Pharmacokinetic-Pharmacodynamic Analysis of Ciprofloxacin in Elderly Chinese Patients with Lower Respiratory Tract Infections Caused by Gram-Negative Bacteria

Pharmacokinetic-Pharmacodynamic Analysis of Ciprofloxacin in Elderly Chinese Patients with Lower Respiratory Tract Infections Caused by Gram-Negative Bacteria

Lower respiratory tract infections (LRTIs), including pneumonia, are a significant cause of morbidity and mortality worldwide, particularly among the elderly population. In China, LRTIs pose a substantial health burden, especially in elderly patients with chronic lung or heart disease. Gram-negative bacteria, such as Pseudomonas aeruginosa, are common pathogens in these infections and are associated with high mortality rates, often exceeding 40%. Antibiotic therapy in elderly patients is particularly challenging due to age-related changes in drug absorption, distribution, metabolism, and excretion. Ciprofloxacin, a third-generation quinolone, is widely used for treating LRTIs caused by Gram-negative bacteria due to its broad-spectrum antimicrobial activity, particularly against P. aeruginosa. However, recent international studies have raised concerns about the adequacy of ciprofloxacin dosing in severe infections, suggesting that underdosing may lead to poor clinical outcomes and the development of drug resistance.

This study aimed to perform a pharmacokinetic (PK) and pharmacodynamic (PD) analysis of ciprofloxacin in elderly Chinese patients with severe LRTIs caused by Gram-negative bacteria. The primary objective was to evaluate whether ciprofloxacin dosing regimens achieved the target PK/PD indices, specifically the area under the serum concentration-time curve to the minimum inhibitory concentration ratio (AUC/MIC) and the maximum serum concentration to the MIC ratio (Cmax/MIC). These indices are critical for predicting the clinical and bacteriologic efficacy of ciprofloxacin, a concentration-dependent antibiotic.

The study enrolled 33 elderly patients (mean age: 76.9 ± 6.7 years) with LRTIs caused by Gram-negative bacteria, including P. aeruginosa (17 patients), Acinetobacter baumannii (14 patients), and Klebsiella pneumoniae (2 patients). Patients were empirically treated with a combination of beta-lactams and ciprofloxacin, administered intravenously at doses of 200 mg or 400 mg every 12 hours, depending on the severity of the infection and renal function. Blood samples were collected at multiple time points following ciprofloxacin administration, and serum concentrations were determined using high-performance liquid chromatography. The MIC values for the pathogens were determined using the VITEK 2 identification system, and the AUC/MIC and Cmax/MIC ratios were calculated for each patient.

The results revealed that 93.4% of patients (31 out of 33) did not achieve the target AUC/MIC value of >125, and 87.9% (29 out of 33) did not reach the target Cmax/MIC value of >8. These findings indicate that ciprofloxacin dosing was inadequate in most patients, particularly those infected with pathogens with higher MIC values. The median AUC/MIC and Cmax/MIC ratios for the entire cohort were 12.7 (range: 3.8–214.9) and 1.7 (range: 0.4–17.8), respectively. Only two patients achieved the target AUC/MIC value, and both experienced clinical success. Similarly, four patients reached the target Cmax/MIC value, all of whom achieved bacteriologic success.

The study further compared PK/PD parameters between the clinical success and clinical failure groups. The clinical success group (8 patients) had significantly higher AUC/MIC and Cmax/MIC ratios compared to the clinical failure group (25 patients) (AUC/MIC: 61.1 vs. 10.4; Cmax/MIC: 9.6 vs. 1.3; both P < 0.001). Similarly, patients with bacteriologic success (7 patients) had significantly higher AUC/MIC and Cmax/MIC ratios than those with bacteriologic failure (26 patients) (AUC/MIC: 75.3 vs. 10.5; Cmax/MIC: 11.4 vs. 1.4; both P < 0.001). These results underscore the importance of achieving adequate PK/PD targets for clinical and bacteriologic efficacy.

Receiver operating characteristic (ROC) curve analysis was performed to determine the predictive value of AUC/MIC and Cmax/MIC for clinical and bacteriologic efficacy. The AUC under the ROC curve for AUC/MIC in predicting clinical efficacy was 0.966, with a threshold of 40.9, yielding a sensitivity of 85.7% and specificity of 91.3%. For Cmax/MIC, the AUC under the ROC curve was 0.986, with a threshold of 3.7, demonstrating 100% sensitivity and 90.5% specificity. Similar results were observed for bacteriologic efficacy, with AUC/MIC and Cmax/MIC thresholds of 40.9 and 3.7, respectively, and high sensitivity and specificity values.

The study also highlighted the challenges of treating drug-resistant Gram-negative bacteria. Among the 17 P. aeruginosa isolates, seven had MIC values of 4 mg/L, indicating resistance to ciprofloxacin. Similarly, 11 out of 14 A. baumannii isolates had MIC values of 4 mg/L. These high MIC values contributed to the low AUC/MIC and Cmax/MIC ratios observed in the study, as ciprofloxacin dosing regimens were insufficient to achieve the target PK/PD indices for resistant pathogens.

The findings of this study align with previous international research, which has also reported inadequate ciprofloxacin dosing in patients with severe infections. For example, Forrest et al. demonstrated that patients with AUC/MIC values ≥125 had significantly higher clinical and bacteriologic success rates compared to those with lower ratios. Similarly, Haeseker et al. found that a significant proportion of patients did not achieve the target AUC/MIC value, particularly those infected with pathogens with higher MIC values. These studies collectively emphasize the need for optimized dosing regimens to ensure adequate drug exposure and improve clinical outcomes.

The study also explored the potential benefits of combination therapy with beta-lactams. While all patients received beta-lactams in addition to ciprofloxacin, most Gram-negative bacteria were resistant to the combined beta-lactams in vitro. However, the clinical success observed in some patients may be attributed to the synergistic effects of ciprofloxacin and beta-lactams, as demonstrated in previous in vitro studies. This highlights the importance of considering combination therapy in the treatment of severe LRTIs caused by Gram-negative bacteria, particularly in the context of increasing drug resistance.

In conclusion, this study provides valuable insights into the PK/PD characteristics of ciprofloxacin in elderly Chinese patients with LRTIs caused by Gram-negative bacteria. The findings underscore the importance of achieving adequate AUC/MIC and Cmax/MIC ratios for clinical and bacteriologic efficacy. However, the current dosing regimens appear to be inadequate, particularly for drug-resistant pathogens with higher MIC values. The study also highlights the potential benefits of combination therapy and the need for optimized dosing strategies based on patient-specific PK/PD parameters and pathogen MIC values. Future research should focus on developing population PK models and individualized dosing regimens to improve treatment outcomes in this vulnerable patient population.

doi.org/10.1097/CM9.0000000000000136

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