QTc prolongation during ciprofloxacin and fluconazole combination therapy: prevalence and associated risk factors

Abstract

Aim(s)

Ciprofloxacin and fluconazole combination therapy is frequently used as prophylaxis for, and treatment of, infections in patients with haematological malignancies. However, both drugs are known to prolong the heart rate‐corrected QT (QTc) interval, which is a serious risk factor for torsade de pointes (TdP). Therefore, the aim of the current study was to assess the prevalence of QTc prolongation during ciprofloxacin and fluconazole use. The secondary objective was to determine associated risk factors of QTc prolongation in these patients.

Methods

A prospective observational study was performed in patients admitted to the Erasmus University Medical Centre and treated with ciprofloxacin and fluconazole. A 12‐lead electrocardiogram (ECG) was recorded at the estimated time to peak concentration (T_max) for the last added drug. The main outcome was the proportion of patients with QTc prolongation during treatment. Data on the following potential risk factors were collected: patient characteristics, serum electrolyte levels, dosage of ciprofloxacin and fluconazole, renal and liver function and concomitant use of other QTc‐prolonging drugs and cytochrome P450 3A4 inhibitors.

Results

A total of 170 patients were included, of whom 149 (87.6%) were treated for haematological malignancies. The prevalence of QTc prolongation was 4.7%. No risk factors were found to be associated with QTc prolongation. The QTc interval increased by 10.7 ms [95% confidence interval (CI) 7.2, 14.1 ms] during ciprofloxacin and fluconazole combination therapy.

Conclusion

The prevalence of QTc prolongation in patients using ciprofloxacin and fluconazole is low compared with the prevalence in the general population, which varies from 5% to 11%. In addition, no risk factors were found. Given the low prevalence, routine ECG monitoring in patients on this therapy should be reconsidered.

What is Already Known about this Subject

• Ciprofloxacin and fluconazole are both known to prolong the QTc interval and are included in the CredibleMeds® QT list of drugs with a known risk of TdP by the Arizona Centre for Education and Research on Therapeutics (AZCERT).

• The current guidelines of the American Heart Association and the American College of Cardiology Foundation require routine electrocardiogram (ECG) monitoring for patients using drugs with a known risk of TdP.

• The exact risk of this drug–drug interaction (DDI) in developing QTc prolongation or TdP is not known.

What this Study Adds

• The prevalence of QTc prolongation in patients using ciprofloxacin and fluconazole combination therapy is low (4.7%), and the QTc interval did not rise to abnormal levels above 500 ms in any of these patients.

• No risk factors were found to be associated with QTc prolongation in these patients.

• Routine ECG monitoring in patients using ciprofloxacin and fluconazole combination therapy should be reconsidered.

Introduction

A combination of ciprofloxacin and fluconazole is frequently used as prophylaxis for, and treatment of, infections in patients with haematological malignancies. This drug combination decreases the severity of bacterial and fungal infections and is incorporated into the guidelines on the use of antimicrobial agents in neutropenic cancer patients 1, 2, 3, 4, 5. Both drugs are also known to prolong the QT interval 6, 7, 8. QT or heart rate‐corrected QT (QTc) interval prolongation is a serious risk factor for the development of ventricular tachyarrhythmia such as TdP, which can lead to sudden cardiac death 9, 10, 11, 12. Several other risk factors play a key role in developing QTc prolongation – for example, hypokalaemia, hypomagnesaemia, heart diseases, renal impairment and unmodifiable risk factors such as an older age and female gender 10, 13, 14, 15, 16. As haematology patients frequently encounter these comorbidities during chemotherapy, they might be at increased risk.

Ciprofloxacin, a broad‐spectrum second‐generation fluoroquinolone antibiotic, blocks the outward potassium current (I_kr) in the cardiac myocyte. A delay in the efflux of potassium in the myocyte will delay ventricular repolarization, which ultimately leads to a prolonged QTc interval 8, 17, 18. Fluconazole, a triazole antifungal agent, seems to prolong the QTc interval via the same mechanism. In addition, fluconazole inhibits cytochrome P450 (CYP) 3A4, resulting in increased levels of QTc‐prolonging drugs that are metabolized by CYP3A4 8, 19.

The actual QTc‐prolonging effect and risk of TdP associated with these drugs have not been studied extensively, apart from several case reports 20, 21, 22, 23, 24, 25, 26. Furthermore, most studies on drug‐induced QTc prolongation have focused on the risk of QTc prolongation and TdP when using only one QTc‐prolonging drug. It is not known whether combining two or more QTc‐prolonging drugs leads to a cumulative or perhaps even synergistic prolongation of the QTc interval 13, 27, 28.

Zeuli et al. 29 studied the effect of fluoroquinolone and azole therapy on QTc prolongation in 94 haematology patients. In this retrospective study, 21 (22%) patients had clinically significant changes from baseline in the QTc interval, and several associated risk factors were found, such as hypokalaemia (P = 0.03) and a left ventricular ejection fraction of <55% (P = 0.02). Zeuli et al. recommended that these haematology patients are monitored extensively 29. In line with this study, ciprofloxacin has recently been added to the list of QTc‐prolonging drugs with a known risk of TdP according to the CredibleMeds® QT drug list by the AZCERT 7. However, several studies have suggested that ciprofloxacin is the least ‘torsadogenic’ of all fluoroquinolones, as indicated by the paucity of reported TdP cases and its high human Ether‐à‐go‐go‐Related Gene (hERG) half‐maximal inhibitory concentration (IC₅₀) values. High hERG IC₅₀ values illustrate a low association with clinical QTc prolongation 8, 21, 30. Frothingham 30 showed in a retrospective database analysis that the occurrence of TdP was lowest with ciprofloxacin (0.3 cases/10 million prescriptions) compared with other fluoroquinolones. Additionally, a large bi‐national cohort study showed that an increased risk of serious arrhythmia in the general adult population was not associated with the use of oral fluoroquinolones. Ciprofloxacin was the most commonly used oral fluoroquinolone (82.6%). This raises the question of whether the medication safety alerts generated by the electronic prescribing system should lead to electrocardiogram (ECG) monitoring in patients receiving treatment with ciprofloxacin and fluconazole, as a pathophysiological association might not even be present. If not, these alerts only contribute to alert fatigue, potentially resulting in unsafe prescribing 31, 32.

Therefore, the aim of the present study was to assess the prevalence of QTc prolongation in hospitalized patients treated with ciprofloxacin and fluconazole as part of their usual care. The secondary objective was to assess the association of QTc prolongation with possible risk factors such as patient characteristics, electrolyte parameters, dosage of the interacting drugs and concomitant medication.

Methods

Study design

The present prospective observational cohort study was conducted at the Erasmus University Medical Centre in Rotterdam, the Netherlands, as part of the QT‐INTERACT study. This study has focused on the prevalence and associated risk factors of patients using two or more QTc‐prolonging drugs. These drugs are listed in the CredibleMeds® QT drug list as having a known risk of TdP 7. An observational study design was chosen as the main objective of the present study was to assess the prevalence of QTc prolongation in patients using two or more QTc‐prolonging drugs as part of their usual care. However, it is important to mention that we included only patients treated with ciprofloxacin and fluconazole for this analysis, as the largest group of patients were taking these drugs in combination. Permission was obtained from the medical ethics committee of the Erasmus University Medical Centre in Rotterdam (MEC‐2015‐364), and written informed consent was obtained from all individual participants included in the study, after a full explanation of what was involved. The study was conducted according to the principles of the Declaration of Helsinki.

Study population

All adult patients (≥18 years of age) admitted to the Erasmus University Medical Centre using two or more QTc‐prolonging drugs were eligible to participate during the 12‐month study period (September 2015 to September 2016) according to the protocol of the QT‐INTERACT study.

Patients with an implantable cardioverter defibrillator or a pacemaker, or with a diagnosis of congenital long QT syndrome were excluded. Patients whose ECGs showed a left or right bundle branch block (LBBB/RBBB), atrial fibrillation or other ECG abnormalities due to cerebral pathology, ischaemia or bigeminy were excluded from further analysis owing to interference of these factors with the QTc interval. ECGs showing a QRS complex >120 ms, RR intervals >1800 ms or <500 ms, or ECGs with a QTc interval >700 ms or <300 ms were excluded as such ECGs do not allow the reliable measurement of QTc intervals.

Outcome measures

The primary outcome measure of the study was the proportion of patients with QTc prolongation during combined treatment with ciprofloxacin and fluconazole. QTc prolongation was defined as >450 ms in males and >470 ms in females, based on the European Society of Cardiology (ESC) guidelines. However, a QTc interval of ≥500 ms or an increase of ≥60 ms from baseline were considered to be clinically relevant 33. Twelve‐lead ECGs were recorded with the Mortara® ELI‐350 ECG device (Milwaukee, WI, USA). QT intervals were measured manually, preferably from lead II, from the beginning of the onset of the QRS complex to the end of the T‐wave 34, 35. The measured QT intervals were corrected for heart rate using the Fridericia formula (QTcF) as this formula has the best rate correction, along with the Framingham formula, according to Vandenberk et al. $\left(\mathit{\text{QTcF}},=,\frac{\mathbf{QT}}{\sqrt[3]{\mathit{RR}}}\right)$ 36.

Secondary outcome measures were the potential risk factors associated with QTc prolongation, such as age, gender, race, body mass index (BMI), serum electrolyte parameters, dosage of interacting drugs, comorbidities, renal and liver function parameters, and the concomitant use of other QTc‐prolonging drugs and CYP3A4‐inhibitors.

Data collection

The hospital pharmacy used a medication surveillance system to identify DDIs. All patients on treatment with two or more QTc‐prolonging drugs were identified using the medication surveillance system from September 2015 until September 2016. If patients were eligible for inclusion, informed consent was obtained. Subsequently, a 12‐lead ECG was recorded at the estimated time to peak concentration (T_max) of the last added drug, or at the longest T_max in the case of both drugs being started at the same time. Ciprofloxacin and fluconazole have T_max values of 60–120 min and 30–90 min, respectively. Most patients (91.2%) received 500 mg ciprofloxacin twice daily at 08:00 h and 18:00 h, and 400 mg fluconazole at 12:00 h. For each patient, data on the following characteristics were collected from the electronic patient records: age, gender, race, BMI, medical history and medical condition at the time of the ECG recording, as well as the dose of the interacting drugs that was given. The serum sodium, potassium, magnesium and calcium concentrations were collected within 5 days before or after the ECG recording, using the measurement closest to the time of the ECG recording. Calcium levels were corrected for albumin levels using the following formula: [corrected calcium in mmol l^–1] = [measured calcium in mmol l^–1] + (0.025 × (40 – [albumin in g l^–1]) 37. The estimated glomerular filtration rate, and creatinine, aspartate transaminase, alanine aminotransferase and bilirubin levels were also obtained within 5 days before or after the ECG recording. Concomitant medication data were collected from the electronic medication prescription system Medicator (Computer Sciences Corporation Healthcare Group, Leiden, the Netherlands) within 8 hours prior to the ECG recording. A sub‐classification was made into concomitant QTc‐prolonging drugs with a possible or conditional risk of TdP according to the CredibleMeds® QT drug lists, and CYP3A4‐inhibiting drugs 38. The ECGs selected to represent the baseline were carried out within a maximum of 90 days prior to the ECG recording during treatment, and with no use of QTc‐prolonging drugs with a known risk of TdP according to the CredibleMeds® QT drug list 7.

All data were captured in an electronic clinical data management system (OpenClinica, LLC, Waltham, MA, USA). Data were handled confidentially, according to the Dutch Personal Data Protection Art (Wbp). The study was audited to evaluate and improve the effectiveness of processes and related controls. Data monitoring was performed by an independent data monitor, to ensure completeness and plausibility. Informed consent was obtained from all individual participants included in the study.

Statistical analysis

A sample size calculation could not be made because the exact prevalence of QTc prolongation in the presence of ciprofloxacin and fluconazole combination treatment was unknown. Data were analysed using IBM SPSS Statistics version 21.0 (IBM Corporation, Armonk, NY, United States). The primary outcome was determined by dividing the number of patients with QTc prolongation by the total number of patients included in the study. The QTc interval was dichotomized as either prolonged or not prolonged, according to the ESC guidelines (>450 ms for males and >470 ms for females). Univariate logistic regression analysis was performed to determine associated risk factors. Factors that were associated with a probability of P < 0.05 in the univariate analyses were entered into multivariate models to adjust for confounding. Effect sizes were presented as odds ratios (ORs) with their corresponding 95% confidence intervals (CIs). Additionally, a post hoc analysis was performed in patients with available baseline ECGs, to study the change in the QTc interval during treatment, using a paired t‐test.

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 39, and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 40.

Results

Participants

Of the 849 screened patients, 567 were excluded according to the exclusion criteria, as shown in Figure 1. A total of 282 patients provided informed consent, and in these patients an ECG was recorded. For this analysis, only patients on combined treatment with ciprofloxacin and fluconazole were taken into account. After exclusion of patients with ECG abnormalities, a total of 170 patients using ciprofloxacin and fluconazole were included in the analysis. The mean age of this cohort was 56 years. Most patients were male (64.1%) and had haematological malignancies (87.6%). A detailed overview of the baseline patient characteristics is presented in Table 1.

Figure 1.

Flowchart of patient inclusion. DDI, drug–drug interaction; ECG, electrocardiogram; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; RBBB, right bundle branch block

Table 1.

Characteristics of patients using ciprofloxacin and fluconazole combination therapy (n = 170)

Patient characteristics
Age (years), median; IQR	56.0; 45.0 – 63.0
≤50, n (%)	61 (35.9)
51–75, n (%)	106 (62.4)
≥76, n (%)	3 (1.8)
Female gender, n (%)	61 (35.9)
Caucasian race, n (%)	154 (90.6)
BMI kg m–2, median; IQR	25.2; 6.13
Comorbidities, n (%)
Myocardial infarction	6 (3.5)
Heart failure	–
Arrhythmia a	3 (1.8)
Bradycardia	–
Hypertension	36 (21.2)
Diabetes mellitus	13 (7.6)
COPD/asthma	11 (6.5)
Haematological malignancies	149 (87.6)
Hepatic dysfunction, n (%) b
Increased ASAT (>170 U l –1 for males; >150 U l –1 for females)	3 (1.8)
Increased ALAT (>220 U l –1 for males; >165 U l –1 for females)	3 (1.8)
Increased bilirubin (>16 μmol l –1 )	36 (21.2)
Renal dysfunction, n (%)
Increased creatinine (>115 μmol l –1 for males; >90 μmol l –1 for females)	9 (5.3)
eGFR <50 ml min –1	7 (4.1)
Electrolyte disturbances, n (%) c
Hyponatraemia (Na + <136 mmol l –1 )	19 (11.2)
Hypokalaemia (K + <3.5 mmol l –1 )	5 (2.9)
Hypocalcaemia (Ca 2+ <2.2 mmol l –1 )	45 (26.5)
Hypomagnesaemia (Mg 2+ <0.7 mmol l –1 )	15 (8.8)
>2 ‘known’ QTc‐prolonging drugs, n (%) d	11 (6.5)
Concomitant medication
Total number, median; IQR	8.0; 6.8 – 10.0
Loop diuretics, n (%)	51 (30.0)
Co‐treated with additional QTc‐prolonging drugs, n (%) e
0	13 (7.6)
1	50 (29.4)
≥2	107 (62.9)
CYP3A4 inhibitors, n (%) f	2 (1.1)

ALAT, alanine aminotransferase; ASAT, aspartate transaminase; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CYP, cytochrome P450; IQR, interquartile range; eGFR; estimated glomerular filtration rate; QTc, heart rate‐corrected QT; TdP, torsade de pointes

^aA history of supraventricular tachycardia (n = 3) including atrial fibrillation (n = 2)

^bMissing values: ASAT (n = 2); ALAT (n = 2); bilirubin (n = 4)

^cMissing values: Ca²⁺ (n = 53); Mg²⁺ (n = 60)

^dQTc‐prolonging drugs with a known risk of TdP

^eQTc‐prolonging drugs with a possible and a conditional risk of TdP in addition to that associated with ciprofloxacin and fluconazole combination therapy 7

^fCiprofloxacin and fluconazole were excluded as CYP3A4 inhibitors

Primary outcomes

Eight patients had QTc prolongation during ciprofloxacin and fluconazole combination therapy [mean ± standard deviation (SD) QTc interval 461.1 ± 10.8 ms] when the Fridericia formula was used. This resulted in a prevalence of 4.7%. The QTc interval did not rise to abnormal levels above 500 ms in any of these patients. Seven out of eight patients (87.5%) with QTc prolongation were men.

A baseline ECG was available in 137 patients. The mean ± SD QTc interval at baseline was 400.3 ± 19.6 ms compared with a mean ± SD QTc interval of 411.4 ± 21.7 ms during treatment. The overall mean QTc change from baseline was 10.7 ms (95% CI 7.2, 14.1; P = 0.000), as shown in Figure 2. In two patients, the QTc intervals increased by ≥60 ms during treatment (63 ms and 98 ms, respectively); both patients had a prolonged QTc interval after administration of ciprofloxacin and fluconazole (451 ms and 483 ms, respectively; ECGs are included in Figure S1). A baseline ECG was available in seven out of eight patients with QTc prolongation during treatment. One of these patients had a prolonged QTc interval at baseline (464 ms); the prolonged QTc interval was pre‐existing and apparently not caused by the DDI. Thus, with regard to patients with baseline ECGs (n = 137), six patients had a prolonged QTc interval that was presumably caused by ciprofloxacin and fluconazole combination therapy (4.4%).

Figure 2.

QTc (Fridericia formula) intervals at baseline and during treatment (n = 137)

Most patients (91.2%) received oral ciprofloxacin 500 mg twice daily and fluconazole 400 mg once daily. The deviating dose regimens are listed in Table 2. One out of the three patients who received ciprofloxacin and/or fluconazole intravenously had a prolonged QTc interval (465 ms). This patient also received 1 mg haloperidol, a third QTc‐prolonging drug with a known risk of TdP 7.

Table 2.

Daily dose in patients in whom the dose regimen deviated (n = 15)

Ciprofloxacin (mg)		Fluconazole (mg)		Patients, n
1200	iv	400	iv	1
800	iv	400	iv	1
800	iv	400	po	1
1000	po	200	po	6
1000	po	150	po	1
500	po	200	po	4
250	po	200	po	1

iv, intravenously; po, per os (oral administration)

In addition to the ciprofloxacin and fluconazole treatment, 6.5% of the cohort was exposed to concomitant treatment with a third QTc‐prolonging drug with a known risk of TdP (Table 3). Two of these patients (18.2%) had a prolonged QTc interval, using, respectively, flecainide 200 mg and haloperidol 1 mg daily. During our study period, no cases of TdP occurred.

Table 3.

Patients using >2 QTc‐prolonging drugs with a known risk of TdP (n = 11)

Third QTc‐prolonging drug (daily dose)	Patients, n = 11	Baseline QTc (ms)	Follow‐up QTc (ms)
Citalopram (30 mg)	1	426	410
Flecainide (200 mg)	1	–	468
Haloperidol (0.5 mg)	1	421	419
Haloperidol (1 mg p.r.n.)	1	419	465
Haloperidol (2 mg)	1	–	377
Haloperidol (2 mg)	1	397	415
Haloperidol (2 mg)	1	399	452
Methadone (10 mg)	1	418	407
Sotalol (120 mg)	1	420	453
Sotalol (120 mg)	1	–	407
Sotalol (80 mg)	1	–	436

p.r.n, pro re nata (as needed); QTc, heart rate‐corrected QT; TdP, torsade de pointes

Bold text refers to patients with QTc prolongation

Secondary outcomes

The association between various potential risk factors and QTc prolongation is shown in Table 4. Due to the small number of patients with QTc prolongation, univariate logistic regression was not feasible for each determinant. We found an association between age and QTc prolongation (OR 1.08; 95% CI 1.00, 1.17), as well as between the use of three QTc‐prolonging drugs with a known risk of TdP and QTc prolongation (5.67; 95% CI 1.00, 32.15). After multivariate regression analysis, no risk factors were statistically significantly associated with QTc prolongation.

Table 4.

Association of potential risk factors with QTc (Fridericia formula) prolongation (n = 170)

Potential determinants	QTcF prolongation n =8	No QTcF prolongation n = 162	OR	95% CI	Multivariate regression
					OR adj	95% CI	Adj.
Age (years), median; IQR	66.0; 56.0 – 66.8	55.0; 44.8 – 63.0	1.08	1.00, 1.17	1.07	0.99, 1.16	QTC‐prolonging drugs
≤ 50, n (%)	1 (12.5)	60 (37.0)	Ref.	Ref.
51–75, n (%)	7 (87.5)	99 (61.1)	4.24	0.51, 35.3
≥ 76, n (%)	–	3 (1.9)	–	–
Female gender, n (%)	1 (12.5)	60 (37.0)	0.24	0.03, 2.02
Caucasian race, n (%)	6 (75.0)	148 (91.4)	0.28	0.05, 1.54
BMI, median; IQR	25.3; 4.9	25.2; 6.3	0.95	0.80, 1.13
Comorbidities, n (%)
Myocardial infarction	–	6 (3.7)	–	–
Arrhythmia a	–	3 (1.9)	–	–
Hypertension	3 (37.5)	33 (20.4)	2.35	0.53, 10.31
Diabetes mellitus	–	13 (8.0)	–	–
COPD/asthma	–	11 (6.8)	–	–
Haematological malignancies	6 (75.0)	143 (88.3)	0.40	0.08, 2.12
Organ failure
Hepatic dysfunction, n (%) b
Increased ASAT	–	3 (1.9)	–	–
Increased ALAT	–	3 (1.9)	–	–
Increased bilirubin	4 (50.0)	32 (19.8)	3.94	0.94, 16.06
Renal dysfunction, n (%)
Increased creatinine	–	9 (5.6)	–	–
eGFR <50 ml min –1	–	7 (4.3)	–	–
Electrolyte disturbances, n (%) c
Hyponatraemia	–	19 (11.7)	–	–
Hypokalaemia	–	5 (3.1)	–	–
Hypocalcaemia	2 (250)	43 (26.5)	0.79	0.14, 4.50
Hypomagnesaemia	1 (12.5)	14 (8.6)	1.29	0.14, 11.83
> 2 QTc‐prolonging drugs, n (%) d	2 (25.0)	9 (5.6)	5.67	1.00, 32.15	4.35	0.73, 25.82	Age
Concomitant medication
Total number, median; IQR	9.0; 8.0 – 9.8	8.0; 6.0 – 10.0	1.10	0.86, 1.42
Loop diuretics, n (%)	4 (50.0)	47 (29.0)	2.45	0.59, 10.19
Co‐treated with additional QTc‐prolonging drugs, n (%) e
0	–	13 (8.0)	–	–
1	2 (25.0)	48 (29.6)	–	–
≥ 2	6 (75.0)	101 (62.3)	–	–
CYP3A4 inhibitors, n (%) f	–	2 (1.2)	–	–

Adj, adjusted; ALAT, alanine aminotransferase; ASAT, aspartate transaminase; BMI, body mass index; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CYP, cytochrome P450; eGFR; estimated glomerular filtration rate; IQR, interquartile range; OR, odds ratio; OR_adj, adjusted Odd Ratios; QTc, heart rate‐corrected QT; QTcF, QTc (Fridericia formula); Ref., Reference; TdP, torsade de pointes

^aA history of atrial fibrillation (n = 2) (QTc prolongation); supraventricular tachycardia (n = 1) (no QTc prolongation)

^bMissing values: no QTc: ASAT (n = 2); ALAT (n = 2); bilirubin (n = 4)

^cMissing values: QTc: Ca²⁺ (n = 2); Mg²⁺ (n = 2); no QTc: Ca²⁺ (n = 51); Mg²⁺ (n = 58)

^dQTc‐prolonging drugs with a known risk of TdP

^eQTc‐prolonging drugs with a possible and a conditional risk of TdP in addition to that associated with ciprofloxacin and fluconazole combination therapy 7

^fCiprofloxacin and fluconazole were excluded as CYP3A4 inhibitors

Most patients (62.9%) were exposed to concomitant treatment with two or more other QTc‐prolonging drugs with a possible or conditional risk of TdP. However, these QTc‐prolonging drugs were not significantly associated with QTc prolongation (Table 4). These drugs included antiemetic agents (89.9%), diuretics (33.8%) and proton pump inhibitors (9.5%).

Discussion

To our knowledge, this was the first prospective study exploring the prevalence of, and risk factors associated with, QTc prolongation in patients treated with ciprofloxacin and fluconazole. In this observational study, 4.7% of the patients showed a prolonged QTc interval during treatment when the Fridericia formula was used. We did not find risk factors associated with QTc prolongation in this population. These results contribute to a better insight into the prevalence and magnitude of QTc interval prolongation in patients using two or more QTc‐prolonging drugs.

According to the American Heart Association/American College of Cardiology consensus statement on the prevention of TdP in hospital settings, a prolonged QTc interval of more than 500 ms or an increase in QTc interval of at least 60 ms from baseline are considered to be clinically relevant 15. Eight patients in our cohort had a prolonged QTc interval according to the cut‐off value of 450 ms for males and 470 ms for females, however, none of these patients had a QTc interval above 500 ms. Only two patients showed an increase in QTc interval of ≥60 ms from baseline. Additionally, the post hoc analysis showed a significant mean increase in QTc interval of 10.7 ms during treatment. However, most baseline ECGs were recorded before the start of chemotherapy as standard care. It is most likely that the patients were in a better medical condition at baseline than when the ECGs were recorded during treatment. As Holter monitoring studies have revealed substantial daily QTc variability (hourly mean QTc range of 38 ± 6 ms), this increase could even be considered as negligible 41, 42.

Patients with QTc prolongation continued treatment and did not have any complications. Moreover, no cases of TdP occurred during our study period. As previously mentioned, Zeuli et al. 29 found a 22% prevalence of clinically relevant significant change in QTc from baseline when fluoroquinolones and azoles were combined. However, only three patients (3.2%) out of their total cohort received ciprofloxacin and fluconazole combination therapy. They also found a small mean QTc change from baseline of 6.1 ms (95% CI 0.2, 11.9 ms) during treatment. According to our results, we consider that the QTc‐prolonging effect of ciprofloxacin and fluconazole therapy is not clinically relevant in this population. It should be noted that most patients (91.2%) received 1000 mg of ciprofloxacin and 400 mg of fluconazole orally per day. One of the three patients receiving intravenous ciprofloxacin and fluconazole developed QTc prolongation, which might imply that more caution is needed when these drugs are administered intravenously.

Many patients (92.3%) were co‐treated with additional QTc‐prolonging drugs with a possible or conditional risk of TdP according to the CredibleMeds® QT drug list 7. However, these additional QTc‐prolonging drugs did not affect the prevalence of QTc prolongation. Moreover, a third QTc‐prolonging drug with a known risk of TdP was not associated with QTc prolongation. Even three patients who received sotalol (daily dose 120 mg) in addition to the study drug combination did not show QTc prolongation (with QTc intervals of 407 ms, 436 ms and 453 ms, respectively). Sotalol is one of the most powerful I_kr voltage‐gated potassium‐channel blockers. This indicates that there might not be a synergistic QTc‐prolonging effect when two or more QTc‐prolonging drugs with a known risk of TdP are combined. Meid et al. 27 supported this hypothesis in a retrospective study of claims data for additive QTc‐prolonging drugs in older people with ventricular tachyarrhythmia. They did not find a supra‐additive or synergistic risk of ventricular tachyarrhythmia when more than one QTc‐prolonging drug was used. Therefore, the validity of the CredibleMeds® QT drug lists should be questioned. AZCERT has developed a process to place drugs in risk categories for their clinical ability to cause TdP and QTc prolongation. This centre collects its data from different sources, including the Food and Drug Administration Adverse Event Reporting System (FEARS), the World Health Organization adverse events database, case reports and reports in the medical literature. However, the evaluation of causality is often difficult, and evidence is frequently incomplete. Nevertheless, a growing number of drugs has been added to the lists since 1999 when AZCERT was established. As a result, the lists lack quantification of relative risks, which makes it difficult for doctors to interpret these risk alerts 43, 44.

With the increasing number of QTc‐prolonging drugs, alert fatigue could set in among physicians, who might no longer react to truly relevant alerts. There should be a balance between the number of alerts generated by the Clinical Decision Support System and their effect on patient care. The results of the present study suggest that the recommendation routinely to monitor the ECGs of patients using ciprofloxacin and fluconazole should be reconsidered.

The prospective study design enabled us to adjust for many variables. Most ECGs were recorded at the T_max of ciprofloxacin as the dose regimens were identical in most patients; in 15 patients, the dose regimen deviated (see Table 2). Moreover, the ECGs were recorded using the same Mortara® Eli‐350 device and performed by three trained investigators. The limitations of the study included, firstly, the fact that the mean age of our population was relatively low (56 years). Older patients treated with ciprofloxacin and fluconazole may have a higher risk of QTc prolongation, as well as a higher risk of developing arrhythmias, as increasing age is a known risk factor for QTc prolongation and TdP 10, 13, 14, 15, 16. Nevertheless, we did not find increasing age to be associated with QTc prolongation when ciprofloxacin and fluconazole were used. Secondly, a baseline ECG was only available when the physician ordered an ECG before treatment as part of routine care because the medication surveillance system could not report real‐time DDIs. Therefore, in patients with QTc prolongation and without a baseline ECG available, the prolonged QTc interval could have been pre‐existing. If that was the case, the prevalence of a prolonged QTc interval caused by ciprofloxacin and fluconazole would even be lower.

Several determinants, such as a female gender, hypokalaemia, hypomagnesaemia, heart diseases and renal impairment, are known risk factors for QTc prolongation 10, 13, 14, 15, 16. However, in our analyses, all known risk factors failed to achieve statistical significance, possibly because of the low number of QTc prolongation events. In addition, several serum electrolyte values were missing. Most patients with QTc prolongation (87.5%) were male, which is in contrast with previous studies that have identified female gender as a risk factor for developing QTc prolongation 10, 13, 14, 15, 16.

A review by Montanez et al. 45 identified seven large population‐based cohort studies evaluating the association between QTc prolongation and cardiovascular mortality. Of the 36 031 individuals included in these cohort studies, 2677 had a prolonged QTc interval (≥440 ms), representing 8.7% of the general population. Straus et al. 11 found an 11.1% prevalence of QTc prolongation in a population of older adults, using >450 ms for men and >470 ms for women as cut‐off values. Therefore, it could be stated that the prevalence of QTc prolongation in patients using this combination is rather low (4.7%).

To conclude, our study confirmed that ciprofloxacin and fluconazole combination therapy prolongs the QTc interval. However, it also showed that this increase is negligible in relation to the daily variability in the QTc interval. No risk factors were found to be associated with QTc prolongation during this treatment. Given the low prevalence of this condition, and the small size of the increase in the QTc interval, the routine ECG monitoring in haematology patients using ciprofloxacin and fluconazole should be reconsidered. However, caution is needed when ciprofloxacin and fluconazole are administered intravenously.

Competing Interests

This study was funded by the Royal Dutch Pharmacists Association (KNMP Holding B.V.). All authors declare that they have no conflicts of interest.

Contributors

P.v.d.B., T.v.G. and N.d.G. designed the research. F.B., N.M., B.S. and A.B. contributed to the conduct of the study, whereby F.B. and N.M. collected data, and B.S. and A.B. contributed to patient care. Data analysis was performed by F.B. The results were analysed, interpreted and discussed by F.B., H.v.d.S., P.v.d.B., N.d.G., T.v.G. and M.B. F.B. drafted the manuscript and all co‐authors revised and approved the final version of the manuscript.

Supporting information

Figure S1 (a.1) baseline ECG of patient A (a.2) ECG during treatment of patient A (b.1) baseline ECG of patient B (b.2) ECG during treatment of patient B. In both patients, the QTc interval increased by >60 ms

Berger, F. A. , Monadian, N. , de Groot, N. M. S. , Santbergen, B. , van der Sijs, H. , Becker, M. L. , Broers, A. E. C. , van Gelder, T. , and van den Bemt, P. M. L. A. (2018) QTc prolongation during ciprofloxacin and fluconazole combination therapy: prevalence and associated risk factors. Br J Clin Pharmacol, 84: 369–378. doi: 10.1111/bcp.13457.