Safety issues and drug-drug interactions with commonly used quinolones.

Review

Safety issues and drug--drug interactions with commonly used quinolones 1.

Introduction

2.

Quinolone-induced direct toxicity

3.

Quinolone-induced indirect

Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Korea University on 01/09/15 For personal use only.

toxicity 4.

Drug--drug interactions with quinolones

5.

Transporters

6.

Kidney function

7.

Critically ill

8.

Expert opinion

Antonios Douros†, Katja Grabowski & Ralf Stahlmann Charit e -Universita¨tsmedizin Berlin, Department of Clinical Pharmacology and Toxicology, Berlin, Germany

Introduction: Quinolones are widely used antimicrobials with good efficacy and favourable safety. Recently, forms of quinolone toxicity such as peripheral neuropathy, retinal detachment or QTc-prolongation have attracted attention. Areas covered: Data on different aspects of direct quinolone toxicity are reviewed and consider risk factors and predisposing structural properties. Indirect forms of quinolone toxicity such as Clostridium difficile infections or adverse reactions associated with drug--drug interactions are also discussed. Finally, the role of transporters in the pharmacokinetics of these antimicrobials and their utilisation in critically ill patients are illustrated. A MEDLINE PubMed search for articles published in English from January 1960 to June 2014 was completed using the terms: quinolone, quinolone-induced toxicity, quinolone pharmacokinetics, quinolone and critically ill, drug--drug interactions. Expert opinion: Quinolones exhibit an important component of the antibiotic arsenal. Although several adverse events have been associated with their use, taking into consideration risk factors, contraindications and potential drug--drug interactions can drastically reduce the respective risks. Keywords: drug--drug interactions, quinolones, safety, toxicity Expert Opin. Drug Metab. Toxicol. (2015) 11(1):25-39

1.

Introduction

Quinolones are antimicrobial agents indicated for treatment of a wide range of bacterial infections. Due to their good efficacy and favourable safety profiles, they are the most commonly prescribed antibiotic class in ambulatory care in the US with 25 million prescriptions per year [1]. Since their introduction into clinical practice, quinolones have been associated with various adverse events, and several reviews on this matter were published over the last years [2-4]. Regarding the agents mostly used nowadays, that is, ciprofloxacin, levofloxacin and moxifloxacin (Figure 1), the vast majority of adverse events show low incidence rates, have a mild-to-moderate severity and are self-limiting [5]. They are usually a result of direct toxicity, with heart arrhythmias, neurotoxicity, drug-induced liver injury (DILI) or phototoxicity being known examples, but they can also be indirectly connected to quinolone use, as in case of Clostridium difficile infections (CDI) or drug--drug interactions. Regarding quinolone-associated neurotoxicity, the first respective cases were reported > 30 years ago [6]. Adverse reactions affecting the peripheral or CNS have been integrated in the summaries of product characteristics of all quinolones [7-9]. A modification regarding ‘the serious side effect of peripheral neuropathy’ was required last year by the US FDA. The background was an analysis of the Adverse Event Reporting System (AERS) database which indicated that aspects of 10.1517/17425255.2014.970166 © 2015 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted

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A. Douros et al.

Article highlights. .

.

.


.

.

.

Peripheral neuropathy is a potential adverse reaction of quinolone treatment, and severe forms cannot be ruled out. Postauthorisation safety studies on this matter are needed. The risk of retinal detachment could be slightly increased for high-risk individuals (e.g., ophthalmologic patients, older adults). The arrhythmogenic risk of quinolones can be reduced when known risk factors are considered. Divalent or trivalent cations contained for example in antacids can strongly reduce quinolone absorption and thus compromise their efficacy. As ciprofloxacin is a CYP1A2 inhibitor, coadministration of CYP1A2 substrates such as clozapine or theophylline should proceed with caution. Recent publications suggest an important role for transporters in quinolone pharmacokinetics and toxicity, but further research is required.

This box summarises key points contained in the article.

peripheral neuropathy such as ‘the potential rapid onset or the risk of permanence were not adequately described’ [10]. In this article, we emphasise on quinolone-induced toxicity of the peripheral nervous system (PNS) and provide an update on other important aspects of quinolone safety focusing on ciprofloxacin, levofloxacin and moxifloxacin. Moreover, we point out the importance of drug--drug interactions due to inhibition of metabolism or due to effects on transporters, as well as other pharmacokinetic aspects regarding quinolone toxicity. 2.

Quinolone-induced direct toxicity

Peripheral nervous system Drug-induced peripheral neuropathy is a well-known entity, and in an early review on this topic antiinfectives such as isoniazid or nitrofurantoin were identified as possible causes [11]. The first report on quinolone-associated PNS toxicity was published in 1988, and it concerned a patient with Gramnegative osteomyelitis developing peripheral paraesthesia under ciprofloxacin use [12]. Several other publications followed revealing further symptoms, such as hyperaesthesia, hypoaesthesia, allodynia or even peripheral paresis [13-15]. Small-fibre neuropathy has been proposed as a possible pattern of quinolone-induced PNS toxicity based on clinical and neurophysiological findings of a patient receiving ciprofloxacin due to a urinary tract infection [16]. An overview of case reports and case series of peripheral neuropathy connected to quinolones can be found in Table 1. The incidence of this adverse reaction is probably < 1%, but with almost 30 million people getting annually treated with quinolones in the US alone, the actual number of respective cases could be substantial [10,15]. Recently, a pharmacovigilance study searched for a possible association between quinolones and PNS toxicity 2.1

26

including Guillain--Barre syndrome (GBS), a potentially severe form of acute peripheral polyneuropathy [17]. Cases recorded in the AERS database were examined, and disproportionality analysis was conducted. Significant disproportional reporting of PNS toxicity and GBS was identified for quinolones as a class, whereas within-class analysis revealed signals of PNS toxicity for ciprofloxacin and levofloxacin and a GBS signal for ciprofloxacin [17]. An increased risk of PNS toxicity was also found for antiinfective agents with known neurotoxic risk such as metronidazole, linezolid and nitrofurantoin, thereby supporting the overall validity of the results [17]. In summary, quinolone-induced PNS toxicity deserves further attention as it can affect many patients and even severe courses of the disease cannot be ruled out. However, recent publications reviewing drug-induced peripheral neuropathy have not included quinolones as potentially causative agents [18,19]. Further postauthorisation safety studies are needed in order to quantify the risk of PNS toxicity for these antimicrobials. CNS In contrast to peripheral neuropathy, quinolone-induced toxicity of the CNS is well-established and has been thoroughly reviewed [5,20]. The most common CNS adverse reactions are anxiety, restlessness, nervousness, euphoria or dizziness which have an incidence of up to 2% [9,20]. More severe forms such as seizures or psychiatric events are rare [20,21]. The proconvulsant properties of some quinolones possibly derive from their resemblance to GABA agonists. Therefore, they can displace GABA from its receptors and thus decrease GABA-mediated inhibition in CNS as well as the seizure threshold [20]. Another proposed mechanism for quinoloneinduced seizures is through the activation of the NMDA subtype of the excitatory glutamate receptors. A recent study conducted with mice showed that ciprofloxacin-induced seizures were associated with a significant increase in brain glutamate levels. Furthermore, pre-treatment with a noncompetitive NMDA receptor antagonist led to attenuated seizures [22]. Except for seizures, other severe CNS reactions include delirium, hallucinations, psychosis, mania, encephalopathy, orofacial dyskinesia, action myoclonus, ataxia, dysarthria or chorea [20,21]. Although the underlying pathomechanisms of these adverse effects remain largely unknown, glutamatemediated activation and disruption of the GABA-mediated system were implicated in the development of quinoloneinduced psychosis and orofacial dyskinesia, respectively [23,24]. 2.2

Eye (retinal detachment) A case-control study conducted in 2012 by a Canadian research group showed an increased risk for retinal detachment (RD) associated with oral use of quinolones. Ophthalmologic patients from the British Columbia Linked Health Database served as cases and controls [25]. Current users displayed an adjusted rate ratio of 4.5 (95% CI: 3.56 -- 5.70), 2.3

Expert Opin. Drug Metab. Toxicol. (2015) 11(1)

Safety issues and drug--drug interactions with commonly used quinolones

O

O

F OH

Ciprofloxacin

N

N

The most often used quinolones show a very similar structure

HN


O

O

F

Moxifloxacin

H N

H

OH

N H3C

N O

Arrows indicate the common part of each clinically used quinolone that is required for antibacterial activity. Here, the molecules form chelate complexes with magnesium and other di- or trivalent cations

H

O

O

F

Levofloxacin

OH

N N H3C

N O H

CH3

Figure 1. Structural formulas of widely used quinolones.

whereas for past and recent users no significantly increased risks were found. Further pharmacoepidemiological research was launched after this publication in order to corroborate the alarming findings. Assessment of the respective hazard in the general population was an additional motivation, as ophthalmologic patients possess a higher baseline risk for ocular diseases and adverse drug reactions. Interestingly, a cohort study based on the general adult population in Denmark published 1 year later showed no association between quinolone use and RD [26]. The authors referred to the difference in the baseline risk of the source population between both studies, as the incidence rate of RD in the Canadian cohort was approximately fourteen times higher than the one in the Danish cohort [26]. Furthermore, they underlined the lack of control for potential confounders in the Canadian study such as severe eye trauma, retinopathy, disorders of the vitreous and major eye surgery. Meanwhile, medical literature concerning this matter has significantly expanded, as several retrospective populationbased database studies of various designs have been published (Table 2). The vast majority of them revealed no increased risk associated with quinolone exposure [27-31]. Interestingly, Fife et al. performed both a case-control analysis and a selfcontrolled self series (SCSS) analysis using US patients, with the former design showing a slightly increased risk and the

latter design no risk whatsoever [29]. SCSS analysis is a wellestablished method in pharmacoepidemiology, with only cases being included and each subject serving as his or her own comparator [32]. It permits an improved control for confounding, which is particularly important when health databases are used, as they generally do not fully capture several of the patients’ characteristics. The findings of Fife et al. suggest that the modest association found in case-control studies could be due to confounding. In summary, quinolone-induced RD remains a controversial issue, with findings implicating increased relative risks but altogether low absolute risks for ophthalmologic patients. As discrepancies across different populations were observed, the importance of ethnicity should be further elucidated. Skin Skin reactions induced by quinolones are rare, but they can comprise a wide range of clinical manifestations spanning from mild erythema in sun-exposed areas to various skin pigmentations, purpura or bullus eruptions [5,33,34]. Quinoloneassociated dermatologic adverse reactions and phototoxicity in particular have been reviewed several times in the past [5,35,36]. We know that phototoxicity rate differs between quinolones and that it is strongly influenced by specific features of the molecular structure. Drugs with an additional halogen 2.4


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A. Douros et al.

Table 1. Case reports and case series on quinolone-induced peripheral neuropathy. Quinolone(s) Ciprofloxacin Ciprofloxacin Ciprofloxacin

Ciprofloxacin Ciprofloxacin Levofloxacin Expert Opin. Drug Metab. Toxicol. Downloaded from informahealthcare.com by Korea University on 01/09/15 For personal use only.

Norfloxacin

Indication(s)

Symptom(s)

Osteomyelitis Osteitis Osteitis (n = 2), abscess (n = 2), prostatitis (n = 1) UTI UTI Prostatitis

Ofloxacin Perfloxacin Perfloxacinz

UTI (n = 26), genital infection (n = 3), fever of unknown cause (n = 2) UTI UTI Osteomyelitis

Temafloxacin Trovafloxacin

Sinusitis Pneumonia

Various quinolones ----Levofloxacin (n = 33) ----Ciprofloxacin (n = 11) ----Ofloxacin (n = 6) ----Lomefloxacin (n = 1) ----Trovafloxacin (n = 1)

Sinusitis (n = 13), prostatitis (n = 9), UTI (n = 6), pulmonary infection (n = 6), postabdominal surgery (n = 2) and others

Cases

Ref.

Year

Peripheral paraesthesia Peripheral neuropathy Paraesthesia (n = 5), numbness (n = 2), hypoaesthesia (n = 1), pain (n = 1)

1 1 5

[12] [96] [15]

1988 1993 1996

Peripheral paraesthesia, numbness, weakness Peripheral allodynia Peripheral numbness, burning pain, muscle weakness Paraesthesia (n = 25), numbness (n = 14), pain (n = 8), hyperaesthesia (n = 3), hypoaesthesia (n = 2)

1 1 1

[97] [16] [98]

2002 2013 2011

31

[15]

1996

Guillain--Barr e syndrome Paraesthesia, numbness* Peripheral paraesthesia, progressive muscle weakness Paraesthesia Proximal muscle weakness, demyelinating neuropathy PNS sensory abnormalities (n = 41), PNS motor abnormalities (n = 25)

1 1 1

[99] [100] [13]

1993 1990 1992

1 1

[15] [101]

1996 2000

45

[14]

2001

*Causality of this adverse drug reaction is classified as certain, as neuropathic symptoms occurred again after reexposure to perfloxacin. z Relapse under ofloxacin and ciprofloxacin. PNS: Peripheral nervous system UTI: Urinary tract infection.

atom as substituent at position 8 such as clinafloxacin, fleroxacin, lomefloxacin or sparfloxacin show a considerably increased risk, but their role in clinical practice is meanwhile insignificant [37]. In contrast, drugs with a methoxy substituent at position 8 such as moxifloxacin exhibit a very low toxicity under therapeutic conditions [37]. Taking several studies into consideration, Liu proposed a ‘phototoxicity scale’ for quinolones: lomefloxacin > fleroxacin > enoxacin > pefloxacin > ciprofloxacin > grepafloxacin > gemifloxacin > levofloxacin > norfloxacin > ofloxacin > moxifloxacin [2]. Recently, a Dutch population-based case-control study showed a slight positive association between quinolones and cutaneous melanoma (adjusted odds ratio [OR]: 1.33, 95% CI: 1.01 -- 1.76) [38]. The use of a drug dispensing database eliminated recall bias, a potential problem in case-control studies using questionnaires to assess drug intake. However, possible confounders such as family history of melanoma or exposure to ultraviolet light could not be considered in the analysis, as no such information was available in the examined registries. Moreover, given the well-established structure--phototoxicity relationship of quinolones, separate analyses for different agents would have been useful. The authors concluded that the observed association has to be investigated in further epidemiological studies. Nevertheless, sun-protective behaviour should be followed by patients receiving quinolones not 28

only to avoid acute phototoxicity but also ‘to minimise the risk of possible long-term effects’ [38].

Digestive tract Gastrointestinal symptoms including dyspepsia, nausea, vomiting or diarrhoea are probably the most frequent adverse reaction associated with quinolone use having a prevalence of up to 20% (5;21). Of note, nausea and vomiting can also be a consequence of CNS toxicity. Area postrema is not surrounded by the blood--brain barrier and is thus susceptible to potentially neurotoxic compounds such as quinolones, irrespective of their ability to pass through the blood--brain barrier or not. Diarrhoeas associated with CDI will be separately discussed. Regarding hepatic adverse effects, transient elevations of transaminases are not uncommon, but serious hepatic damage is very rare. Moderately increased hepatotoxic risks were found for moxifloxacin and levofloxacin but not ciprofloxacin in a Canadian population-based case-control study in 2012 [39]. In contrast, a slightly increased likelihood of developing DILI was found for quinolones as a drug class and for ciprofloxacin but not for levofloxacin or moxifloxacin in a recent US study [40]. The conflicting results could be related to age and sex differences between the two study populations, but they also reflect the overall moderate hepatotoxic risk of quinolones. 2.5




Table 2. Retrospective database studies on quinolone-associated retinal detachment. Study design

Source population

Mean age (y)

Female rate (%)

Risk

Ref.

Year

Nested case-control study (4384 RD patients [cases] vs 43,840 non-RD patients [controls]) Cohort study (748,792 quinolone users vs 5,520,446 non-quinolone users) Self-controlled case series (1416 quinolone users with RD serving as their own controls) Cohort study (178,179 quinolone users vs 178,179 amoxicillin users) Case-control study (I) (7844 RD patients [cases] vs 77,654 non-RD patients [controls]){ Case-control study (II) (3059 RD patients [cases] vs 30,230 non-RD patients [controls]){ Self-controlled case series (I) (19,191 quinolone users with RD serving as their own controls) Self controlled case series (II) (6896 quinolone users with RD serving as their own controls) Cohort study (247,073 quinolone users vs 3,303,641 b-lactam users) Cohort study (38,046 quinolones users vs 48,074 macrolide users and 69,079 b-lactam users)

Ophthalmologic patients (Canada)

61.1

41.8

Adjusted rate ratio for current quinolone use: 4.50 (95% CI: 3.56 -- 5.70) Adjusted rate ratio for current quinolone use: 1.29 (95% CI: 0.53 -- 3.13) Adjusted incidence ratio for quinolone use: 1.26 (95% CI: 0.65 -- 2.47) Adjusted hazard ratio for recent quinolone use: 2.07 (95% CI: 1.45 -- 2.96) Adjusted odds ratio for overall quinolone use: 1.17 (95% CI: 1.09 -- 1.26)* Adjusted odds ratio for overall quinolone use: 1.22 (95% CI: 1.09 -- 1.38)z Adjusted rate ratio for quinolone use: 1.13 (95% CI: 0.99 -- 1.29) Adjusted rate ratio for quinolone use: 0.85 (95% CI: 0.66 -- 1.09)

[25]

2012

General population (Denmark)

57.7

62.0

[26]

2013

General population (Hong Kong, Taiwan)

50.4

49.3

[27]

2014

General population (Taiwan)

47.0

59.2

[31]

2014

Ophthalmologic patients (USA)

55.3

40.3

[29]

2014

Ophthalmologic patients (USA)

58.2

40.3

[29]

2014

General population (USA)

52.8

38.0

[29]

2014


54.4

38.1

[29]

2014

General population (UK)

55.1

54.0

30-day hazard ratio for quinolone use: 0.78 (95% CI: 0.11 -- 5.71)

[28]

2014


50.6

61.0

Incidence of rhegmatogenous RD repair for quinolones use in the first year: 0.03% (95% CI 0.01 -- 0.06)§

[30]

2014

*Adjusted odds ratio for current quinolone use: 1.33 (95% CI: 0.99 -- 1.80). z Adjusted odds ratio for current quinolone use: 0.93 (95% CI: 0.48 -- 1.81). § Respective figures for macrolide and b-lactam users were 0.02% (95% CI: 0.01 -- 0.03) and 0.03% (95% CI: 0.02 -- 0.05), respectively. { Replication of the study of Etminan et al. by applying the same design in a different cohort [25]. RD: Retinal detachment.

2.6

Cardiovascular system (QTc prolongation)

The QT interval represents the time from onset of ventricular depolarisation (beginning of the Q wave) to completion of repolarisation (end of the T wave). Due to its dependence on heart rate, a heart-rate-corrected form is used (QTc). QTc prolongation means prolonged repolarisation and thus increased risk of cardiac events including ventricular arrhythmias such as torsade de pointes, or cardiac arrest [41]. In 2011, the Pharmacovigilance Working Party of the European Medicines Agency released a report on

the risk of QTc prolongation for different quinolones, with moxifloxacin being classified as having a respective potential and levofloxacin as having a low respective potential [42]. In a review published earlier this year, ciprofloxacin was suggested as the quinolone with the lowest risk for overall cardiac arrhythmias [43]. Concerning the cardiac safety of moxifloxacin, Haverkamp et al. examined 64 Phase II to IV clinical trials using moxifloxacin 400 mg compared to various antimicrobials [41]. While they corroborated the risk of QTc prolongation for this agent, no


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Divalent cations, e.g. Mg2+, regulate integrin function

Ligand (extracelluar matrix) α

β α

2. Deficit of functionally available magnesium in target tissues

β Integrins on cell surface (α- and β-chain)


1. Quinolones form chelate complexes with magnesium (regulator of intergrin function)

3. Lack of magnesium is not quickly counterbalanced due to poor vascularisation of tendons and cartilage (difference to other tissues) 4. Impairment of cell-matrix interaction 5. Radical formation, apoptosis, tissue damage

Cytoplasma

Figure 2. Magnesium as a regulator of integrin function -- a possible target for quinolone-induced chondro- and tendotoxicity.

increase of cardiac AE under moxifloxacin therapy could be identified. Importantly, several risk factors for quinolone-induced QTc prolongation exist: female sex, cardiac disease, hypokalaemia, hypomagnesaemia, excessive dosing, concomitant intake of other QTc-interval-prolonging drugs, concomitant intake of class Ia (e.g., quinidine) or class III (e.g., amiodarone) antiarrhythmics, history of congenital long QT syndrome [5]. With all these risk factors being easily identifiable through medical history and clinical evaluation, the arrhythmogenic risk of quinolones can be decreased. Glucose homeostasis Over the last years, several case reports, case series and formal epidemiological studies have assessed the potential of quinolones to affect glucose homeostasis, in terms of either hypoglycaemia or hyperglycaemia [5,44-46]. A proposed pathomechanism regarding quinolone-associated hypoglycaemia involves increased insulin release following a dose-dependent blockage of potassium channels in the pancreatic islets [47]. Hyperglycaemia could result from vacuolation of pancreatic b cells, leading to reduced insulin secretion, or from secretion of epinephrine, which is a well-known regulator of serum glucose concentration [48,49]. Recently, a population-based inception cohort study was conducted to investigate the influence of quinolones on the risk of dysglycaemia in diabetic patients [50]. The investigators used data from the Taiwan National Health Insurance, and macrolide antibiotics instead of quinolone non-users served as the reference group, in order to control the possibility of dysglycaemia due to infection, and because no reports on macrolide-associated dysglycaemia exist. Higher risks for hyperglycaemia and hypoglycaemia were found for moxifloxacin compared to levofloxacin, ciprofloxacin and macrolide antibiotics. The adjusted OR and 95% CI of levofloxacin, 2.7

30

ciprofloxacin and moxifloxacin compared to macrolides were 1.75 (1.12 -- 2.73), 1.87 (1.20 -- 2.93) and 2.48 (1.50 -4.12) for hyperglycaemia and 1.79 (1.33 -- 2.42), 1.46 (1.07 -- 2.00) and 2.13 (1.44 -- 3.14) for hypoglycaemia. Moreover, the hypoglycaemic risk was significantly higher with moxifloxacin than with ciprofloxacin. Skeletal system (arthropathy) Connective tissue structures, such as the juvenile articular cartilage, the growth plate or tendons, are potential targets of quinolone toxicity. Impaired function of b1-integrins in these poorly blood-supplied tissues has been postulated as a possible mechanism. b1-integrins are transmembrane glycoproteins responsible for cell--cell and cell--matrix interactions and their function critically depends on magnesium. As most quinolones are chelating compounds which form complexes with this cation, a lack of functionally available magnesium may develop and integrin function can thus be disturbed (Figure 2). In a series of experiments with juvenile rats, it was shown that magnesium deficiency induces cartilage damage that is undistinguishable from quinolone-induced lesions. A detailed review of quinolone-induced arthropathy focusing on mechanistic and clinical data has been published earlier [51]. One consequence of the pathological findings in cartilage of weight-bearing joints in immature animals is the contraindication of these antibacterial agents in children and adolescents. However, data from prospective controlled clinical trials with, for example, ciprofloxacin, gatifloxacin and levofloxacin in children did not indicate a clear-cut risk for joint cartilage damage as observed in rats, dogs, non-human primates and other animals (Table 3). A recent prospective safety study followed paediatric patients who received antibiotics for 12 months. Those who developed antibioticassociated musculoskeletal adverse events were further 2.8



Table 3. Studies with ciprofloxacin, gatifloxacin and levofloxacin assessing the risk of musculoskeletal toxicity in children.


Quinolone

Indication

Ciprofloxacin

Lung infections in patients with cystic fibrosis*

Ciprofloxacin

Complicated urinary tract infection

Gatifloxacin

Recurrent otitis media or acute otitis media treatment failure

Levofloxacin

Pneumonia or recurrent otitis media

Study design, number of children

Age

Musculoskeletal adverse events/time of evaluation

Ref.

Double-blind comparative; 67 patients CIP i.v. (10 mg/kg i.v. q8h for 1 week plus 20 mg/kg p.o. for 3 -- 14 d) 62 patients ceftazidime/ tobramycin i.v. Double-blind comparative; mean treatment duration: 11 d; 335 patients CIP (i.v. and/or orally) 349 cephalosporin (not specified) Pooled data of 867 children from two non-comparative clinical trials and two randomised, investigator-blinded trials with GATI (10 mg/kg once daily) for 10 d versus AC

5 -- 17 year

Arthralgia: CIP: 10% COMP: 11% Time of evaluation: 23 d after completing treatment

[9,102]

1 -- 17 year

[9,102]

Pooled data of 1534 children treated with LEVO (10 mg/kg) from three comparative trials; COMP: 989 children; mean treatment duration: 10 d

6 months to 16 year (mean: 3.2 year)

Incidence of musculoskeletal adverse events within 6 weeks of treatment initiation: 9.3% (6% in the cephalosporin arm); all events resolved within 30 d after treatment Overall incidence: transient arthralgia in 1.4%; incidence of arthralgia in the COMP studies 1.5% (7/453) and 1.3% (4/309) in the AC arm; no evidence of arthropathy at 1-year safety follow-up (n = 671); one 4-year-old girl developed transient Achilles-tendon pain 5 d after GATI therapy Incidence of musculoskeletal AE: (A) End of therapy: 1.6% (LEVO) versus 0.7% (COMP), p = 0.046 (B) Subset of 1340 (LEVO) and 893 (COMP) children studied in long-term surveillance trial: 1 month post-therapy: 1.7% (LEVO) versus 0.8% (COMP), p = 0.063 2 months post-therapy: 2.1% (LEVO) versus 0.9% (COMP), p = 0.038 12 months post-therapy: 3.4% (LEVO) versus 1.8% (COMP), p = 0.025 (C) Subset of 124 (LEVO) and 83 (COMP) children who were potentially at higher risk: 60 months post-therapy Result: no case likely related

6 months to 7 year

[103]

[52,104]

AC: Amoxicillin-clavulanate; CIP: Ciprofloxacin; COMP: Comparator; d: Day; GATI: Gatifloxacin; LEVO: Levofloxacin.

observed for the next 4 years. The investigators found no cases of musculoskeletal toxicity being ‘likely related’ to quinolones (levofloxacin) during the entire follow-up time, and they concluded that ‘risks of cartilage injury with levofloxacin appear to be uncommon, are clinically undetectable during 5 years, or are reversible’ [52].

The velocity of postnatal growth in animals and humans differs considerably. If the assumption is correct that damage to the immature joint cartilage can only occur during growth periods, the low degree of human susceptibility is explainable by the discontinuous growth of children [51]. Nevertheless, it is still generally accepted that quinolones should not be used


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A. Douros et al.

in paediatrics for routine treatment if safe and effective alternatives are available.

3.

Quinolone-induced indirect toxicity

Clostridium difficile infection CDI and in particular infections caused by the virulent strain referred to as the North American Pulsed Field type 1 (NAP1) and PCR ribotype 027 (NAP-1/027) strain are known complications of quinolone treatment [58]. Concerning CDI epidemiology, one of the most important shifts in the last years has been the increased incidence among populations in the community historically classified as ‘low risk’, such as healthy peripartum women, children or antibiotic-naive patients [58]. A population-based cohort study with US patients showed, for example, that community-acquired CDI accounted for 41% of all CDI cases during the study period [59]. This could lead to a further increase of CDI caused by antibiotics used in ambulatory care including quinolones. A recent systematic review followed by a meta-analysis regarding hospital-acquired CDI exhibited increased risks for several antimicrobial classes (Figure 3): third-generation cephalosporins (e.g., cefotaxime) (OR: 3.20, 95% CI: 1.80 -- 5.71), clindamycin (OR: 2.86, 95% CI: 2.04 -4.02), second-generation cephalosporins (e.g., cefuroxime) (OR: 2.23, 95% CI: 1.47 -- 3.37), fourth-generation cephalosporins (e.g., cefepime) (OR: 2.14, 95% CI: 1.30 -- 3.52), carbapenems (OR: 1.84, 95% CI: 1.26 -- 2.68), trimethoprim/ sulphonamides (OR: 1.78, 95% CI: 1.04 -- 3.05), quinolones (OR: 1.66, 95% CI: 1.17 -- 2.35) and penicillin combinations (OR: 1.45, 95% CI: 1.05 -- 2.02). Macrolides, tetracyclines or aminoglycosides showed no increased risks [60]. 3.1


2.9

Tendon

Therapy with quinolones is associated with increased risk for tendinitis and tendon rupture. Evidence for the tendotoxic potential of these drugs comes from in vitro studies with human tendocytes, animal experiments and human observations [53-55]. Since 2008, the FDA requires a Boxed Warning to the prescribing information on the increased risk of tendon damage in patients in all ages taking quinolones. The most common symptom is pain, which may be associated with inflammation or swelling. In some cases, a rupture of the tendon occurred after an asymptomatic latency period of some weeks. Ultrasound and magnetic resonance imaging are useful tools for diagnosis. Especially in the aged patient, the consequences of a tendinopathy requiring prolonged immobilisation may be severe as the case of a healthy 91-year-old man illustrates. He was treated with levofloxacin 500 mg once daily for a presumed bacterial lung infection. His estimated creatinine clearance (CrCl) was 32 ml/min and levofloxacin dose should have possibly been adjusted to his renal insufficiency. Subsequently, he developed bilateral heel pain, oedema and ecchymoses leading to a diagnosis of bilateral complete Achilles tendon rupture. These adverse reactions have obviously been responsible for his subsequent physical and psychological decline and death [56]. Data allowing a substantial determination of the incidence of tendon disorders during quinolone therapy are not available. In a retrospective study, four cases of tendinitis were identified within 400 patients treated with ofloxacin [57]. A possible risk factor for this adverse effect seems to be age over 60 years, but inflammation and tendon rupture have also been described for younger patients. In a compilation of 42 case reports eight patients were younger than 50 years [55]. It is assumed that the pathomechanisms of quinoloneinduced arthropathy and tendinopathy are closely related, although the experimental and clinical data indicate that arthropathy is a problem of the immature organism and tendinopathy mainly occurs in older adults. However, cellular pathological effects observed in cartilage and tendons show many identical features, indicating that quinolone-induced arthropathy and quinolone-induced tendinopathy probably are different clinical manifestations of the same toxic effect on cellular components of connective tissue structures. Time- and concentration-dependent increases of matrix metalloproteinases and the apoptosis marker activated caspase-3 were found in human tendon cells exposed to low, therapeutically relevant quinolone concentrations. Apoptotic changes were confirmed by electron microscopy: the drugs caused typical alterations, such as condensed material in the nucleus, swollen cell organelles, apoptotic bodies and bleb formation at the cell membrane. After exposure of human tendocytes to a combination of a quinolone plus dexamethasone changes occurred more rapidly and were more pronounced [53]. 32

4.

Drug--drug interactions with quinolones

Absorption The enteral absorption of quinolones has been reviewed before [61]. Clinically significant interactions between different members of this antibiotic class and mineral antacids or other oral divalent or trivalent cation-containing drugs (DTCC) are well-established [61]. The first study evaluating the enteral absorption of quinolones in the presence of antacids was already published in 1985. H€offken et al. had found that the concomitant intake of ciprofloxacin and Maalox (Cassella-med GmbH & Co.), a magnesium/aluminium containing antacid, led to a dramatic decrease in peak plasma concentrations and AUC [62]. A retrospective cohort study conducted at two US hospitals examined the impact of concomitant DTCC intake on subsequent development of bacterial resistance against levofloxacin [63]. The investigators identified 3134 patients receiving this quinolone for 3 days or longer. In almost half of the patients (48%), a DTCC was coadministered with at least one levofloxacin dose. When comparing levofloxacin patients on DTCC with levofloxacin patients without DTCC, the former group exhibited a higher risk for subsequent identification of resistant isolates [63]. Those isolates included 4.1



4 3. Generation cephalosporins Clindamycin


Odds ratio

3 2. Generation cephalosporins 4. Generation cephalosporins Trimethoprim/ Carbapenems sulphonamides

2

Quinolones

Penicillin combinations

1

0

Figure 3. Odds ratio of different antimicrobial classes regarding hospital-acquired Clostridium difficile infection [60].

Enterococcus species, coagulase-negative staphylococci, Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Acinetobacter baumannii. The underlying mechanism of this drug--drug interaction is the formation of chelate complexes between antimicrobials and cations. With few exceptions [64-66], quinolones bind to a DNA/gyrase complex via a magnesium ion, making thus the development of new agents with no affinity to magnesium or other divalent or trivalent cations and at the same time uncompromised antibacterial activity challenging. The magnitude of the interaction is stronger when antacids are taken shortly before the quinolone (£ 2 h). Most likely, no clinical relevance exists if the antacid is taken ‡ 2 h after the quinolone. As most antacids can be acquired free of prescription, increased awareness among physicians regarding potential interactions and precise medication history including overthe-counter (OTC) medications is of major importance. CYP Among ciprofloxacin, levofloxacin and moxifloxacin, enzymes of the CYP family have a clinical relevance only regarding the metabolism of ciprofloxacin. Levofloxacin is excreted for the most part unchanged through the kidneys, and moxifloxacin in glucuronidated in the liver. Ciprofloxacin is an inhibitor of CYP1A2, and substrates of this enzyme include antipsychotics (clozapine, olanzapine, haloperidol), antidepressants (amitriptyline, clomipramine, imipramine, duloxetine), cardiovascular medications (triamterene, verapamil, propranolol), the muscle-relaxant tizanidine, the bronchodilator theophylline and caffeine [67]. Coadministration of ciprofloxacin with one of these substances will result in reduced clearance of the latter. A well-studied example is the decreased theophylline clearance during ciprofloxacin treatment. Recently, a 4.2

population-based, nested case-control study including elderly Ontario residents was conducted in order to assess the magnitude of this interaction [68]. The authors observed an almost twofold increase in the risk of theophylline toxicity after receiving ciprofloxacin (adjusted OR: 1.86, 95% CI: 1.18 -2.93). It is plausible that increased theophylline levels could account for some of the CNS effects originally attributed to ciprofloxacin use [36]. Ciprofloxacin-induced CYP1A2 inhibition associated with increased clozapine concentrations has been a further topic of interest [69]. In a pharmacokinetic study from Finland, clozapine patients were randomised and received either ciprofloxacin 250 mg twice daily or placebo. The investigators found only moderately elevated serum levels of this atypical antipsychotic under ciprofloxacin treatment (~ 30% on average) with pronounced interindividual variability. Medication was well tolerated -- increased sedation was reported by one patient in the ciprofloxacin arm and one patient in the placebo arm [70]. Importantly, in case of higher doses of clozapine or ciprofloxacin coadministration may lead to serious adverse reactions such as rhabdomyolysis [71]. The most pronounced drug--drug interactions were observed with tizanidine, an antispastic agent commonly used in the treatment of multiple sclerosis or neurologic sequelae of stroke [72]. Concomitant therapy with ciprofloxacin led to a 10-fold increase in AUC and a sevenfold increase in Cmax of tizanidine in healthy volunteers resulting in enhanced toxicity [73]. Therefore, ciprofloxacin intake is contraindicated in patients receiving tizanidine [9]. Inhibition of CYP3A4 associated with ciprofloxacin use has been implicated in several case reports, with two of them describing patients developing a serotonin syndrome [74,75]. Furthermore, an in vitro study testing the inhibitory potential


33

A. Douros et al.

of quinolones on different CYP enzymes showed a weak inhibition of CYP2C9 due to ciprofloxacin [76]. However, the clinical significance of ciprofloxacin-induced CYP inhibition except for CYP1A2 remains unclear. Quinolones and warfarin Several antimicrobials including quinolones have been reported to affect warfarin pharmacokinetics. Suggested mechanisms for this interaction involve warfarin displacement from protein binding sites, CYP inhibition and disruption of intestinal flora that contributes to vitamin K synthesis [77]. Although data from the medical literature regarding the validity of these assumptions are inconsistent [77], careful monitoring of international normalised ratio in warfarin patients receiving quinolones is currently recommended [7-9]. Baillargeon et al. have recently conducted a case-control study nested within a cohort of 38,762 elderly warfarin users in order to assess the bleeding risk in case of concurrent use of warfarin and antibiotics [78]. The investigators found increased risks for all six specific antibiotic drug classes examined with quinolones showing an adjusted OR of 1.69 (95% CI: 1.09 -- 2.62).


4.3

Quinolones and NSAIDs An increased risk for quinolone-induced seizures when coadministered with NSAIDs has been postulated, and the mechanism suggested is a pharmacodynamic interaction in terms of combined GABA-mediated inhibition. An animal study examining potential synergistic effects found that concomitant administration of the NSAIDs flurbiprofen or ketoprofen (but not ibuprofen or diclofenac) moderately enhanced the convulsant activity of ciprofloxacin, whereas no changes were seen in the convulsant activity of levofloxacin [79]. A pharmacokinetic study with healthy volunteers receiving diclofenac and ciprofloxacin revealed an increase in ciprofloxacin AUC (from 12.93 ± 2.47 mg/h/l to 18.92 ± 5.845 mg/h/ l) and Cmax (from 2.48 ± 0.33 mg/l to 3.91 ± 0.8 mg/l) as well as reduced total body clearance [80]. In the summary of product characteristics of levofloxacin but not of ciprofloxacin or moxifloxacin caution regarding the combination with NSAIDs due to the potential lowering of seizure threshold is suggested [7-9]. 4.4

5.

renal elimination, in intestinal secretion or in CNS distribution [20,81]. Recently, a case report presented a patient who developed generalised seizures shortly after a levofloxacin infusion without having any predisposing factors or concomitant interacting therapies [82]. As levofloxacin is a quinolone with generally low CNS toxicity, the investigators suspected the existence of genetic modifications affecting levofloxacin concentration in brain tissue. Therefore, they conducted a genotypic analysis in genes coding for P-gp and breast cancer resistance protein, another ABC efflux transporter, as they are both expressed in blood--brain barrier and have a substrate specificity for quinolones. With both genes showing functional alterations, it was hypothesised that an impaired activity of these efflux mechanisms could have led to a higher-thanexpected penetration of the drug into the brain [82]. 6.

Renal elimination displays the main route of excretion for levofloxacin, with > 85% of the substance being detected in urine. Therefore, in patients with renal insufficiency or undergoing chronic haemodialysis lower doses are necessary to avoid accumulation of the drug and thus enhanced toxicity. According to the summary of product characteristics of levofloxacin, half of the normal dose is recommended if CrCl is < 50 ml /min, and quarter of the normal dose is recommended if CrCl is < 20 ml/min or in patients receiving haemodialysis [7]. Regarding continuous haemofiltration, relatively high doses are recommended, although as the drug can be removed to a significant amount during this procedure [83]. Ciprofloxacin exhibits a higher percentage of non-renal elimination than levofloxacin, with the hepatobiliary route accounting for > 30% of drug excretion. However, as the possibility of drug accumulation in case of renal insufficiency or haemodialysis cannot be excluded, a dose reduction in respective patients is also recommended [9]. Finally, moxifloxacin undergoes Phase II metabolism and is predominantly eliminated through the hepatobiliary route (~ 80%). It shows similar pharmacokinetics in healthy patients as in patients with reduced kidney clearance or renal replacement therapy. Therefore, no dosage modification is needed [8].

Transporters 7.

During the last years, first attempts were undertaken to elucidate the significance of various transporters in quinolone pharmacokinetics. In a comprehensive review in 2012, Mulgaonkar et al. underlined the possibility that absorption, distribution and elimination of quinolones could be affected by active transport mechanisms, since these antimicrobial agents exist as charged molecules in blood and urine [81]. For example, members of the ATP-binding cassette (ABC) superfamily such as the efflux transporter P-glycoprotein (P-gp) might be involved in renal tubular secretion and thus 34

Kidney function

Critically ill

Antibiotic therapy in critically ill patients is challenging, as several factors affecting drug pharmacokinetics may show considerable variations. Concerning renal function, both hypofiltration (in case of renal dysfunction) and hyperfiltration (in case of hyperdynamic states with high cardiac output) are possible. For drugs predominantly eliminated through the kidneys such as levofloxacin, this could result in increased or decreased plasma concentrations, respectively. Consistent with this hypothesis, a pharmacokinetic study on intensive




case unit (ICU) patients found CrCl to be the most reliable predictor of variability in total levofloxacin clearance [84]. Higher volumes of distribution due to altered fluid balance in case of aggressive rehydration treatment, increased disease severity or capillary leakage can lead to reduced drug plasma concentrations in critically ill patients, thereby increasing the risk of treatment failure or development of bacterial resistance. However, the fact that quinolones already possess high volumes of distribution make them less susceptible to such changes in comparison to b-lactams, aminoglycosides or other hydrophilic antibiotics [85]. An advantage of quinolones in the ICU setting is their good tissue penetration, allowing them to reach sites where extracellular pathogens accumulate such as the epithelial lining fluid [85]. Furthermore, they show good antimicrobial activity against intracellular pathogens such as Legionella pneumophila, a common cause of severe pneumonia requiring ICU admission [86]. Specific drug recommendations for quinolones do not exist for critically ill patients, but several studies have shown suboptimal concentrations of these drugs when standard dosing regimens were used [87-89]. This underlines the need for individualised treatment in this setting including dose adjustment based on therapeutic drug monitoring. 8.

Expert opinion

Since 2000, only two new classes of systemic antibiotics were introduced to the market for human use [90]. This so-called ‘innovation gap’ underlines the importance of already approved agents with high efficacy and favourable safety such as ciprofloxacin, levofloxacin and moxifloxacin. Quinolones show good antimicrobial activity against Gram-positive, Gram-negative and atypical pathogens. Therefore, they can be used in the setting of various bacterial infections affecting the urinary tract, lung, gastrointestinal tract, bone or soft tissue. The incidence of different adverse reactions is not higher than for other antibiotics, and the risk of serious toxicity such as DILI or acute kidney injury is low [39,40,91]. Quinolones should not be used for routine treatment in children if safe and effective alternatives are available. However, the results of a recent prospective study examining levofloxacininduced arthropathy in children are reassuring, showing no musculoskeletal adverse events likely related to levofloxacin use during 5 years of follow-up [52]. A distressing development of the last years is the enhanced quinolone resistance. Several mechanisms responsible for this phenomenon have been identified including mutations in genes encoding quinolone targets (e.g., type II topoisomerases), plasmid-mediated transmission of respective genes between bacteria, changes in membrane permeability or overexpression of efflux systems resulting in an active drug removal from the pathogen’s cell [92]. In particular, E. coli and Klebsiella pneumoniae species have been reported to show considerable increases in resistance rates. Not surprisingly, the decline of bacterial susceptibility to quinolones exhibits a high correlation

with the frequency of their use. Another relevant factor is, however, lower-than-adequate drug dosing, indicating that merely restricting quinolone use would probably not suffice to minimise resistance [92]. Hughes et al. argued in the same vein in a recent review that a significant part of overall antibioticresistance evolution may occur when bacteria are exposed to non-lethal drug concentrations [93]. The importance of appropriate antimicrobial dosing further highlights the need to avoid comedications leading to lower serum quinolone levels such as the widely used antacids. A current internet-based survey from Denmark examined the utilisation patterns of gastrointestinal OTC medications in a cohort representative of the Danish adult general population. Among the 9390 participants, 2164 (23%) reported using antacids within the past year [94]. In an older Canadian study that included several hundred patients from a university-based family-practice, 51.1% of the cohort had taken antacids at least once in the previous 6 months and 10.9% of the cohort were taking antacids on a daily basis. As the investigators commented, the fact that these OTC drugs were mentioned in only every second chart of respective users indicates that ‘patients do not consider antacids as medication their doctor should know they are taking’ [95]. Since mild dyspepsia is a common adverse event of quinolones, and antacids enjoy such widespread consumption, patient information by treating physicians regarding possible interactions cannot be emphasised enough. Over the last years, efforts to develop new quinolones with improved efficacy and safety have not ceased and several compounds are being currently tested. Nemonoxacin exhibited potent activity against pathogens involved in communityacquired pneumonia in preclinical, Phase I and Phase II clinical trials [90]. Recently, a Phase III trial was completed, but the results have not been published yet (http://clinicaltrials.gov). Other agents such as JNJ-Q2 or delafloxacin were mainly evaluated in the therapy of acute or chronic skin and skin structure infections [90]. For all three new quinolones enhanced activity against Gram-positive bacteria has been implicated. Moreover, JNJ-Q2 may lead to lower rates of spontaneous development of resistance in Streptococcus pneumoniae, methicillin-resistant S. aureus and E. coli compared to other members of this drug class [90]. In summary, despite increasing resistance rates especially concerning Gram-negative pathogens, quinolones still represent a very useful part of the antibiotic arsenal. They exhibit a broad antibacterial spectrum combined with favourable pharmacokinetics, and safety issues usually play a minor role if contraindications, risk factors and potential drug--drug interactions are taken into consideration.

Declaration of interest A Douros and K Grabowski have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject


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Affiliation

Antonios Douros† MD, Katja Grabowski & Ralf Stahlmann † Author for correspondence Charite-Universita¨tsmedizin Berlin, Department of Clinical Pharmacology and Toxicology, Chariteplatz 1, 10117 Berlin, Germany Tel: +49 30 450 525 306; Fax: +49 30 7 525 112; E-mail: [email protected]

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Interactions of some commonly used drugs with human α-thrombin.

Drug interactions with quinolones.

Safety profile of the quinolones.

Commonly used endocrine drugs.

Commonly used gastrointestinal drugs.

Comparing NICU teamwork and safety climate across two commonly used survey instruments.

Safety evaluation of metal exposure from commonly used moisturizing and skin-lightening creams in Nigeria.

Sugar content, cariogenicity, and dental concerns with commonly used medications.

Deterioration of organic packing materials commonly used in air biofiltration: effect of VOC-packing interactions.

Actual tracheal oxygen concentrations with commonly used oxygen equipment.

Comparison of two commonly used standard IVGTTs.

Neurotoxicity of commonly used hepatic drugs.

Interpretation of commonly used statistical regression models.

Commonly used drugs in hematologic disorders.

The microdose problem and the most commonly used metals.

Commonly used stimulants: Sleep problems, dependence and psychological distress.

Sodium content and neutralising capacity of some commonly used antacids.

Compatibility study between acetylcysteine and some commonly used tablet excipients.

Stable radicals from commonly used precursors trichlorosilane and diphenylchlorophosphine.

MRI information for commonly used otologic implants: review and update.

Vitamin B6 safety issues.

Dysglycemia associated with quinolones.

Intrarenal pressure and irrigation flow with commonly used ureteric access sheaths and instruments.

Evaluation of Safety in Exceeding Maximum Adult Doses of Commonly Used Second-Generation Antiepileptic Drugs in Pediatric Patients.