Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin, and gemifloxacin) which are classified as potent antibiotic agents are the most important ones that used to treat various infections both in UTI, prostatitis, respiratory infections, gastroenteritis, skin infection, and STIs [1,2,30]. The generations of quinolones have developed since the description of nalidixic acid in 1962 ranging from second generation, represented by ciprofloxacin, third generation as levofloxacin, and fourth generation as moxifloxacin that provide increased gram positive activity and bioavailability [1,15,30]. These antibiotics are DNA gyrase and topoisomerase IV inhibitors, and thus interfere with DNA syntheses [2,39]. They show a remarkable ability in penetrating tissues with different ways of elimination, renally for levofloxacin and hepatically for moxifloxacin [1,37]. However, their safety profile which has come under scrutiny especially the cardiovascular implications (i.e., QT interval prolongation and torsades de pointes (TdP)) has resulted in quinolones that were otherwise effective such as grepafloxacin and sparfloxacin being withdrawn [3, 5].

The electrocardiographic (ECG) intervals are QT is the time interval on an ECG from the onset of Q wave (depolarization) to the T wave end, which characterizes the ventricular depolarization and repolarization .[4] Long QTc (>450 ms in males or >470 ms in females and/or change from baseline >60 ms after correction, by Bazett’s equation: QTc = QT/√RR) carries increased risk for TdP, a potentially fatal arrhythmia [4,5,14]. QT prolongation is produced by quinolones through concentration-dependent inhibition of the rapid delayed rectifier potassium channel (I Kr ), which is more potent for moxifloxacin [15]. Those effects have now been reconfirmed with recent investigations (2017–2025) and an average QTc prolongation for moxifloxacin of 10–20 ms has been observed in healthy volunteers [8,9,18]. Risk factors include disturbances in electrolytes (hypokalemia, hypomagnesemia), female gender, polypharmacy, myocardial ischemia, hypothermia, and congential long QT syndrome [5,15,26,28]. Besides cardiovascular hazards, quinolones induce adverse effects on CNS (eg, headache, dizziness), gastrointestinal (eg, nausea), and dermatological (eg, rash) adverse events [ 5, 28 ].

In Dera Ismail Khan, Pakistan (population: 40,000, few physicians, no/limited follow-up), usage of quinolones is common, and because of the high prevalence of polypharmacy, the lack of locally defined cardiac safety is troubling [6]. The current study attempts to fill this gap by examining quinolone induced QT prolongation in healthy volunteers, focusing among other aspects on regional pharmacovigilance [7]. A 2020 review emphasized the misuse of antibiotics in Pakistan and urged the requirement for broad studies [6,10]. This cross sectional study seeks to estimate the effect of Ciprofloxacin, Levofloxacin, Moxifloxacin and Gemifloxacin on the QT interval in healthy volunteers, with application to prescription safety, especially in low resource areas.

Study Design and Setting

This descriptive cross-sectional study was conducted in 2023 at the Department of Pharmacology, Gomal Medical College, Dera Ismail Khan, Pakistan, over six months. All research activities, including volunteer recruitment, ECG recording, and data analysis, occurred in 2023. Ethical approval was granted from Khyber Medical University (KMU) Ethical Board (No.KMU/EB/2023/012) and Advanced Study and Research Board (ASRB, No.KMU/ASRB/2023/005) for observance of STROBE guidelines [11].

Participants

A total of 100 healthy volunteers (aged 20–40 years, 85% male) were recruited via simple random sampling. The volunteers were randomised into four groups (n = 25 per group) according to an initial oral administration of a single dose of one dose of moxifloxacin (400 mg), ciprofloxacin (500 mg), levofloxacin (500 mg) and gemifloxacin (320 mg) . Healthy subjects aged between 20 and 60 years were considered as inclusion criteria. The exclusion criteria were as follows: pregnancy; diabetes; hypertension; history of coronary artery disease; and the presence of conditions that prohibited the use of quinolones.

Procedures

Three baseline ECGs were obtained in each subject with a 12-lead ECG machine before giving quinolones. A second ECG was recorded either at the time of the highest plasma concentrations (Tmax) or the steady state (48 h after dosing) according to the guideline [. QT intervals were predominantly measured from lead II; if this lead was unreadable, leads aVR, aVF, V5, V6, V4 or V2 were used depending on T wave clarity (voltage >1 square, clear downslope) to the nearest 10th of a millisecond, and tracing with QT unknownness 450 ms for men >470 ms for women or 60 ms change from baseline. The QRS complex duration was also monitored.

Statistical Analysis

Data analysis was conducted in SPSS V.16. Numbers and percentages for categorical variables (sex, age categories) were reported. Continuous variables (e.g., QTc, QRS duration) were presented as mean ± SD. The QTc values before and after dosing were compared by paired t-test, and differences at p<0.05 were considered significant. To compare QRS interval modification among the quinolones, there was also an one-way ANOVA (robust statistical assessment) [7].

One hundred healthy volunteers were evaluated to assess the effects of fluoroquinolones (moxifloxacin, ciprofloxacin, levofloxacin, gemifloxacin) on QTc intervals and QRS complex duration [7]. The study subjects included 85 males (85%) and 15 females (15%) (Table 1). The number of volunteers of age <25 years, 25–45 years and 45–65 years old were 21, 37 and 42, respectively (Table 2). Sex and age were distributed in different ways among quinolone groups (25 volunteers each) moxifloxacin (20 males, 5 females, mean age 45.32 years), ciprofloxacin (23 males, 2 females, mean age 50.12 years), levofloxacin (21 males, 4 females, mean age 41.56 years) and gemifloxacin (21 males, 4 females, mean age 49.58 years) (Tables 3, 4).

Table 1: Sex Distribution of Volunteers

Table 2: Age Distribution of Volunteers

Table 3: Frequency of Males and Females in Each Fluoroquinolone Group

Table 4: Mean Age of Volunteers Receiving Different Fluoroquinolones

QTc prolongation was observed in 13 volunteers (Table 5). Moxifloxacin prolonged the QTc in 7 subjects (28%) with 5 (20%) showing a >60 ms change from baseline or torsades de pointes (TdP) risk (mean baseline QTc: 376.00±16.88 ms; steady-state: 450.60±13.83 ms; p0.05). The order of QTc prolongation was moxifloxacin > ciprofloxacin > levofloxacin > gemifloxacin, consistent with IKr inhibition potency . Statistical analysis (paired t-tests) indicated significant differences in QTc duration for moxifloxacin, ciprofloxacin and levofloxacin.

Table 5: Fluoroquinolone and Frequencies of Recipients with Prolonged QTc and TdP Risk

Note: TdP risk defined as QTc change >60 ms from baseline [20].

Table 6: Volunteers with QTc Change >60 ms

There were no significant QRS complex changes in any of the quinolones (p>0.05, one-way ANOVA) . Nine had changes (table 7). Moxifloxacin induced changes in 5 subjects (4 males, 105 ms baseline, 160 steady-state; 1 female, 100 baseline, 155 steady-state). Ciprofloxacin caused Rt-RT prolongation in 1 male (baseline 110 ms, steady-state 165 ms), levofloxacin in 2 (1 male, baseline 108 ms, steady-state 162 ms; 1 female, baseline 102 ms, steady-state 158 ms) and gemifloxacin in 1 female (baseline 105 ms, steady-state 160 ms).

Table 7: Fluoroquinolone and Frequencies of Recipients with Prolonged QRS Complex

ECG tracings demonstrated QTc changes (Figures 1–3). Its effect can be observed in Figure 1 (baseline QTc = 376 ms, QTc at steady state = 450.6 ms). Figure 2 shows ciprofloxacin (baseline, 359.5 ms; steady-state, 426.5 ms). The same administration with levofloxacin is shown in Fig. 3 (baseline: 410 ms, steady-state: 470.5 ms). Similar patterns for moxifloxacin and ciprofloxacin were revealed by other tracings but were not presented for the purpose of brevity . The majority of subjects at TdP risk in the present study were male, reflecting (in part) the larger proportion of the subjects group being male (85%) .

This cross-sectional study shows that moxifloxacin, ciprofloxacin, and levofloxacin lead to significant increases in QTc intervals in healthy subjects, while gemifloxacin has less effect [7]. Moxifloxacin caused the most pronounced QTc interval prolongation (20% of subjects with >60 ms intervention-related change), followed by ciprofloxacin (12%) and levofloxacin (8%), consistent with relative affinities to block the rapid component of the delayed rectifier potassium channel (IKr) [15]. The IC50 for IKr blockade by moxifloxacin in vitro of 129 µmol/L was much lower than that of levofloxacin (915 µmol/L) or ciprofloxacin (966 µmol/l) explaining its high impact [15]. Previously, moxifloxacin was reported to have more potent inhibition of human ether-a-go-go-related gene (HERG) channels compared with ciprofloxacin and levofloxacin [84]. The average increase in the QTc interval with moxifloxacin was 10 to 20 ms in normal healthy subjects, with a larger potential risk in patients with underlying cardiac comorbidities [18].

The observed QTc change, especially those >60 ms, suggest a “definite concern” regarding the risk of TdP as per the regulators [20]. The similar effects of ciprofloxacin and levofloxacin is consistent with their identical IKr inhibition profiles, and was also observed in a 2020 study that reported ciprofloxacin’s QTc prolongation as 5–15 ms, while levofloxacin’s impact was modestly higher in elderly patients [8,19]. AMES data Ciprofloxacin and levofloxacin had IC50 values of 966 µmol/L and 915 µmol/L, respectively, on the hERG channel [15]. The absence of marked QTc prolongation by gemifloxacin may point to its safer cardiac profile, conceivably through less interference with IKr or the influence of physiological heart rate, as recently indicated by a 2020 review [16]. A neutral effect of gemifloxacin might indicate different heart rates, rather than direct ventricular repolarization modifications, that should need to be proven.

The polypharmacy is common in Dera Ismail Khan because of constrained healthcare facilities and quinolones are mostly simultaneously given with other QT-prolonging agents like antifungals and antidepressants to exacerbate TdP risk [6,21]. This region is known to have low use in quinolones in monotherapy which further increases the potentially of drug interaction . A retrospective study in 2021 showed that 2–5% of ICU patients treated with fluoroquinolones had QTc intervals >500 ms suggesting the importance of ECG monitoring in high-risk environments [22]. Local health problems, such as a shortage of experienced doctors and the poor continuation of follow-up care, are risk factors for the consequences of the unevaded consumption of antibiotics [6]. QTc-prolongation with ciprofloxacin was observed in the female volunteers in this study, which is in line with published literature demonstrating a greater propensity to TdP in females because of longer baseline QT intervals [5,28]. *Studies report female gender as a risk factor for TdP [28].

Methodologically, several considerations arise [7]. The use of Bazett’s formula for QTc correction may overestimate prolongation at higher heart rates, a limitation noted in a 2016 study [23]. Alternative correction methods such as Fridericia’s formula might improve accuracy, especially for participants with inconsistent heart rates [24]. ECGs recorded at steady-state concentration (48 hours after dose) may not catch peak QTc-effect, which usually takes place around the time of peak plasma concentration (Tmax, 1–4 hours for quinolones) [12]. In a study conducted in 2017 in moxifloxacin, the highest changes of the QTc occurred 2–3 h after the drug was administered, reinforcing the idea of pre-dose or continuous ECG monitoring [25]. Furthermore, differences in baseline QTc estimates become a source of concern due to inconsistent lead selection methods [83, 85] while manually measuring and the resultant reproducibility of the measurements is limited[84]. Noel et al. reported similar challenges in their study and stressed the importance of using standardized baseline methods to obtain reliable comparison of QTc [84]. These potential methodological issues, although not detracting from the findings, should be considered in cautious interpretation of the degree of QTc elongation.

The clinical significance of these findings is unclear . Moxifloxacin’s marked prolongation of the QTc should be interpreted with caution especially among those with risk factors (e.g., hypokalemia, hepatic dysfunction, or concurrent QT-prolonging drugs) in whom its impact translates into the risk of TdP remains largely undetermined in practice [27]. The QTc changes in healthy volunteers cannot completely reflect the results of patients with complications and arrhythmia might be more frequent [28]. A 2018 review also made note ofpotential drug–drug interactions QTc (e.g. quinolones with azole antifungals) enlarging QTc in baseline by as much as 20-30 ms, which underscores the importanceof complete med rec [9]. Ciprofloxacin and levofloxacin are less powerful than moxifloxacin but are also risky in polypharmacy; this may not mean synergy with other drugs. The promising cardiac safety profile of gemifloxacin makes it potentially the antibiotic of choice for low risk patients, but however requires further studies in populations having racial and geographic variations to establish its cardiac safety [16].

The findings have particular relevance in Dera Ismail Khan, where limited access to healthcare resources, including ECG monitoring, complicates the safe use of quinolones [6]. Due to only a small number of qualified doctors in the region (population ~40,000 people), follow-up is poor and there is an increased reliance on patients receiving more drugs (polypharmacy) [6]. In this context, it is increasingly important to have a perception of the risk associated with quinolone-induced QT prolongation in clinical practice for prescription. A 2020 review of antibiotics in Pakistan also explored extensive misuse and rationality on systemic level and indicated the need of focused pharmacovigilance services in such scenarios [6]. Increased surveillance should be considered to avert cardiac complications .

Further investigation is warranted in order to overcome these limitations and to better determine the clinical relevance of the observed QTc modifications [7]. Larger trials in a heterogeneous patient population (including those with cardiac or hepatic diseases) are also needed to examine the real-world risk. [19] Cumulative QTc effects on multi-dose trials were possible as suggested in a 2021 study of fluoroquinolone safety [22]. The Tmax constraint would be mitigated through continuous ECG monitoring, which was suggested in a 2019 study to better capture maximum QTc effect [18]. The results are in agreement with those of Noel et al. that standardized QTc measurement procedures are required to decrease the baseline QTc variation. s results of HERG channel experiments [84]). Methods to correct QTc other than Bazett’s should be pursued to enhance accuracy [24]. Moreover genetic and/or electrolyte imbalances might also personalize risk stratification [23]

This research adds to the growing concern over quinolone-related cardiac safety and demonstrates moxifloxacin as the fluorquinolone with the highest associated QTc prolongation risk.Although the effectiveness of moxifloxacin against gram-positive organisms is beneficial, such cardiac risks need to be used judiciously, especially when there is polypharmacy [27]. Ciprofloxacin and levofloxacin are less potent, but should be used with the same caution [26]. The good profile of gemifloxacin is indicating possible safety pending more study [16]. The challenge is to extend these findings beyond healthy volunteers to clinical populations with comorbidities that can increase the risk . This work suggests the importance of improving pharmacovigilance to promote judicious and safe use of quinolones and is more crucial in the resource-constrained settings like Dera Ismail Khan [6,10].

Limitations

This study has several limitations . The small sample size (n=100) reduces statistical power and generalizability, especially of rare events such as TdP. The single-dose study design does not evaluate such cumulative or long-term QTc effects, which are important with chronic exposure to a quinolone. Use of Bazett’s formula might overcorrect for QTc prolongation at faster heart rates, and thus bias the results.Its emphasis on studies in the healthy volunteers precludes work in higher risk populations (e.g., patients with cardiac comorbidity or electrolyte imbalance), thus limiting clinical application. Period ECGs (SSC, 48 hours) might not detect maximal QTc effects, which usually are observed around the time of Cmax . Poor health infrastructure in Dera Ismail Khan limits availability of continuous ECG monitoring and ability to undertake risk stratification in real-time.

This study demonstrates that moxifloxacin, ciprofloxacin, and levofloxacin significantly prolong QTc intervals in healthy volunteers, with moxifloxacin posing the greatest risk (20% with >60 ms change), while gemifloxacin shows no notable effect These findings highlight moxifloxacin’s stronger inhibition of the rapid delayed rectifier potassium channel (IKr), contributing to its pronounced QTc prolongation . Ciprofloxacin and levofloxacin induce moderate prolongation, indicating potential cardiac risks, whereas gemifloxacin’s lack of effect suggests a safer cardiac profile . The >60 ms QTc changes observed, particularly with moxifloxacin, indicate a concern for torsades de pointes (TdP) risk, though the clinical significance in healthy volunteers remains uncertain .

In Dera Ismail Khan, where limited healthcare resources and prevalent polypharmacy exacerbate risks, these findings underscore the importance of understanding quinolone-induced QT prolongation [6]. Local challenges, such as a scarcity of physicians and inadequate follow-up, complicate safe antibiotic use in a population reliant on multiple medications . However, translating these results from healthy volunteers to clinical populations with comorbidities or concurrent QT-prolonging drugs is challenging . The observed QTc changes may not directly predict TdP incidence in patients, necessitating further research to elucidate clinical risks.

Future studies should investigate quinolone effects in diverse cohorts, including patients with cardiac or hepatic conditions, to assess real-world implications . Continuous ECG monitoring and alternative QTc correction methods could clarify the timing and magnitude of prolongation . Enhanced pharmacovigilance, particularly in resource-limited settings like Dera Ismail Khan, is critical to ensure patient safety amidst widespread quinolone use . This study calls for rigorous evaluation of quinolone cardiac safety to guide clinical practice.

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