Ciprofloxacin can be administered enterally. Enteral administration is a desired alternative route for step-down therapy in patients who cannot eat but whose gastrointestinal tract is functioning. We identified 8 potentially eligible trials reporting on administration of different doses of ciprofloxacin to patients receiving continuous enteral feeds. On detailed examination, only one trial met the inclusion criteria. The other 7 trials were excluded because of various methodologic issues, such as lack of randomization, lack of a control group and/ or lack of a cross-over design, study population of healthy volunteers, or lack of direct comparison of the treatment regimens outlined in the research question.
In the trials that have been performed to date, clinical outcomes have not been measured. Therefore, pharmacokinetic data must be extrapolated to evaluate the optimal dose of ciprofloxacin for patients receiving continuous enteral feeds. As such, an analysis of randomized cross-over trials is most appropriate. The only trial meeting this criterion that we identified was that of De Marie and others. These authors reported the AUC, Cmax, and Tmax after steady state was achieved in 5 tube-fed patients with severe gram-negative intra-abdominal infections who were receiving ciprofloxacin either 400 mg BID intravenously or 750 mg BID enterally. All of the patients had either nasogastric or nasoduodenal tubes for enteral administration. Unfortunately, the authors did not differentiate the pharmacokinetic parameters according to whether the patients had nasogastric or nasoduodenal tubes. Absorption of ciprofloxacin may be more favourable in the duodenum, which may affect the AUC. However, it has also been reported that ciprofloxacin is absorbed well in the upper gastrointestinal tract, with greater absorption in the stomach and duodenum than in the jejunum; as such, as long as the enteral tube is not placed beyond the jejunum, placement may not be clinically important.
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De Marie and others demonstrated that IV and enteral administration achieve similar AUC values, but the Cmax for enterally administered ciprofloxacin is lower than that for the parenteral route. Unfortunately, these authors did not report patient-specific MIC values for the indicated organisms; therefore, we were unable to determine the patient-specific AUC/MIC and Cmax/MIC ratios, which have been shown to correlate with clinical outcomes. We could not extrapolate population MIC values to generate the AUC/MIC and Cmax/MIC ratios, since population estimates of organism-specific MICs do not necessarily predict the outcome for individual patients in response to a particular antibiotic. The actual MIC values of the infective organism in a particular patient may be higher or lower than the estimated population MIC values. Other limitations of the study by De Marie and others were the small sample size (5 patients) and the fact that all patients had a gram-negative intra-abdominal infection, which limits the applicability of these results to other patient populations, including patients with other infections. Of note is the study by Kanji and others, who analyzed the pharmacokinetic parameters of gatifloxacin in critically ill patients. This trial had a design similar to that of the study by De Marie and others. Kanji and others found that Cmax levels for gatifloxacin were lower when tablets were given orally with enteral feeds than when the gatifloxacin was given intravenously; however, AUC levels were similar for the 2 dosage forms. Kanji and others did not report patient- specific MICs for the indicated organisms; we were therefore unable to determine the patient-specific AUC/MIC and Cmax/MIC ratios, nor could we make any suggestions about correlations with clinical outcomes according to different dosage forms.
Fluoroquinolones display unique pharmacodynamic properties, whereby the drugs exhibit both concentration- dependent and time-dependent bacterial killing. In previous studies, both Cmax/MIC and AUC/MIC ratios reflected the effectiveness of quinolones, whereas the AUC/MIC ratio provided a better representation of the effectiveness of these drugs. Providing maximal drug exposure allows eradication of bacteria and reduces the risk of antibiotic resistance. Thus, the therapeutic goal is to maximize drug exposure, as represented by the extent of bioavailability from the AUC. Other studies have shown that a Cmax/MIC ratio of at least 10 would eradicate bacteria, and AUC/MIC ratios greater than 125 were associated with successful clinical outcomes. In a retrospective study of IV ciprofloxacin treatment of seriously ill patients, Forrest and others15 associated the AUC/MIC ratio with clinical and microbiological outcomes. They found that with an AUC/MIC ratio above 125, the probability of clinical cure was 80% and the probability of microbiological cure was 82%. However, debate continues as to whether AUC/MIC ratios are organism-specific. Some claim that gram-positive bacteria require an AUC/MIC ratio of 30-50 and gram-negative bacteria an AUC/MIC ratio of 100-125. Others have stated that “at this time, it is clear that for different organisms, different free drug AUC/MIC ratios are desirable. Attempts to standardize exposure to one AUC/MIC ratio are erroneous.”