Antibiotics are toxic to bacteria. Sadly, they are also sometimes toxic to humans. There are a range of factors that influence the safety and tolerability of different compounds; it isn't just the drug per se. One factor is age of the patient. The older the patient, the more likely that problems will occur, partly because the ability of the body to metabolize and excrete drugs is diminished or altered. This problem can be exacerbated by the use of concomitant competitive medications such as those metabolized by the cytochrome P450 pathway. In addition to factors such as metabolism and excretion, others include allergic responses as well as the dosage and the concentration of the drug. While it is important to give enough drug for a long enough duration to kill all the bacteria, the more drug that is given, the higher the likelihood of adverse events. That is the background against which health care professionals make decisions on a daily basis—whether or not certain risks are acceptable.

The risk of fatal penicillin anaphylaxis is 0.002% (Table 11). This is a risk that is generally accepted. The risk of fatal chloramphenicol aplasia is 0.005%. The risk of temafloxacin-associated hemolytic uremic syndrome is 0.056%. Co/amoxiclav-related cholestasis occurs at an incidence of 0.002%. Finally, there is the risk of erythromycin-associated cardiac events of less than 1 in 200,000.

Some of these reactions are idiosyncratic reactions of individual patients. Moreover, the mechanisms of antimicrobial toxicity are many and varied. Some adverse events are related to the structure of a compound as is seen with the quinolones.

All of the quinolones have a parental core that comes from quinine (Figure 11), from which are derived two main classes. One is the quinolones, of which oxolinic acid was a very early member; the other is the naphthyridines, of which nalidixic acid is an early example. They differ chemically at one position: the eighth position on the core of the naphthyridines is a nitrogen, but a carbon on the quinolones.

Not all fluoroquinolones are alike when it comes to adverse events or reactions (Table 12). Lomefloxacin, fleroxacin, sparfloxacin, and clinafloxacin may cause phototoxicity. Temafloxacin and trovafloxacin have been associated with significant allergic reactions. In Japan, tosufloxacin has been linked to pulmonary eosinophilia, also allergy-related.

Virtually every fluoroquinolone, when given to certain patients with AIDS and very occasionally when used to treat exacerbations of cystic fibrosis, can result in anaphylaxis. Hypoglycemia has been seen with temafloxacin and clinafloxacin, but not with third-generation quinolones such as grepafloxacin, sparfloxacin, trovafloxacin, and moxifloxacin.

Adverse events have been recognized for certain atoms or moieties at key positions around the molecule. Positions 2, 3, and 4 do not appear to have much effect in terms of adverse events (Figure 12).¹¹ However at position 5, the presence of a halogen atom, an amine, or a methyl group can trigger phototoxic or cardiotoxic problems respectively. At position 6, it has been suggested that a fluorine atom common in all fluoroquinolones may be responsible for nausea or other gastrointestinal effects, but generally this is not a major issue or reason for premature discontinuation.

At the C7 position, moieties such as pyrrolidines interfere with GABA and theophylline to cause marked CNS side effects. At position 8, a halogen such as fluorine, chlorine, or, with some of the early drugs, bromine, can lead to phototoxicity, whereas drugs with a hydrogen or methoxy group at this position do not cause phototoxicity.

There have been various theories as to why there were adverse problems with temafloxacin and trovafloxacin. Both of them had 2-4-difluorophenyl at the C1 position. Alternatively, with trovafloxacin it could also have been due to the naphthyridone core as eosinophilia has also been reported with enoxacin and tosufloxacin. The final reason is still unclear.

What are anticipated fluoroquinolone "class effects?" The five most common adverse reactions include: connective tissue or joint and tendon effects; gastrointestinal adverse reactions; skin reactions; CNS effects; and cardiac events.

Arthropathy, tendonitis, and tendon rupture are seen more often with concomitant medications, such as nonsteroidal anti-inflammatory drugs. A marked incidence was observed with pefloxacin in the United States. Levofloxacin has been associated with 3 incidences in 1000, and rare cases have been reported with ciprofloxacin. It is unclear whether these are antimicrobial-associated; they could also be disease-related.

Gastrointestinal Adverse Reactions

These include diarrhea, nausea, vomiting, and occasional abdominal pain. These tend to occur at a rate of around 3% to 5% and are not usually the cause of drug discontinuation. Pseudomembranous colitis is a very rare event with the fluoroquinolones.

Phototoxicity

The major skin problem with quinolones is phototoxicity, although there is some suggestion of cutaneous rashes associated with some of the newer compounds. Phototoxicity can range from a reddening to a blistering of the skin, which can lead to scarring. This toxic reaction is usually seen when there is a halogen in the 8^th position and tends to occur more frequently in multihalogenated compounds such as fleroxacin. This compound, which has been used in Europe quite extensively, is trifluorinated and has been reported as having 11% phototoxicity. The newer compounds, moxifloxacin and gatifloxacin, as well as ciprofloxacin and levofloxacin are not associated with phototoxicity (Figure 13).

CNS Effects

The CNS effects that are reported with the fluoroquinolones are dizziness, headache, and insomnia. The only quinolone associated with a significant incidence of dizziness was trovafloxacin, with an incidence between 8% and 12%, and a higher occurrence in young females. Most other class members have a rate of dizziness of 2% to 4%.

The European CPMP group has defined four categories of cardiac outliers who may be at risk for a significant event such as tachycardia or similar effects. The two more frequent QTc changes include a 30 to 60 msec shift, and a QTc change of 60 msec or more, whatever the baseline, is considered significant.

To put things in perspective, terfenadine has an average 44 msec QTc prolongation (Figure 14)^12-13 whereas with the fluoroquinolones, moxifloxacin averages 6 msec, levofloxacin and gemifloxacin are at 5 msec, and gatifloxacin is at 3 msec average QTc prolongation. Grepafloxacin and sparfloxacin are between 10 and 15 msecs. Because the quinolones are derived from quinine, which is related to quinidine used in cardiac conditions, there may well be a structural relationship.

In studies of almost 6200 moxifloxacin-treated patients, the typical adverse events were the class effects: nausea, diarrhea, dizziness, abdominal pain, headache, vomiting, dyspepsia, dry mouth, taste perversion, and LFTs. Nausea and diarrhea each occurred at an incidence of 5% (Table 13). In early Phase I studies of moxifloxacin using the IV formulation, a few subjects exhibited a prolonged QTc, in the order of 6 to 9 msec. That prompted more research.

Subsequently, the manufacturer examined moxifloxacin use in over 2600 patients using paired EKGs looking for significant QTc readings of greater than 500 msec or changes greater than 60 msec at maximal serum concentrations. Significant QTc changes were seen in 2.8% of the moxifloxacin-treated patients. Overall, 10% to 14% of patients exhibited some form of QTc change (Table 14). But what were the clinical implications? There were no arrhythmias, ventricular tachycardias, or other malignant arrhythmias, nor were there any cardiac deaths. Overall, adverse drug events were 26%; serious adverse events were less than 1% (Table 15). Premature discontinuations or withdrawals were 3.3%. There were no severe effects seen on liver function.

In early 2000, the manufacturer also looked at post-launch safety experience on 18,500 patients in the United States, 17,000 patients in Germany, and 5300 patients in Spain. Incidence of diarrhea was about 1% in Spain and lower in Germany. Rates of dizziness, nausea, vomiting, and dyspepsia were all very low at 2% to 4%—around one-tenth of the incidences reported in Phase III clinical trials. This is what is typically seen in "real world" studies, while in clinical trials ALL drug-related events are noted.

Again, rates for these side effects for both drugs are considerably lower in real-world experience than standard Phase III clinical trials. Both moxifloxacin [Avelox]and gatifloxacin ]Tequin] have been thoroughly researched and have been shown to be safe and reliable."

1. "AVELOX Tablets (400 mg once daily for five days) were evaluated for the treatment of acute bacterial exacerbation of chronic bronchitis in a large, randomized, double-blind, controlled clinical trial conducted in the US. The trial included 629 patients."
2. "A large, randomized, double-blind, controlled clinical trial was conducted in the US to compare the efficacy of AVELOX Tablets (400 mg once daily) to that of high-dose clarithromycin (500 mg twice daily) in the treatment of patients with clinically and radiologically documented community acquired pneumonia. This study enrolled 474 patients."
3. "In a large, controlled double-blind study conducted in the US, AVELOX (400 mg once daily for ten days) was compared with cefuroxime axetil (250 mg twice daily for ten days) for the treatment of acute bacterial sinusitis. The trial included 457 patients."
4. "An additional non-comparative study was conducted to gather bacteriological data and to evaluate microbiological eradication in adult patients treated with AVELOX 400 mg once daily for seven days. The trial included 336 patients"
5. "Clinical efficacy trials enrolled over 4900 moxifloxacin treated patients, of whom over 4300 patients received the 400 mg dose. Most adverse events reported in moxifloxacin trials were described as mild to moderate in severity and required no treatment. Moxifloxacin was discontinued due to adverse reactions thought to be drug-related in 3.8% of patients."this drug has been "thoroughly researched" and the following results to be considered both safe and effective:

   "Adverse reactions, judged by investigators to be at least possibly drug-related, occurring in greater than or equal to 1% of moxifloxacin treated patients were: nausea (8%), diarrhea (6%), dizziness (3%), headache (2%), abdominal pain (2%), vomiting (2%), taste perversion (1%), abnormal liver function test (1%), and dyspepsia (1%).

   Additional events, judged by investigators to be at least possibly drug-related, that occurred in greater than 0.05% and less than 1% of moxifloxacin treated patients were:

   Body as a Whole: asthenia, moniliasis, pain, malaise, lab test abnormal (not specified), allergic reaction, leg pain, pelvic pain, abdominal pain, back pain, chills, infection, pain, chest pain, hand pain

   Cardiovascular: palpitation, vasodilatation, tachycardia, hypertension, peripheral edema, hypotension

   Central Nervous System: insomnia, nervousness, anxiety, confusion, hallucinations, depersonalization, hypertonia, incoordination, somnolence, tremor, vertigo, paresthesia

   Digestive: dry mouth, constipation, oral moniliasis, anorexia, stomatitis, gastritis, glossitis, gastrointestinal disorder, cholestatic jaundice, GGTP increased

   Hemic And Lymphatic: prothrombin time decrease, prothrombin time increase, thrombocythemia, thrombocytopenia, eosinophilia, leukopenia

   Metabolic And Nutritional: amylase increased, hyperglycemia, hyperlipidemia, lactic dehydrogenase increased

   Musculoskeletal: arthralgia, myalgia

   Respiratory: asthma, dyspnea, cough increased, pneumonia, pharyngitis, rhinitis, sinusitis

   Skin/Appendages: rash, pruritus, sweating, urticaria, dry skin,

   Special Senses: tinnitus, amblyopia

   Urogenital: vaginal moniliasis, vaginitis, cystitis, kidney function abnormal

   LABORATORY CHANGES

   Changes in laboratory parameters, without regard to drug relationship, which are not listed above and which occurred in ³2% of patients and at an incidence greater than in controls included: increases in MCH, neutrophils, WBCs, PT ratio, ionized calcium, chloride, albumin, globulin, bilirubin; decreases in hemoglobin, RBCs, neutrophils, eosinophils, basophils, PT ratio, glucose, pO2, bilirubin and amylase. "

   Having read and responded to Dr. Cohen’s report he continues to state: "Both moxifloxacin [Avelox]and gatifloxacin ]Tequin] have been thoroughly researched and have been shown to be safe and reliable."