Nephrotoxic antibiotic use among patients with chronic kidney disease

INTRODUCTION

Chronic kidney disease (CKD) is a long-term condition marked by the gradual deterioration of renal function and impacts a substantial portion of the global population.¹ Individuals living with CKD are at increased risk for infections because of impaired immune defenses, recurrent hospital admissions, and the presence of multiple underlying health conditions.^2–4 Consequently, antibiotic therapy is a common component of CKD management, aimed at treating or preventing infections. However, many antibiotics, especially broad-spectrum agents, carry a risk of nephrotoxicity, which can further compromise renal function.⁵

Nephrotoxic antibiotics are agents that can cause renal damage through direct injury to renal cells, impaired renal perfusion, or the induction of inflammatory responses.⁵ Antibiotic-induced nephrotoxicity can occur through various mechanisms, such as damage to the glomeruli and renal tubules, impaired tubular function, blockage of distal tubules due to cast formation, and the development of acute interstitial nephritis (AIN), which is frequently triggered by a delayed-type hypersensitivity reaction.⁵ Frequently implicated antibiotics include aminoglycosides, glycopeptides, beta-lactams, and folate synthesis inhibitors (such as sulfonamides, fluoroquinolones, tetracyclines, and polymyxins), all of which are associated with acute kidney injury (AKI) and worsening CKD.⁵ The pathophysiology commonly involves oxidative stress, mitochondrial dysfunction, and apoptosis of renal tubular cells. Individuals with existing CKD have kidneys that are especially susceptible to further damage, which may accelerate renal function decline, prolong hospital stays, and increase the likelihood of developing end-stage renal disease.⁶

Despite the recognized risks, nephrotoxic antibiotics continue to be prescribed, sometimes inappropriately, to patients with CKD.^6,7 Inappropriate prescribing, such as incorrect dosing, prolonged duration, or use of nephrotoxic agents without renal function monitoring, can exacerbate kidney damage.^8–12 Studies have underscored the high prevalence of nephrotoxic antibiotic use in patients with CKD. In a study conducted in Ethiopia, a considerable proportion of hospitalized patients with CKD received nephrotoxic antibiotics, leading to AKI and worsening renal outcomes.¹² Similarly, studies from India highlighted a high rate of inappropriate antibiotic prescriptions in patients with CKD.^10,13 These findings underscore the urgent need for antimicrobial stewardship programs (ASPs) tailored to patients with CKD, focusing on rational prescribing, dose adjustments, and therapeutic drug monitoring (TDM). The World Health Organization and other health agencies have advocated for prudent antibiotic use to combat antimicrobial resistance and minimize the adverse effects of antibiotics.^14,15 In CKD management, integrating ASPs can help reduce nephrotoxicity by promoting the selection of appropriate antibiotics and dosage regimens. Emphasizing renal function monitoring and individualized treatment plans is vital for optimizing care and improving outcomes in patients with CKD. The lack of targeted antimicrobial stewardship measures and limited awareness among prescribers often results in the unwarranted use of inappropriate antibiotics in patients with CKD, compromising patient safety and treatment outcomes.¹³ Common risk factors for antimicrobial-associated AKI include an existing diagnosis of CKD and the simultaneous use of other nephrotoxic medications.¹⁶ Despite the critical importance of rational antibiotic use in patients with CKD, currently, comprehensive information on the prevalence and predictors of nephrotoxic antibiotic use in this population in Nigeria is lacking. Addressing these gaps is vital for optimizing antibiotic use, minimizing nephrotoxicity, and improving clinical outcomes. This study can generate critical evidence to guide the development of context-specific ASPs in the CKD population. Understanding the drivers of nephrotoxic antibiotic prescribing in patients with CKD will help tailor interventions to promote rational use and prevent renal complications. By informing evidence-based clinical guidelines, the study will contribute to safeguarding renal function and enhancing patient safety.

This study aims to determine the prevalence and describe the prescribing patterns of nephrotoxic antibiotics, identify predictors of nephrotoxicity, evaluate the impact of nephrotoxic antibiotic exposure on renal function, and provide evidence-based recommendations for optimizing antibiotic use and reducing nephrotoxicity in patients with CKD.

MATERIAL AND METHODS

RESULTS

Prevalence and prescribing patterns of nephrotoxic antibiotics

Out of 195 patients, 173 (88.7%) were prescribed nephrotoxic antibiotics. Of these, 147 (85.0%) received a single nephrotoxic antibiotic per prescription, while 26 (15.0%) received two nephrotoxic antibiotics concurrently in Figure 1. Among the mono-nephrotoxic prescriptions, ceftriaxone was the most frequently prescribed (35.8%), followed by amoxicillin-clavulanic acid (26.6%) and ciprofloxacin (16.2%). For dual nephrotoxic prescriptions, the combination of ceftriaxone and ciprofloxacin was most common (12.1%), followed by amoxicillin-clavulanic acid and ciprofloxacin (2.3%) [Figure 1].

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Figure 1:

Number of potentially nephrotoxic antibiotics per prescription (n = 173). n represents number of patients.

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Overall nephrotoxic antibiotics by class and individual drugs

In terms of antibiotic classes, cephalosporins were the most frequently used nephrotoxic agents (45.2%), followed by fluoroquinolones (26.6%) and penicillins (26.1%). Individually, ceftriaxone remained the most commonly prescribed antibiotic (40.7%), followed by ciprofloxacin (26.6%) and amoxicillin-clavulanic acid (25.6%). Less common agents included neomycin (0.5%), ampicillin-cloxacillin (0.5%), and doxycycline (0.5%), as shown in Figure 2.

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Figure 2:

Overall potentially nephrotoxic antibiotics by class and individual drugs (n = 199). n represents number of patients.

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DISCUSSION

The results demonstrate a high prevalence of nephrotoxic antibiotic prescriptions among patients living with CKD, with cephalosporins, fluoroquinolones, and penicillins being the most frequently prescribed. The concurrent use of multiple antibiotics is associated with an increased risk of nephrotoxicity. Although no immediate impact on renal function was observed between groups, prolonged exposure could lead to a significant reduction in renal function within the exposed group over time. These findings underscore the need for cautious antibiotic prescribing and enhanced antimicrobial stewardship to safeguard patients with CKD from further renal impairment.

The findings of this study reveal a significant prevalence of nephrotoxic antibiotic prescriptions, with 88.7% of patients receiving potentially harmful agents. This aligns with previous research emphasizing the widespread use of nephrotoxic antibiotics in clinical practice. For instance, a Swedish study reported a comparable frequency of nephrotoxic antibiotic prescriptions.¹⁸ These findings raise serious concerns about prescribing safety in renal-impaired populations. It highlights a need for heightened awareness and caution among prescribers.

The predominance of cephalosporins, particularly ceftriaxone, as the most frequently prescribed nephrotoxic antibiotic aligns with trends observed in other studies. A previous study similarly identified cephalosporins (cefixime) as commonly implicated in nephrotoxicity in an Indonesian cohort.¹⁹ The high utilization of cephalosporins is likely due to their broad-spectrum efficacy, making them a preferred choice in diverse clinical settings. However, AIN associated with cephalosporins is more frequently linked to first-generation cephalosporins.⁵ AIN typically presents as non-oliguric AKI in approximately 10 days post-exposure, often accompanied by pyuria, hematuria, and low-grade proteinuria.¹⁶ Although eosinophilia and allergic-type symptoms may be present, they are often absent.^15,20 These findings highlight the importance of reevaluating prescribing patterns to mitigate renal impairment risks.

In contrast, vancomycin was the most frequently prescribed nephrotoxic antibiotic among patients with renal impairment in Ethiopia.¹² This discrepancy may be attributed to differences in bacterial resistance patterns and prescribing habits across healthcare settings in different countries. Notably, ciprofloxacin ranked as the second most prescribed nephrotoxic antibiotic in both the present study and a previous study,¹² consistent with evidence linking fluoroquinolones, particularly ciprofloxacin, to AKI.^16,20,21 AKI associated with fluoroquinolones is predominantly secondary to AIN but has also been reported to result from acute tubular necrosis (ATN) in cases of overdose, as well as rare occurrences of granulomatous interstitial nephritis and crystalluria.^20,22–24 In the present study, penicillins, primarily amoxicillin-clavulanic acid, ranked third among the most frequently prescribed antibiotics that are nephrotoxic. Granulomatous AIN has been observed on biopsy following the use of penicillins (such as methicillin, ampicillin, and oxacillin) and cephalosporins,²⁵ further reinforcing the necessity of cautious prescribing, particularly in patients with CKD. While most patients in the present study received a single nephrotoxic agent, the occurrence of dual nephrotoxic prescriptions warrants concern. The most common combination observed was ceftriaxone with ciprofloxacin. This underscores the necessity of rational prescribing when treating infection in CKD populations by more stringent evaluation of alternatives or favoring antibiotics with a lower nephrotoxicity profile when clinically appropriate.

The present study also identified a strong relationship between the number of antibiotics prescribed and the risk of nephrotoxicity, a pattern consistent with previous research.¹² This reinforces the importance of minimizing antibiotic exposure through judicious prescribing. Notably, neither age nor sex emerged as significant predictors of nephrotoxicity in the present cohort, a finding that contrasts with prior studies that identified older age as a risk factor for AKI in patients receiving nephrotoxic medications.^12,26 The absence of significant age-related differences in the present study suggests the need for further investigation into potential confounding factors unique to this patient population. Nevertheless, poly-antibiotic therapy should be carefully justified and closely monitored in patients with CKD.

Furthermore, a slight trend suggesting males were less likely to develop nephrotoxicity compared to females adds complexity to the interpretation of sex-related risks. While some studies have reported increased susceptibility in female patients, potentially due to pharmacokinetic differences and variations in body composition,^12,27 further research is warranted to clarify these associations. Between-group comparisons revealed that at baseline, patients exposed to nephrotoxic antibiotics and those not exposed had similar median eGFR values, indicating no pre-existing differences in renal function. However, at 3-month follow-up, the exposed group exhibited a slight decline in eGFR compared to the unexposed group. While not statistically significant, this trend aligns with the findings of a prior study conducted in the same study area, which also reported no statistically significant differences in the mean change in eGFR per month among patients with CKD exposed to several nephrotoxic medications.⁶ The absence of significant differences in eGFR progression between the exposed and unexposed groups may reflect either a short follow-up period or the presence of potential confounders. Nonetheless, the clinical burden of impaired renal function in these patients warrants close surveillance.

CONCLUSION

The study findings highlight the need for heightened awareness, careful monitoring of renal function, and avoidance of unnecessary exposure to nephrotoxic antibiotics. The increased risk of nephrotoxicity associated with dual antibiotic prescriptions emphasizes the need for rational prescribing, favoring lower-risk alternatives whenever feasible.

While certain demographic variables did not emerge as significant predictors, the results suggest the need for continued research into the nuanced interactions between antibiotic prescribing patterns and renal outcomes. Moving forward, a balanced approach to antibiotic therapy is critical, ensuring effective infection management while minimizing nephrotoxicity. Strengthening antibiotic stewardship programs and fostering a multidisciplinary approach involving nephrologists, infectious disease specialists, and clinical pharmacists will be instrumental in optimizing patient outcomes and preserving renal function in this high-risk population.