378
Review
Vol. 10. No. 4
Eur. J. Clin. Microbio[.Infect. Dis., April 1991, p. 378-383 0934-9723/91/04 0378-06 $ 3.00/0
Side-Effects of Quinolones: Comparisons between Quinolones and Other Antibiotics S.R. N o r r b y
Fluoroquinolones are generally very safe antibiotics which do not cause serious or lifethreatening adverse reactions. The most frequent side-effects are gastrointestinal reactions (nausea, dyspepsia, vomiting ) and CNS reactions such as dizziness, insomnia and headache. Many of the more severe CNS reactions seem to be due to metabolic interaction with theophylline, especially when enoxaiSn is used. Of the potentially serious sideeffects, photoxicity has been reported in varying frequencies with the different fluoroquinolones. Caution is necessary when this group of drugs, especially pefloxacin, is prescribed to patients who will have intensive exposure to UV light during treatment. The finding in juvenile animals of cartilage damage after administration of high doses have resulted in recommendations that fluoroquinolones should not be used in children. Carefully monitored studies should be performed in paediatric patients to assess whether there is a real risk of such adverse reactions.
The older non-fluorinated quinolones, such as naildixie acid, cinoxacin, pipcmidic acid and oxolonic acid, were used mainly for treatment of urinary tract infections. However, the doses of these antibiotics were high, especially of nalidixic acid. This might be one of the reasons for the relatively high frequencies of adverse reactions, particularly central nervous system (CNS) symptoms and also to some extent phototoxicity, associated with this group of antibiotics. Knowledge of the side-effect profile of these older derivatives initiated a careful monitoring of clinical adverse reactions to the new and more active fluoroquinolones when first introduced in the early 1980s (1-4). It also led to relatively extensive requirements for documentation of animal toxicology and safety in patients in addition to the routine tests done with all antibacterial agents. This article provides a short overview of the accumulated knowledge on adverse reactions to fluoroquinolones with special emphasis on the clinical relevance of the animal toxicity of these antibiotics. The title of the overview is somewhat misleading; it will deal with comparisons to other antibiotics only to a minor extent. The reason for that is simple - few systematic and large-scale comparisons between quinolones and other antibiotics have been performed.
Department of Infectious Diseases, University of Lund, Lurid University Hospital, S-22185 Lurid, Sweden.
B o n e and Joint Adverse Reactions Fluoroquinolones are not recommended for use in pregnant women or in children. The recommendation has to a large extent been based on the finding that administration of high doses of quinolones to juvenile animals may produce cartilage damage in weight-bearing joints (4). Most probably such damage is irreversible. As can be seen in Table 1, the incidence of cartilage toxicity varied between quinolones. This could be due either to a true difference between the drugs or to differences in their pharmacokineties. However, it should be noted that in many countries, such as Sweden, nalidixic acid is approved for use in infants and children as well as for administration to pregnant women at dose levels which are high compared to those used of the fluoroquinolones. Comparing norfloxacin (which is not recommended for use in children or pregnant women) and nalidixic acid, the former is administered in a maximal dose of 400 mg twice daily, giving peak plasma concentrations of about 1.5 rag/l, while the latter is administered in a dose of 1 g four times daily with peak plasma concentrations of up to 40 mg/l. In patients treated with quinolones (fluorinated or non-fluorinated), no case of severe cartilage damage has been reported. Published data show that in 268 children treated with nalidixic acid, no clinical or radiological signs of arthropathy were found during treatment or at long-term follow-up (5). Scattered
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379
Table1: Cartilage toxicityof quinolonesinj uvenilerats. Data from reference 4, Quinolone Ciprofloxacin
Dose (mg/kg)
Incidenceof cartilagedegeneration
100 250 5oo
0/20 0/20 1/20
(5 %)
Nalidixicacid
100 250 500
7/20 6•20 8/20
(35 %) (30 %) (40 %)
Norfloxacin
100 250 500
5/20 8/20 9/20
(25 %) (40 %) (45 %)
Otloxacin
100 250 500
1/20 1/20 0/20
(5 %) (5 %)
reports have, however, appeared on arthralgias and myalgias in patients treated with ciprofloxacin, nalidixic acid, norfloxacin and ofloxacin as reviewed by Hooper and Wolfson (2).
varies and seems to depend to a large extent on the methods used for registration of adverse effects in clinical trials. However, the frequencies have generally been rather low as seen in Table 2.
The restrictions of the use of fluoroquinolones in children has in some instances been ignored due to the obvious advantages of this group of antibacterial agents for oral treatment of infections such as pseudomonas osteitis and pulmonary infections in patients with cystic fibrosis. For example, ciprofloxacin has been used in children with cystic fibrosis and so far no reports on arthropathies have appeared in the literature. However, one case of osteoporosis has been observed in a child with cystic fibrosis treated with high doses ofciprofloxacin for a prolonged time (B. Strandvik, personal communication). It seems clear that the risk-benefit ratio is such that carefully controlled trials should be undertaken to evaluate if the fluoroquinolones can be used in children. Such studies are, however, rendered difficult as it is argued that it will take more than 20 years to evaluate possible long-term effects on the cartilage of these compounds (4).
With one of the new quinolones, temafloxacin, a careful registration of adverse events has been performed and the majority of clinical trials performed have been comparative and double-blind, allowing objective monitoring of adverse events. As seen in Table 3, the frequencies of adverse CNS reactions were higher than with the other fluoroquinolones, however this is probably due not to increased neurotoxicity of temafloxacin but rather to the way in which the registration was performed (Abbott, data on file). This was even more obvious when diary cards were used in some studies. The frequencies of headache, dizziness and somnolence reported on such diary cards were 11.6 %, 9.5 % and 4.4 %, respectively, for tcmafloxacin and 13.2 %, 9.2 % and 1.3 %, respectively, in patients on comparative quinolones. Spontaneous reporting of thc same adverse events occurred in 3.t %, 3.3 % and 1.3 %, respectively, of patients treated with temafloxacin and in 2.3 %, 3.0 % and 1.8 %, respectively, of patients on comparative quinolones.
Neurotoxicily
The mechanism(s) by which quinolones affect the CNS are not convincingly elucidated. Several investigators have suggested an interaction with quinolones and the gamma-aminobutyric acid (GABA) receptors (9). However, there are studies indicating that GABA receptor interaction cannot be the only mechanism of quinolonc neurotoxicity (4). Another possibility which should be investigated is that quinolones stimulate production ofinterleukin-2. In animals, inlcrleukin-2 produces sideeffects similar to those seen when high doses of fluoroquinolones are administered. Moreover, in
Quinolones have been associated with a relatively high frequency of non-specific CNS adverse reactions such as insomnia, dizziness, confusion and anxiety (4). In the case of nalidixic acid case reports have appeared documenting convulsions without any other obvious explanation (6-8). Likewise with the fluoroquinolones cases of seizures have been reported but have in many cases been explained by interaction with theophylline (2). The occurrence of more non-specific and less severe CNS reactions
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E u r . J. Clin. M i c r o b i o l . Infect. Dis.
Table 2: CNS adverse reactions with fluoroquinolones. Data from reference 1. Reactions occurring in frequencies below 0.1% are not listed and one patient may have had more than one reaction. Quinolone
Adverse CNS reaction and frequency (%) Total
Insomnia
Headache
Dizziness
Sleepiness
Norfloxacin (n 1540)
1.4
0,1
0.3
0,5
NR
Ciprofloxacin (n = 1690)
1.6
NR
0,3
0,5
NR
Ofloxacin (n = 4785)
0.9
0.3
0.2
0.3
NR
Enoxacin (n = 2530)
1,2
0.1
0.2
0,4
0.2
Pefloxacin (n = 781)
1.1
0.3
0.3
0.1
NR
=
NR = not recorded.
Table 3" CNS reactions to temafloxacin and comparators (Abbott, data on file).
Adverse reaction
Any CNS reaction Dizziness Somnolence Nervousness Insomnia
Temafloxacin (n = 2602)
7.3 % 4.0 % 2.0 % 0.6 % 0.5 %
Comparator drug Quinolone (n = 1169)
Non-quinolone (n = 862)
6,9 % 3.4 % 1.8 % 0.8 % 0.7 %
5,8 % 2,6 % 1,9 % 0.3 % 0.5 %
Table 4: Gastrointestinal adverse reactions in temafloxacin clinical trials. Adverse event
Temafloxacin (n = 2602)
Comparators Quinolones (n = 1169)
Any gastrointestinal event Nausea Nausea and vomiting Dyspepsia Flatulence Diarrhoea Constipation
13.4 % 5.6 % 1.3 % 1.9 % 0.6 % 2.3 % 0.7 %
15.7 % * 7.4 % 1.0 % 1.5 % 1.4 % 3.6 % 0.3 %
Non-quinolones (n = 862) 11.6% 4.9 % 1.2 % 1.2 % 0.7 % 2.7 % 0.7 %
*Significantly higher frequency with quinolone comparators than with non-quinolone comparators.
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vitro, interleukin-2 production is increased in stimulated lymphocytes exposed to fluoroquinolones (A. Forsgren, personal communication).
Ocular Toxicity Opacity of the lens has been found after administration of high doses of rosoxacin to rats or pe floxacin to clogs (4). These findings initiated extensive ophthalmological investigations in a large proportion of patients involved in trials of fluoroquinolones in the USA. In none of these investigations were therapeutic doses of the quinolones found to be related to ophthalmological toxicity.
Gastrointestinal Adverse Reactions The most commonly ret~orted side-effects after oral administration of fluoroquinolones are gastrointestinal. In clinical trials with temafloxacin, such events occurred at a high frequency both among those receiving temafloxacin and those receiving comparative quinoloncs (Table 4). Nausea might be a result of effects of the quinoloncs on the CNS since intravenous ciproftoxaein has been reported to cause nausea at a rather high frequency (10). The likelihood of diarrhoea caused by the fluoroquinolones seems small since these drugs have been extensively used for treatment of bacterial enteritis and are known to markedly reduce the gram-negative aerobic flora while not affecting the anaerobes.
Nephrotoxicity All quinolones are cxcretcd via the kidneys, either as the main route of elimination as for ofloxacin or in combination with liver metabolism and transintestinal excretion as for ciprofloxacin. The quinolones do not seem to affect glomerular or tubular function if they arc dissolved. In animals crystalluria occurs and may causc marked rcnal damage. This phenomenon is related to thc solubility of the quinolones which is lowest at pH 7 to 9 for most of the derivatives. The risk of crystalluria is increased in animals compared to man since they normally have more alkaline urine (4). Crystalluria has not been associated with nephrotoxicity in man, although the phenomenon has been scen in patients and volunteers receiving high doses of ciprofloxacin or norfloxacin (11). However, it seems prudent to warn against the use of high doses of these antibiotics in patients with alkaline urine, for instance those with pyelonephritis caused by Proteus spp.
381
Skin Reactions Hypersensitivity reactions to quinolones have been reported in low frequencies with all fluoroquinolones. Skin rashes seem to occur at frequencies below 1% even if very carefully monitored. Of the older quinolones, nalidixie acid is well known to cause occasional cases of phototoxic skin reactions (12,13). With the fluoroquinolonesvaryingfrequencies of photosensitization have been reported. Clearly, norfloxacin, ofloxacin and ciprofloxacin have caused phototoxicity in only very few patients treated, even when they are exposed to intensive sun, as for example in connection with treatment of or prophylaxis against travellers' diarrhoea in the tropics. Peftoxacin seems to carry the highest risk of phototoxic reactions and should therefore be avoided in patients who will be exposed to intensive UV light. As suggested by Christ and Lehnert (4), for new quinolones the phototoxic potential should be evaluated in volunteers. Such studies are relatively easy to perform and seem to demonstrate differences between various derivatives (J. Ferguson et al., Third International Symposium on New Quinolones, Vancouver, 1990, Abstract no. 455).
Drug Interactions Antacids. Absorption of all fluoroquinolones is reduced if they are co-administered with antacids containing Mg2+ or A13+ as shown by lower peak serum concentrations and lower areas under the serum concentration curves (4). This is probably the result of a chelate binding between the quinolone and the ions, and not of reduced gastric acidity since H2-blockers do not interfere with the absorption of quinolones. Liver Metabolism of Other Drugs. Most quinolones are metabolised in the liver, although to a varying dedegree. They have been shown to interact with several other pharmaceutical drugs. This interaction is probably not due to the cytochrome P-450 system since rat studies have failed to detect any type of interaction with that system (14). It has therefore been suggested that quinolones may inhibit specific enzyme systems (4). Some interactions reported in the literature are summarised in Table 5. Of these, the interactions of enoxacin, but also ciprofloxacin and pefloxacin, with theophylline are clearly important, and regular monitoring of theophylline plasma levels should therefore be performed to avoid a markedly increased risk of theophylline side-effects. Such monitoring does not seem to be necessary with ofloxacin, norfloxacin or temafloxacin. The interaction between caffeine and fluoroquinolones is of
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Eur. J. Clin. Microbiol. Infect. Dis.
Table 5: Interactions in man between fluoroquinolonesand other drugs. Modifiedfrom references 1 and 4.
Quinolone
Otherdrugs
Interaction
Enoxacin
Theophylline and caffeine
Marked decrease of theophylline/caffeine clearance
Pefloxacinand ciprofloxacin Theophylline and caffeine
Moderate decrease of theophylline/ caffeine clearance
Lomefloxacin,norfloxacin and ofloxacin
Theophytlinc andca ffeine
No or minor decrease of theophylline/ caffeineclearance
Enoxacin
Antipyrine
Decreased clearance of antipyrine
Pefloxacin
Cimetidine
Decreased non-renal clearance of pefloxacin
Enoxacin
Warfarin
Decreased clearance of (R)-warfarin
clinical importancc only if enoxacin is used. Of the other interactions, none have proven clinical significance. The effects of enoxacin on warfarin metabolism results in minimal, if any, reduction of the prothrombin time since the most active moiety is (S)warfarin, the metabolism of which is not affected by enoxacin.
Non-SteroidalAnti-lnflammatory Drugs.Treatment of mice with a combination of fcnbufcn and quinolones, especially enoxacin and lomcfloxacin, significantly increased the frequency of convulsions (4). Such interactions, but to a less marked degree, werc also seen with ciprofloxacin, pcfloxacin and norfloxacin while ofloxacin caused no convulsions at doses up to 1200 mg/kg with or without fenbufen 200 mg/kg. In agreement with these experimental findings, cases of clinical convulsions have bccn reported in patients receiving enoxacin and fenbufen concomitantly (4). It is believed that this intcraction is due not to altered liver metabolism of either drug but rather to interaction at the rcccptor [cvcl in the CNS. Interactions between enoxacin and other fluoroquinolones and other non-steroideal anti-inflammatory drugs have been incompletely studied.
Comments
Few new classes of drugs havc been so extensively evaluated for safety as the fluoroquinokmcs. This has partly been due to their unique mode of action inhibition of bacterial DNA gyrase leading to an extensive, and fortunately negative, search for mutagenic activity of the quinolones. Another reason for extensive safety studies has been the somewhat negative record of nalidixic acid with respect to gastrointestinal and CNS adverse reactions. It now seems clear that CNS side-effects
caused by fluoroquinoloncs themselves arc relatively rare and in a majority of cases of mild intensity and always reversible. More severe CNS reactions, especially convulsions, seem in most cases to have been associated with metabolic interaction between the quinolone and theophylline or interaction at the CNS level between the quinolone and fenbufen. Drug interaction is a problem mainly with enoxacin but also to some cxtcnt with pcfloxacin, while ofloxacin, having minimal liver metabolism, represents the other end of the scale. The most common side-effects of fluoroquinolones are gastrointestinal, especially nausea, dyspepsia and vomiting. Again, thcsc reactions are of mild or moderate intensity and can be tolerated by most patients. Since self-treatment or in special risk groups even prophylaxis of travellers' diarrhoea may become important indications for treatment with fluoroquinotones, the risk of phototoxic reactions should be considered. This risk seems to vary and to be highest with pefloxacin. It is easy today to test the phototoxic potential of a drug exposure o f volunteers to UV, and such tests should be required for pre-registration of a quinolone. In conclusion, fluoroquinolones are safe antibiotics which only rarely cause serious side-effects.
References
1. Stahlmann R, Lode H: Safety overview: toxicity, adverse effects and drug interactions. In: Andriole VT (ed): The quinolones. Academic Press, San Diego, CA, t988, p. 201-233. 2. Hooper DC, Wolfson JS: Adverse effects of quino]one antimicrobial agents. In: Wolfson JS, Hooper DC (ed): Quinolone antimicrobial agents. American Society for Microbiology, Washington, DC, 1988, p. 249-271.
Vol. 10, 1991
3. Halkin H: Adverse effects of tile fluoroquinolones. Reviews of Infectious Diseases 1988, 10, Supplement 1: 258-261. 4. Christ W, Lehnert T: Toxicity of the quinolones. In: Ciporin, C, Heifetz CL, Domasala JM (ed): The new generation quinolones. Marcel Dekker, New York, 1990, p. 165-187. 5. Adam D" Use of quinolones in pediatrics. Reviews of Infectious Diseases 1989, 11, Supplement 5: 1113-1116. 6. Islam MA, Sreedharan 1"."Convulsions, hyperglycaemia and glycosuria from an overdose of nalidixic acid. Journal of the American Medical Association 1965, 192: 1000-1001. 7. Ronald AR, Turck M, Petersdord RG" A critical evaluation of nalidixie acid in urinary tract infections. New England Medical Journal 1966, 275: 1081-1089. 8. Fraser AG, Harrower AI)B: Convulsions and hyperglycaemia associated with nalidixic acid. British Medical Journal 1977, 2: 1518.
383
9. Tsuji A, Sato H, Kume Y, Tamai J, Okezaki E, Nagata O, Ka|o H: Inhibitory effects ofquinolone antibacterial agents on gamma-aminobutyricacid binding to receptor sites in rat brain membranes. Antimicrobial Agents and Chemotherapy 1988, 32: 190-194. 10. Thorsteinsson SB, Rahm V, Bergan 1"."Tolerance of intravenous ciprofloxacin. ScandinavianJournal of Infectious Diseases 1989, Supplement 60: 116-119. 11. Thorsteinsson SB, Rohwedder R, Bergan T: Urinary crystal formation upon administration of ciprofloxacin, nalidixic acid, norfloxacin and ofloxacin. Proceedings of the 15th International Congress of Chemotherapy, Istanbul, 1987, p. 1748-1749. 12. Birkett DA, Garretts M, Stebenson CJ: Phototoxic bulleous eruptions due to nalidixic acid. British Journal of Dermatology 1969, 81: 342-344. 13. Epstein JH, Wintroub BU: Photosensitivity due to drugs. Drugs 1985, 30: 42-57. 14. Okazazi O, Kurata T, Tachizawa H: Effect of new quinolones on drug-metabolizing enzyme system of rat hepatic microsomes. Chenaotherapy 1988, 34: 149-154.
Review
Vol. 10. No. 4
Eur. J. Clin. Microbio[.Infect. Dis., April 1991, p. 378-383 0934-9723/91/04 0378-06 $ 3.00/0
Side-Effects of Quinolones: Comparisons between Quinolones and Other Antibiotics S.R. N o r r b y
Fluoroquinolones are generally very safe antibiotics which do not cause serious or lifethreatening adverse reactions. The most frequent side-effects are gastrointestinal reactions (nausea, dyspepsia, vomiting ) and CNS reactions such as dizziness, insomnia and headache. Many of the more severe CNS reactions seem to be due to metabolic interaction with theophylline, especially when enoxaiSn is used. Of the potentially serious sideeffects, photoxicity has been reported in varying frequencies with the different fluoroquinolones. Caution is necessary when this group of drugs, especially pefloxacin, is prescribed to patients who will have intensive exposure to UV light during treatment. The finding in juvenile animals of cartilage damage after administration of high doses have resulted in recommendations that fluoroquinolones should not be used in children. Carefully monitored studies should be performed in paediatric patients to assess whether there is a real risk of such adverse reactions.
The older non-fluorinated quinolones, such as naildixie acid, cinoxacin, pipcmidic acid and oxolonic acid, were used mainly for treatment of urinary tract infections. However, the doses of these antibiotics were high, especially of nalidixic acid. This might be one of the reasons for the relatively high frequencies of adverse reactions, particularly central nervous system (CNS) symptoms and also to some extent phototoxicity, associated with this group of antibiotics. Knowledge of the side-effect profile of these older derivatives initiated a careful monitoring of clinical adverse reactions to the new and more active fluoroquinolones when first introduced in the early 1980s (1-4). It also led to relatively extensive requirements for documentation of animal toxicology and safety in patients in addition to the routine tests done with all antibacterial agents. This article provides a short overview of the accumulated knowledge on adverse reactions to fluoroquinolones with special emphasis on the clinical relevance of the animal toxicity of these antibiotics. The title of the overview is somewhat misleading; it will deal with comparisons to other antibiotics only to a minor extent. The reason for that is simple - few systematic and large-scale comparisons between quinolones and other antibiotics have been performed.
Department of Infectious Diseases, University of Lund, Lurid University Hospital, S-22185 Lurid, Sweden.
B o n e and Joint Adverse Reactions Fluoroquinolones are not recommended for use in pregnant women or in children. The recommendation has to a large extent been based on the finding that administration of high doses of quinolones to juvenile animals may produce cartilage damage in weight-bearing joints (4). Most probably such damage is irreversible. As can be seen in Table 1, the incidence of cartilage toxicity varied between quinolones. This could be due either to a true difference between the drugs or to differences in their pharmacokineties. However, it should be noted that in many countries, such as Sweden, nalidixic acid is approved for use in infants and children as well as for administration to pregnant women at dose levels which are high compared to those used of the fluoroquinolones. Comparing norfloxacin (which is not recommended for use in children or pregnant women) and nalidixic acid, the former is administered in a maximal dose of 400 mg twice daily, giving peak plasma concentrations of about 1.5 rag/l, while the latter is administered in a dose of 1 g four times daily with peak plasma concentrations of up to 40 mg/l. In patients treated with quinolones (fluorinated or non-fluorinated), no case of severe cartilage damage has been reported. Published data show that in 268 children treated with nalidixic acid, no clinical or radiological signs of arthropathy were found during treatment or at long-term follow-up (5). Scattered
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Table1: Cartilage toxicityof quinolonesinj uvenilerats. Data from reference 4, Quinolone Ciprofloxacin
Dose (mg/kg)
Incidenceof cartilagedegeneration
100 250 5oo
0/20 0/20 1/20
(5 %)
Nalidixicacid
100 250 500
7/20 6•20 8/20
(35 %) (30 %) (40 %)
Norfloxacin
100 250 500
5/20 8/20 9/20
(25 %) (40 %) (45 %)
Otloxacin
100 250 500
1/20 1/20 0/20
(5 %) (5 %)
reports have, however, appeared on arthralgias and myalgias in patients treated with ciprofloxacin, nalidixic acid, norfloxacin and ofloxacin as reviewed by Hooper and Wolfson (2).
varies and seems to depend to a large extent on the methods used for registration of adverse effects in clinical trials. However, the frequencies have generally been rather low as seen in Table 2.
The restrictions of the use of fluoroquinolones in children has in some instances been ignored due to the obvious advantages of this group of antibacterial agents for oral treatment of infections such as pseudomonas osteitis and pulmonary infections in patients with cystic fibrosis. For example, ciprofloxacin has been used in children with cystic fibrosis and so far no reports on arthropathies have appeared in the literature. However, one case of osteoporosis has been observed in a child with cystic fibrosis treated with high doses ofciprofloxacin for a prolonged time (B. Strandvik, personal communication). It seems clear that the risk-benefit ratio is such that carefully controlled trials should be undertaken to evaluate if the fluoroquinolones can be used in children. Such studies are, however, rendered difficult as it is argued that it will take more than 20 years to evaluate possible long-term effects on the cartilage of these compounds (4).
With one of the new quinolones, temafloxacin, a careful registration of adverse events has been performed and the majority of clinical trials performed have been comparative and double-blind, allowing objective monitoring of adverse events. As seen in Table 3, the frequencies of adverse CNS reactions were higher than with the other fluoroquinolones, however this is probably due not to increased neurotoxicity of temafloxacin but rather to the way in which the registration was performed (Abbott, data on file). This was even more obvious when diary cards were used in some studies. The frequencies of headache, dizziness and somnolence reported on such diary cards were 11.6 %, 9.5 % and 4.4 %, respectively, for tcmafloxacin and 13.2 %, 9.2 % and 1.3 %, respectively, in patients on comparative quinolones. Spontaneous reporting of thc same adverse events occurred in 3.t %, 3.3 % and 1.3 %, respectively, of patients treated with temafloxacin and in 2.3 %, 3.0 % and 1.8 %, respectively, of patients on comparative quinolones.
Neurotoxicily
The mechanism(s) by which quinolones affect the CNS are not convincingly elucidated. Several investigators have suggested an interaction with quinolones and the gamma-aminobutyric acid (GABA) receptors (9). However, there are studies indicating that GABA receptor interaction cannot be the only mechanism of quinolonc neurotoxicity (4). Another possibility which should be investigated is that quinolones stimulate production ofinterleukin-2. In animals, inlcrleukin-2 produces sideeffects similar to those seen when high doses of fluoroquinolones are administered. Moreover, in
Quinolones have been associated with a relatively high frequency of non-specific CNS adverse reactions such as insomnia, dizziness, confusion and anxiety (4). In the case of nalidixic acid case reports have appeared documenting convulsions without any other obvious explanation (6-8). Likewise with the fluoroquinolones cases of seizures have been reported but have in many cases been explained by interaction with theophylline (2). The occurrence of more non-specific and less severe CNS reactions
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E u r . J. Clin. M i c r o b i o l . Infect. Dis.
Table 2: CNS adverse reactions with fluoroquinolones. Data from reference 1. Reactions occurring in frequencies below 0.1% are not listed and one patient may have had more than one reaction. Quinolone
Adverse CNS reaction and frequency (%) Total
Insomnia
Headache
Dizziness
Sleepiness
Norfloxacin (n 1540)
1.4
0,1
0.3
0,5
NR
Ciprofloxacin (n = 1690)
1.6
NR
0,3
0,5
NR
Ofloxacin (n = 4785)
0.9
0.3
0.2
0.3
NR
Enoxacin (n = 2530)
1,2
0.1
0.2
0,4
0.2
Pefloxacin (n = 781)
1.1
0.3
0.3
0.1
NR
=
NR = not recorded.
Table 3" CNS reactions to temafloxacin and comparators (Abbott, data on file).
Adverse reaction
Any CNS reaction Dizziness Somnolence Nervousness Insomnia
Temafloxacin (n = 2602)
7.3 % 4.0 % 2.0 % 0.6 % 0.5 %
Comparator drug Quinolone (n = 1169)
Non-quinolone (n = 862)
6,9 % 3.4 % 1.8 % 0.8 % 0.7 %
5,8 % 2,6 % 1,9 % 0.3 % 0.5 %
Table 4: Gastrointestinal adverse reactions in temafloxacin clinical trials. Adverse event
Temafloxacin (n = 2602)
Comparators Quinolones (n = 1169)
Any gastrointestinal event Nausea Nausea and vomiting Dyspepsia Flatulence Diarrhoea Constipation
13.4 % 5.6 % 1.3 % 1.9 % 0.6 % 2.3 % 0.7 %
15.7 % * 7.4 % 1.0 % 1.5 % 1.4 % 3.6 % 0.3 %
Non-quinolones (n = 862) 11.6% 4.9 % 1.2 % 1.2 % 0.7 % 2.7 % 0.7 %
*Significantly higher frequency with quinolone comparators than with non-quinolone comparators.
VO1.10,1991
vitro, interleukin-2 production is increased in stimulated lymphocytes exposed to fluoroquinolones (A. Forsgren, personal communication).
Ocular Toxicity Opacity of the lens has been found after administration of high doses of rosoxacin to rats or pe floxacin to clogs (4). These findings initiated extensive ophthalmological investigations in a large proportion of patients involved in trials of fluoroquinolones in the USA. In none of these investigations were therapeutic doses of the quinolones found to be related to ophthalmological toxicity.
Gastrointestinal Adverse Reactions The most commonly ret~orted side-effects after oral administration of fluoroquinolones are gastrointestinal. In clinical trials with temafloxacin, such events occurred at a high frequency both among those receiving temafloxacin and those receiving comparative quinoloncs (Table 4). Nausea might be a result of effects of the quinoloncs on the CNS since intravenous ciproftoxaein has been reported to cause nausea at a rather high frequency (10). The likelihood of diarrhoea caused by the fluoroquinolones seems small since these drugs have been extensively used for treatment of bacterial enteritis and are known to markedly reduce the gram-negative aerobic flora while not affecting the anaerobes.
Nephrotoxicity All quinolones are cxcretcd via the kidneys, either as the main route of elimination as for ofloxacin or in combination with liver metabolism and transintestinal excretion as for ciprofloxacin. The quinolones do not seem to affect glomerular or tubular function if they arc dissolved. In animals crystalluria occurs and may causc marked rcnal damage. This phenomenon is related to thc solubility of the quinolones which is lowest at pH 7 to 9 for most of the derivatives. The risk of crystalluria is increased in animals compared to man since they normally have more alkaline urine (4). Crystalluria has not been associated with nephrotoxicity in man, although the phenomenon has been scen in patients and volunteers receiving high doses of ciprofloxacin or norfloxacin (11). However, it seems prudent to warn against the use of high doses of these antibiotics in patients with alkaline urine, for instance those with pyelonephritis caused by Proteus spp.
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Skin Reactions Hypersensitivity reactions to quinolones have been reported in low frequencies with all fluoroquinolones. Skin rashes seem to occur at frequencies below 1% even if very carefully monitored. Of the older quinolones, nalidixie acid is well known to cause occasional cases of phototoxic skin reactions (12,13). With the fluoroquinolonesvaryingfrequencies of photosensitization have been reported. Clearly, norfloxacin, ofloxacin and ciprofloxacin have caused phototoxicity in only very few patients treated, even when they are exposed to intensive sun, as for example in connection with treatment of or prophylaxis against travellers' diarrhoea in the tropics. Peftoxacin seems to carry the highest risk of phototoxic reactions and should therefore be avoided in patients who will be exposed to intensive UV light. As suggested by Christ and Lehnert (4), for new quinolones the phototoxic potential should be evaluated in volunteers. Such studies are relatively easy to perform and seem to demonstrate differences between various derivatives (J. Ferguson et al., Third International Symposium on New Quinolones, Vancouver, 1990, Abstract no. 455).
Drug Interactions Antacids. Absorption of all fluoroquinolones is reduced if they are co-administered with antacids containing Mg2+ or A13+ as shown by lower peak serum concentrations and lower areas under the serum concentration curves (4). This is probably the result of a chelate binding between the quinolone and the ions, and not of reduced gastric acidity since H2-blockers do not interfere with the absorption of quinolones. Liver Metabolism of Other Drugs. Most quinolones are metabolised in the liver, although to a varying dedegree. They have been shown to interact with several other pharmaceutical drugs. This interaction is probably not due to the cytochrome P-450 system since rat studies have failed to detect any type of interaction with that system (14). It has therefore been suggested that quinolones may inhibit specific enzyme systems (4). Some interactions reported in the literature are summarised in Table 5. Of these, the interactions of enoxacin, but also ciprofloxacin and pefloxacin, with theophylline are clearly important, and regular monitoring of theophylline plasma levels should therefore be performed to avoid a markedly increased risk of theophylline side-effects. Such monitoring does not seem to be necessary with ofloxacin, norfloxacin or temafloxacin. The interaction between caffeine and fluoroquinolones is of
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Eur. J. Clin. Microbiol. Infect. Dis.
Table 5: Interactions in man between fluoroquinolonesand other drugs. Modifiedfrom references 1 and 4.
Quinolone
Otherdrugs
Interaction
Enoxacin
Theophylline and caffeine
Marked decrease of theophylline/caffeine clearance
Pefloxacinand ciprofloxacin Theophylline and caffeine
Moderate decrease of theophylline/ caffeine clearance
Lomefloxacin,norfloxacin and ofloxacin
Theophytlinc andca ffeine
No or minor decrease of theophylline/ caffeineclearance
Enoxacin
Antipyrine
Decreased clearance of antipyrine
Pefloxacin
Cimetidine
Decreased non-renal clearance of pefloxacin
Enoxacin
Warfarin
Decreased clearance of (R)-warfarin
clinical importancc only if enoxacin is used. Of the other interactions, none have proven clinical significance. The effects of enoxacin on warfarin metabolism results in minimal, if any, reduction of the prothrombin time since the most active moiety is (S)warfarin, the metabolism of which is not affected by enoxacin.
Non-SteroidalAnti-lnflammatory Drugs.Treatment of mice with a combination of fcnbufcn and quinolones, especially enoxacin and lomcfloxacin, significantly increased the frequency of convulsions (4). Such interactions, but to a less marked degree, werc also seen with ciprofloxacin, pcfloxacin and norfloxacin while ofloxacin caused no convulsions at doses up to 1200 mg/kg with or without fenbufen 200 mg/kg. In agreement with these experimental findings, cases of clinical convulsions have bccn reported in patients receiving enoxacin and fenbufen concomitantly (4). It is believed that this intcraction is due not to altered liver metabolism of either drug but rather to interaction at the rcccptor [cvcl in the CNS. Interactions between enoxacin and other fluoroquinolones and other non-steroideal anti-inflammatory drugs have been incompletely studied.
Comments
Few new classes of drugs havc been so extensively evaluated for safety as the fluoroquinokmcs. This has partly been due to their unique mode of action inhibition of bacterial DNA gyrase leading to an extensive, and fortunately negative, search for mutagenic activity of the quinolones. Another reason for extensive safety studies has been the somewhat negative record of nalidixic acid with respect to gastrointestinal and CNS adverse reactions. It now seems clear that CNS side-effects
caused by fluoroquinoloncs themselves arc relatively rare and in a majority of cases of mild intensity and always reversible. More severe CNS reactions, especially convulsions, seem in most cases to have been associated with metabolic interaction between the quinolone and theophylline or interaction at the CNS level between the quinolone and fenbufen. Drug interaction is a problem mainly with enoxacin but also to some cxtcnt with pcfloxacin, while ofloxacin, having minimal liver metabolism, represents the other end of the scale. The most common side-effects of fluoroquinolones are gastrointestinal, especially nausea, dyspepsia and vomiting. Again, thcsc reactions are of mild or moderate intensity and can be tolerated by most patients. Since self-treatment or in special risk groups even prophylaxis of travellers' diarrhoea may become important indications for treatment with fluoroquinotones, the risk of phototoxic reactions should be considered. This risk seems to vary and to be highest with pefloxacin. It is easy today to test the phototoxic potential of a drug exposure o f volunteers to UV, and such tests should be required for pre-registration of a quinolone. In conclusion, fluoroquinolones are safe antibiotics which only rarely cause serious side-effects.
References
1. Stahlmann R, Lode H: Safety overview: toxicity, adverse effects and drug interactions. In: Andriole VT (ed): The quinolones. Academic Press, San Diego, CA, t988, p. 201-233. 2. Hooper DC, Wolfson JS: Adverse effects of quino]one antimicrobial agents. In: Wolfson JS, Hooper DC (ed): Quinolone antimicrobial agents. American Society for Microbiology, Washington, DC, 1988, p. 249-271.
Vol. 10, 1991
3. Halkin H: Adverse effects of tile fluoroquinolones. Reviews of Infectious Diseases 1988, 10, Supplement 1: 258-261. 4. Christ W, Lehnert T: Toxicity of the quinolones. In: Ciporin, C, Heifetz CL, Domasala JM (ed): The new generation quinolones. Marcel Dekker, New York, 1990, p. 165-187. 5. Adam D" Use of quinolones in pediatrics. Reviews of Infectious Diseases 1989, 11, Supplement 5: 1113-1116. 6. Islam MA, Sreedharan 1"."Convulsions, hyperglycaemia and glycosuria from an overdose of nalidixic acid. Journal of the American Medical Association 1965, 192: 1000-1001. 7. Ronald AR, Turck M, Petersdord RG" A critical evaluation of nalidixie acid in urinary tract infections. New England Medical Journal 1966, 275: 1081-1089. 8. Fraser AG, Harrower AI)B: Convulsions and hyperglycaemia associated with nalidixic acid. British Medical Journal 1977, 2: 1518.
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9. Tsuji A, Sato H, Kume Y, Tamai J, Okezaki E, Nagata O, Ka|o H: Inhibitory effects ofquinolone antibacterial agents on gamma-aminobutyricacid binding to receptor sites in rat brain membranes. Antimicrobial Agents and Chemotherapy 1988, 32: 190-194. 10. Thorsteinsson SB, Rahm V, Bergan 1"."Tolerance of intravenous ciprofloxacin. ScandinavianJournal of Infectious Diseases 1989, Supplement 60: 116-119. 11. Thorsteinsson SB, Rohwedder R, Bergan T: Urinary crystal formation upon administration of ciprofloxacin, nalidixic acid, norfloxacin and ofloxacin. Proceedings of the 15th International Congress of Chemotherapy, Istanbul, 1987, p. 1748-1749. 12. Birkett DA, Garretts M, Stebenson CJ: Phototoxic bulleous eruptions due to nalidixic acid. British Journal of Dermatology 1969, 81: 342-344. 13. Epstein JH, Wintroub BU: Photosensitivity due to drugs. Drugs 1985, 30: 42-57. 14. Okazazi O, Kurata T, Tachizawa H: Effect of new quinolones on drug-metabolizing enzyme system of rat hepatic microsomes. Chenaotherapy 1988, 34: 149-154.
