of skin burns.

Sulfasalazine is also a sulphonamide, but it’s used to treat IBD and is described in that topic.

Sulphonamides and diaminopyrimidines are old drugs, so resistance to the individual ones are widespread. Bacteria have mutated their enzymes to have lower affinity to the drugs, and they’ve changed surface proteins so that the entry of the drug into the pathogen is decreased. However, by combining these drugs this resistance can be overcome. On their own these drugs are bacteriostatic, but the combinations are bactericidal.

You might hear, especially from Professor Pintér, that sulphonamides are not technically antibiotics because according to some (old) definitions a compound must be natural or semisynthetic to qualify as an antibiotic. Sulphonamides and imidazoles like metronidazole are synthetic compounds and should, according to her, be classified as antimicrobials or chemotherapeutical agents rather than antibiotics.

Mechanism of action

Like human cells, bacterial cells need folic acid to synthesize thymidine and therefore DNA. Unlike human cells, bacterial cells synthesize folic acid themselves and can’t take it up from the environment. Inhibition of folic acid metabolism in bacteria has a bacteriostatic effect.

Sulphonamides inhibit dihydropteroate synthase (DHPS), an enzyme essential for the bacterial folic acid synthesis, by being similar in structure to the enzyme’s substrate.

Diaminopyrimidines inhibit bacterial dihydrofolic acid reductase, the next enzyme in the bacterial folic acid synthesis, which converts DHF to THF.

Note that humans also have dihydrofolic acid reductase, but it is structurally different than the bacterial enzyme. The human form is the target of methotrexate. Proguanil inhibits the malarial form of the enzyme and is used as malaria prophylaxis.

Because sulphonamides and diaminopyrimidines inhibit subsequent reactions of folic acid metabolism they potentiate the effects of each other. This effect is called synergism.

Pharmacokinetics and dosing

All are given orally (sulfasalazine is too but is not absorbed). These drugs have excellent distribution, especially into the lungs, while also crossing the blood-brain barrier and the placenta. They have strong plasma protein binding.

Most sulphonamides and diaminopyrimidines are metabolised in the liver and excreted by the kidneys. Those drugs given in combination have similar half-lives. Both sulfamethoxazole and trimethoprim have a half-life of 11 hours, for example.

Side effects

Sulphonamides like penicillins are prone to causing allergic reactions like skin rashes and photosensitivity but also more severe ones like glomerulonephritis and Stevens-Johnsons syndrome (1 per 10 million). Excreted sulphonamides can crystallise in the urine, causing crystalluria which makes the urine cloudy. It is usually benign. People with G6PD deficiency can develop haemolytic anaemia. Due to the extensive plasma protein binding it can displace indirect bilirubin in infants, causing kernicterus.

Side effects related to diaminopyrimidines are similar to those of folic acid deficiency, including megaloblastic anaemia, leukopenia and granulocytopenia. These side effects are avoided by supplementation with leucovorin.

Contraindications

Known allergy. Last trimester of pregnancy, first weeks of life.

Fluoroquinolones

Like cephalosporins these drugs are classified according to their generation. Here are the most important:

• 1. generation
  • Norfloxacin
• 2. generation
  • Ciprofloxacin
  • Ofloxacin
• 3. generation
  • Levofloxacin
• 4. generation
  • Moxifloxacin
  • Gemifloxacin

There was a generation 0, which were not fluorinated and were therefore quinolones. They are carcinogenic (amongst other things) and are therefore no longer used. Nalidixic acid and oxolinic acid belong to this generation.

3rd and 4th generation fluoroquinolones are often called respiratory fluoroquinolones, because they’re effective against streptococci (which often cause typical pneumonia) and atypical bacteria (which often cause atypical pneumonia)

Mechanism of action

Fluoroquinolones inhibit DNA topoisomerase II, also called DNA gyrase, and DNA topoisomerase IV. This makes them bactericidal.

Pharmacokinetics and dosing

Most fluoroquinolones have 100% oral bioavailability, so most (all of those mentioned) are taken orally. Some (cipro, oflo and levo) can be given IV as well. They’re widely distributed into the extracellular and intracellular space but does not penetrate the CNS.

Ciprofloxacin and norfloxacin is eliminated partly by liver metabolism and partly unchanged by renal excretion. Moxifloxacin is eliminated by biliary excretion, making it unfit for treating urinary tract infections.

Clinical use and adverse effects

Fluoroquinolones have wide antibacterial spectra, especially against bacteria usually infecting the respiratory system. They also have favourable pharmacokinetics and are cheap, so they’re widely prescribed. However, they have the largest ecological shadow of all antimicrobials. The term ecological shadow, or eco-shadow refers to the ecological impact of antibiotics. Antibiotics with a large eco-shadow remain for a long time in the environment, increasing the risk of bacteria becoming resistant, among other things. The eco-shadow of fluoroquinolones is so large because they have wide antibacterial spectra and are excreted unchanged by the kidneys. They are also poorly degraded by the environment.

In addition to the above, fluoroquinolones have potentially long-lasting and fatal side effects. In 2018 the FDA and the European Medicines Agency (EMA) released reviews of side effects of fluoroquinolone therapy. These include tendinitis, tendon rupture, QT prolongation, neuropathies, depression, aortic dissection and more. Tendon damage can occur within 48 hours of starting fluoroquinolone treatment but can also occur even months after stopping the treatment. Fluoroquinolones damage growing cartilages and should therefore be avoided in pregnant women and children.

The reviews by the FDA and EMA recommend that the use of fluoroquinolones should be severely limited and that their use should be limited to acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis and uncomplicated urinary tract infections, but only when no other treatment options are available.