In vitro laboratory testing
Nalidixic acid was initially used by clinical laboratories as a surrogate agent to detect Salmonella with FQ resistance due to target site mutations (gyrA and parC). However, the situation has become more complex with the discovery of PMQR. Strains with PMQR may be difficult to detect because the resulting MIC elevations are typically more modest than those associated with QRDR mutations and do not confer resistance to nalidixic acid. (17,18) Low-level FQ resistance is associated with poorer clinical outcomes. (18,19) Moreover, FQ treatment of bacteria with low level resistance may promote the development of high level resistance. (18,20) CLSI and EUCAST recently lowered their susceptibility breakpoints for Salmonella, but surveillance data and pharmacokinetic/pharmacodynamic analyses suggest the FQ breakpoints for other Enterobacteriaceae may still be too high. (18,19)
Adverse Reactions and FDA warning labels
Several FQ have been removed from the market due to rare but very serious adverse reactions. grepafloxacin was removed from the market following fatal cardiovascular events and cases of torsades de pointes (specific form of polymorphic ventricular tachycardia); trovafloxacin was removed from the market due to reports of liver failure, while gatifloxacin was withdrawn from the market because it was found to be associated with symptomatic hypoglycemia and hyperglycemia. (3)
Common adverse effects associated with FQ include gastrointestinal and central nervous system toxicities. Other adverse effects include: rashes and other allergic reactions, tendinitis and tendon rupture, QT prolongation, hypoglycemia and hyperglycemia, hematologic toxicity, and retinal detachment. (3,21)
FQ should not be given together with other drugs known to prolong the QT interval as these interactions may increase the risk of torsades de pointes and sudden death.
FQ labelling has for many years had warnings about the risks for tendonitis, tendon rupture, central nervous system effects, peripheral neuropathy, myasthenia gravis exacerbation, QT prolongation and torsades de pointes, photosensitivity, and hypersensitivity.
More recently the FDA added black box warnings and took the unprecedented step of recommending against FQ for some common infections. An FDA panel advised that serious side effects associated with FQ generally outweigh the benefits for patients with sinusitis, acute exacerbation of chronic bronchitis (AECB), and uncomplicated urinary tract infections. For patients with these conditions, FQ should be reserved for those who do not have alternative treatment options. (22)
One of the FDA panel members was quoted “Very rare side effects will be magnified when we abuse an antibiotic millions of times.” (22)