99
DIAG. MICROBIOL.INFECT. DIS. 1990;13:99-102
Absorption of Ciprofloxacin Administered Through a Nasogastric or a Nasoduodenal Tube in Volunteers and Patients Receiving Enteral Nutrition Jae H. Yuk, Charles H. Nightingale, Richard Quintiliani, Neil S. Yeston, Rocco Orlando III, Eric D. Dobkin, Joseph C. Kambe, Kevin R. Sweeney, and Elizabeth A. Buonpane
The absorption of ciprofloxacin was higher when administered through a nasoduodenal tube than through a nasogastric tube, indicating that even though acidic gastric pH is needed for rapid disintegration, dissolved ciprofloxacin might not be stable in the gastric environment. If the length of exposure or the different gastric environment in each individual affects the
overall absorption of ciprofloxacin, this could explain the reported variability in ciprofloxacin absorption and suggests the need for the development of an enteric-coated tablet. Further studies are needed to fully characterize the absorption of ciprofloxacin in patients with different illnesses, gastric transit times, gastrointestinal environments and of different ages.
INTRODUCTION
feeding tube. Depending on h o w far the tube is passed into the gastrointestinal tract, the nasoenteral tubes can be either nasogastric (NG) or nasoduodenal (ND). External tubes are c o m m o n l y u s e d in the intensive care setting for the administration of both enteral nutrition a n d medications. A l t h o u g h there are considerable data on the bioavailability of ciprofloxacin after oral administration a n d administration t h r o u g h an NG tube in healthy volunteers (Yuk et al., 1989), there is little information about its bioavailability w h e n given via enteral feeding tubes in critically ill patients. Drug absorption variability occurs more likely in patients w h o have unstable clinical conditions requiring intensive care. Such patients t e n d to have an altered physiological status, including the function of the gastrointestinal (GI) tract, a n d the absorption characteristics in these patients might be different from those of healthy volunteers. To clarify the bioavailability of ciprofloxacin in critically ill patients, we studied its absorption characteristics after
Because of its potent microbiological activity against a wide variety of bacteria a n d its excellent absorption from the gastrointestinal tract w h e n orally administered, ciprofloxacin has become a popular drug choice for the treatment of serious infections. It is often considered for critically ill patients, including those w h o require administration t h r o u g h an enteral From the Departments of Pharmacy (J.H.C., C.H.N., K.R.S., E.A.B.), Infectious Diseases (R.Q.), and Critical Care Medicine (N.S.Y., R.O., E.D.D., J.C.K.), Hartford Hospital, Hartford; and the University of Connecticut, School of Pharmacy (J.H.C., C.H.N., K.R.S., E.A.B.), Storrs, and School of Medicine (R.Q., N.S.Y., R.O., E.D.D., J.C.K.), Farrnington, Connecticut. Address reprint requests to: Dr. C.H. Nightingale, Vice President, Hartford Hospital, Hartford, CT 06115. Received January 10, 1990; revised and accepted January 12, 1990. © 1990 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/90/$3.50.
100
administration through NG, gastrostomy (G), or ND tubes.
MATERIALS AND METHODS Patient Population Patients in the intensive care unit (ICU) were screened for normal renal and hepatic function. Patients tolerating enteral feeding without diarrhea or a significant residual (>200 ml) were enrolled in the study. Patients with GI disorders (e.g., malabsorption, ulcer, small bowel obstruction), previous GI surgery (e.g., gastrectomy, small bowel resection), and those on antidiarrheal agents or drugs to promote GI motility (e.g., metoclopramide) were excluded from the study. Antacids and sucralfate, which have been reported to decrease ciprofloxacin absorption (Hoffken et al., 1985; Preheim et al., 1986; Parpia et al., 1989), were substituted by H2 antagonists at least 24 hr prior to the initiation of the study and were not allowed during the entire study period to avoid drug interactions. The demographics of the seven participating patients are summarized in Table 1.
J.H. Yuk et al.
Because the patients' weights varied over a wide range and a fixed dose was used regardless of body size, areas under serum concentration versus time curve (AUCs) obtained by a trapezoidal rule were corrected for lean body weight (LBW) (Hallynck et al., 1981); LBW was chosen over total body weight or ideal body weight, as ciprofloxacin has been reported to be minimally lipid soluble (Ashby et al., 1985; Stein, 1988). Although few in number, patients w h o received ciprofloxacin through an ND tube achieved consistently higher AUCs than patients who received ciprofloxacin through an NG or G tube (25.35 _+ 8.28 vs. 11.27 _+ 5.39 ~g.hr/ml), suggesting a difference in ciprofloxacin absorption as a function of the segments of the GI tract into which ciprofloxacin is introduced or differences in elimination due to age (Fig. 1). Maximum serum concentrations (Cmax) were also much higher after ND administration compared to those after NG or G administration (4.60 + 1.11 vs. 2.57 _+ 1.00 ~g/ml). Although difficult to characterize with few data points, peak concentrations appeared to be achieved rapidly in both cases, as expected with the administration of a suspension dosage form.
Drug Administration
DISCUSSION
Ciprofloxacin tablets (750 rag) (Miles, Inc.) were administered to all study patients after informed consents were obtained. Suspensions were prepared at the bedside (a tablet was crushed with a mortar and pestle and suspended in 40 ml of water) and administered by the same investigator every 12 hr. The suspension was drawn into a syringe and delivered through the feeding tube. An additional 30 ml of water was used twice to rinse the remaining drug from the tube and was then administered to the patients to ensure delivery of the entire dose. Enteral feedings were interrupted only at the time of dosing and were resumed immediately after dosing.
The bioavailability of ciprofloxacin after oral administration varies from 64% to 85% (Davis et al., 1985; Bergan et al., 1986; Borner et al., 1986; Tartaglione et al., 1986). Its absorption from the gastrointestional tract has been reported to be passive and variable, possibly due to the intestinal pH that influences the ionization and dissolution of the tablet (Wingender et al., 1986). The variability in bioavailability reported is greater with larger doses (100 vs. 750 mg) and is partially attributed to more variable disintegration and dissolution rates of the tablet (Plaisance et al., 1987). In this study, there was a tendency for greater absorption when ciprofloxacin was administered directly into the duodenum, as compared with its administration into the stomach, suggesting that there may be a possible degradation of ciprofloxacin w h e n it is exposed to the gastric environment. This difference may also be explained by the fact that the stomach, compared with the small intestine, has a small absorptive area in the GI tract due to the lack of villus-type membrane and the presence of tight junctions between the epithelial cells. Only a few highly lipid-soluble substances or weak acids, such as alcohol and aspirin, can be absorbed at the site in small quantities. Because the stomach delivers its contents into the small intestine, the overall absorption should be equal when a drug is delivered into the stomach rather than the duodenum. The en-
Sample Collection and Assay Blood samples were obtained just before and at 0.5, 1, 2, 3, 6, 9, and 12 hr after the fourth dose. Samples were allowed to clot; sera were removed and stored frozen at -70°C until the time of assay. Samples were assayed using a modified high-performance liquid chromatography (HPLC) assay (Jehl et al., 1985, 1987).
RESULTS The data from four patients with ND tubes and three with NG or G tubes are summarized in Table 2.
A b s o r p t i o n via Enteral Feeding Tubes
101
TABLE 1.
Patient D e m o g r a p h i c s
Patient No.
Feeding Tube
Age
Sex
Weight (kg)
Height (cm)
1 2 3 4 5 6 7b
ND NG ND G ND ND NG
76 61 72 47 76 71 74
M M M M M M M
80 79 110 55 72 65 46
173 170 179 175 185 183 183
Enteral Feeding (ml/hr)" Jevity FS 80 Jevity FS 75 Jevity FS 100 Jevity FS 100 Jevity FS 75 Jevity FS 70 Osmolite FS 60
Underlying Diseases c s/p CABG s/p lobectomy Respiratory failure Hypoglycemic coma s/p AVR s/p AVR s/p urosepsis
=FS, full strength. bNon-lCU patient. CCABG, coronary artery bypass graft; s/p, status post; and AVR, aortic valve replacement.
51
~
4, Mean NG ( A U C = 11.27 mcg.hr/ml) ----o-- Mean ND ( A U C = 25.35 mcg-hr/ml)
4-
::L-J
.o "o =,.
N
E~
2
3- ~
~.
5
10
15
Time (hour)
FIGURE 1. Mean serum concentration versus time curve from patients with ND tubes (open square) and patients with NG or G tubes (solid diamond). Concentrations were corrected for weight by dividing by expected LBW of 70kg male patient's calculated LBW.
TABLE 2.
Area U n d e r the S e r u m C o n c e n t r a t i o n vs. Time C u r v e (AUC)
Feeding Tube
Patient No.
AUC a (~g.hr/ml)
ND ND
1 3
20.52 37.72
ND ND
5 6
20.81 22.36
NG G NG c
2 4 7
10.88 6.09 16.84
Mean AUC _+ SDb (Izg.hr/ml)
25.35 + 8.28
Volunteer data a
11.27 + 5.39 15.26 --- 3.90
"AUC divided by LBW expected in 70-kg male patient's calculated LBW. bMean AUC (normalized by LBW) __-standard deviation (SD). CNon-ICU patient. eData obtained from six healthy male volunteers who received ciprofloxacin through an NG tube with concurrent enteral feeding (Yuk et al., 1989).
h a n c e d absorption of ciprofloxacin t h r o u g h N D tube administration c o m p a r e d with that given t h r o u g h an N G tube is consistent with the postulate that an unfavorable condition exists in the stomach for its absorption. The differences in the rate of a b s o r p t i o n can theoretically affect the AUC if there is a capacitylimited metabolism process. We d o not believe this to be the case, as changes in elimination rates of ciprofloxacin w e r e not observed. The difference observed in our s t u d y is opposite that expected based on n o r m a l physiology. W h e n ciprofloxacin was delivered in a s u s p e n s i o n form, the disintegration step that contributes to the variability after oral administration was circumv e n t e d and this was not responsible for the differences observed. H o w e v e r , the effect of the gastric e n v i r o n m e n t might also have b e e n a u g m e n t e d in our s t u d y with the s u s p e n s i o n form of administration, w h i c h allows m o r e ciprofloxacin to be in direct contact with the gastric e n v i r o n m e n t as c o m p a r e d to the administration of an intact tablet. The slightly greater absorption of ciprofloxacin with enteral feeding in our v o l u n t e e r s t u d y (Yuk et al., 1989) is consistent with this postulate; it might also be explained as a result of the mitigation of the gastric environm e n t b y c o n c u r r e n t enteral feeding. The data from a non-ICU patient, patient 7, is intriguing (see Tables 1 a n d 2) a n d implies a n o t h e r factor that could affect the overall a b s o r p t i o n of ciprofloxacin. This patient h a d a smaller b o d y mass t h a n expected d u e to his p o o r nutritional status (46 kg; ideal b o d y weight, 78 kg); this could have led to a smaller volume of distribution and resulted in falsely elevated concentrations a n d AUC. W h e n the AUC was corrected, taking the difference in b o d y w e i g h t into consideration, the AUC achieved was consistent but slightly h i g h e r t h a n those from other N G or G tube patients. H o w e v e r , this patient was in relatively stable condition (non-ICU patient with urosepsis) compared to the other patients studied, which could have led to a different gastric e n v i r o n m e n t
102
(e.g., less acidity). A l t h o u g h this patient also received a different enteral feeding formula, which might have affected the results, it is not likely due to the overall similarity of the feeding formulas.
J.H. Yuk et al.
A l t h o u g h the n u m b e r of subjects is small, examination of Table 1 reveals a bias in the age of patients; the ND patients are s o m e w h a t older, indicating a possible effect of age on the observed AUC.
REFERENCES
Ashby J, Piddock LJV, Wise R (1985) An investigation of the hydrophobicity of the quinolones. J Antimicrob Chemother 16:805-810. Bergan T, Thorsteinsson SB, Kolstad IM, Jognsen S (1986) Pharmacokinetics of ciprofloxacin after intravenous and increasing oral doses. Eur J Clin Microbiol 5:187-192. Borner K, Hoffken G, Lode H, Koeppe P, Prinzing C, Glatzel P, Wiley R, Olschewski P, Stevens B, Reinitz D (1986) Pharmacokinetics of ciprofloxacin in healthy volunteers after oral and intravenous administration. Eur J Clin Microbiol 5:179-186. Davis RL, Koup JR, Williams-Warren J, Weber A, Smith AL (1985) Pharmacokinetics of three oral formulations of ciprofloxacin. Antimicrob Agents Chemother 18:74-77. HaUynck TH, Soep HH, Thomis JA (1981) Should clearance be normalized to body surface area or to lean body mass? Br J Clin Pharmacol 11:523-526. Hoffken C, Borner K, Glatzel PD, Koeppe P, Lode H (1985) Reduced enteral absorption of ciprofloxacin in the presence of antacids. Eur J Clin Microbiol 4:345. Jehl F, Gallion C, Debs J, Brogard JM, Monteil H, Minck R (1985) High-performance liquid chromatographic method for detection of ciprofloxacin in biological fluids. J Chromatogr 339:347-357. Jehl F, Adloff M, Monteil H, Brogard JM (1987) Ciprofloxacin biliary disposition in cholecystectomized patients with special references to HPLC and bioassay data. Eur J Drug Met Pharmacokin 12:115-122.
Parpia SH, Nix DE, Hejmanowski LG, Goldstein HR, Wilton JH, Shentag JJ (1989) Sucralfate reduces the gastrointestinal absorption of norfloxacin. Antimicrob Agents Chemother 33:99-102. Plaisance KI, Drusano GL, Forrest A, Bustamante CI, Standiford HC (1987) Effects of dose size on bioavailability of ciprofloxacin. Antimicrob Agents Chemother 31:956958. Preheim LC, Cuevas TA, Roccaforte JS, MeUencamp MA, Bittner MJ (1986) Ciprofloxacin and antacids. Lancet 2:48. Stein GE (1988) The 4-quinolone antibiotics: past, present, and future. Pharmacotherapy 8:301-314. Tartaglione TA, Raffalovich AC, Pognor WJ, EspineMngroff A, Kerkerig TM (1986) Pharmacokinetics and tolerance of ciprofloxacin after sequential increasing oral doses. Antimicrob Agents Chemother 29:62-66. Wingender W, Beerman D, Forster D, Graefe K-H, Kuhlmann J (1986) Interaction of ciprofloxacin with food intake and drugs. In First International Ciprofloxacin Workshop, Leverkusen, FRG, 1985. Eds. HC Neu and H Weuta. Amsterdam: Excerpta Medica, pp 136-140. Yuk JH, Nightingale CH, Sweeney KR, Quintiliani R, Lettieri JT, Frost RW (1989) Relative bioavailability of ciprofloxacin administered through a nasogastric tube with and without enteral feeding in healthy volunteers. Antimicrob Agents Chemother (in press).
DIAG. MICROBIOL.INFECT. DIS. 1990;13:99-102
Absorption of Ciprofloxacin Administered Through a Nasogastric or a Nasoduodenal Tube in Volunteers and Patients Receiving Enteral Nutrition Jae H. Yuk, Charles H. Nightingale, Richard Quintiliani, Neil S. Yeston, Rocco Orlando III, Eric D. Dobkin, Joseph C. Kambe, Kevin R. Sweeney, and Elizabeth A. Buonpane
The absorption of ciprofloxacin was higher when administered through a nasoduodenal tube than through a nasogastric tube, indicating that even though acidic gastric pH is needed for rapid disintegration, dissolved ciprofloxacin might not be stable in the gastric environment. If the length of exposure or the different gastric environment in each individual affects the
overall absorption of ciprofloxacin, this could explain the reported variability in ciprofloxacin absorption and suggests the need for the development of an enteric-coated tablet. Further studies are needed to fully characterize the absorption of ciprofloxacin in patients with different illnesses, gastric transit times, gastrointestinal environments and of different ages.
INTRODUCTION
feeding tube. Depending on h o w far the tube is passed into the gastrointestinal tract, the nasoenteral tubes can be either nasogastric (NG) or nasoduodenal (ND). External tubes are c o m m o n l y u s e d in the intensive care setting for the administration of both enteral nutrition a n d medications. A l t h o u g h there are considerable data on the bioavailability of ciprofloxacin after oral administration a n d administration t h r o u g h an NG tube in healthy volunteers (Yuk et al., 1989), there is little information about its bioavailability w h e n given via enteral feeding tubes in critically ill patients. Drug absorption variability occurs more likely in patients w h o have unstable clinical conditions requiring intensive care. Such patients t e n d to have an altered physiological status, including the function of the gastrointestinal (GI) tract, a n d the absorption characteristics in these patients might be different from those of healthy volunteers. To clarify the bioavailability of ciprofloxacin in critically ill patients, we studied its absorption characteristics after
Because of its potent microbiological activity against a wide variety of bacteria a n d its excellent absorption from the gastrointestinal tract w h e n orally administered, ciprofloxacin has become a popular drug choice for the treatment of serious infections. It is often considered for critically ill patients, including those w h o require administration t h r o u g h an enteral From the Departments of Pharmacy (J.H.C., C.H.N., K.R.S., E.A.B.), Infectious Diseases (R.Q.), and Critical Care Medicine (N.S.Y., R.O., E.D.D., J.C.K.), Hartford Hospital, Hartford; and the University of Connecticut, School of Pharmacy (J.H.C., C.H.N., K.R.S., E.A.B.), Storrs, and School of Medicine (R.Q., N.S.Y., R.O., E.D.D., J.C.K.), Farrnington, Connecticut. Address reprint requests to: Dr. C.H. Nightingale, Vice President, Hartford Hospital, Hartford, CT 06115. Received January 10, 1990; revised and accepted January 12, 1990. © 1990 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/90/$3.50.
100
administration through NG, gastrostomy (G), or ND tubes.
MATERIALS AND METHODS Patient Population Patients in the intensive care unit (ICU) were screened for normal renal and hepatic function. Patients tolerating enteral feeding without diarrhea or a significant residual (>200 ml) were enrolled in the study. Patients with GI disorders (e.g., malabsorption, ulcer, small bowel obstruction), previous GI surgery (e.g., gastrectomy, small bowel resection), and those on antidiarrheal agents or drugs to promote GI motility (e.g., metoclopramide) were excluded from the study. Antacids and sucralfate, which have been reported to decrease ciprofloxacin absorption (Hoffken et al., 1985; Preheim et al., 1986; Parpia et al., 1989), were substituted by H2 antagonists at least 24 hr prior to the initiation of the study and were not allowed during the entire study period to avoid drug interactions. The demographics of the seven participating patients are summarized in Table 1.
J.H. Yuk et al.
Because the patients' weights varied over a wide range and a fixed dose was used regardless of body size, areas under serum concentration versus time curve (AUCs) obtained by a trapezoidal rule were corrected for lean body weight (LBW) (Hallynck et al., 1981); LBW was chosen over total body weight or ideal body weight, as ciprofloxacin has been reported to be minimally lipid soluble (Ashby et al., 1985; Stein, 1988). Although few in number, patients w h o received ciprofloxacin through an ND tube achieved consistently higher AUCs than patients who received ciprofloxacin through an NG or G tube (25.35 _+ 8.28 vs. 11.27 _+ 5.39 ~g.hr/ml), suggesting a difference in ciprofloxacin absorption as a function of the segments of the GI tract into which ciprofloxacin is introduced or differences in elimination due to age (Fig. 1). Maximum serum concentrations (Cmax) were also much higher after ND administration compared to those after NG or G administration (4.60 + 1.11 vs. 2.57 _+ 1.00 ~g/ml). Although difficult to characterize with few data points, peak concentrations appeared to be achieved rapidly in both cases, as expected with the administration of a suspension dosage form.
Drug Administration
DISCUSSION
Ciprofloxacin tablets (750 rag) (Miles, Inc.) were administered to all study patients after informed consents were obtained. Suspensions were prepared at the bedside (a tablet was crushed with a mortar and pestle and suspended in 40 ml of water) and administered by the same investigator every 12 hr. The suspension was drawn into a syringe and delivered through the feeding tube. An additional 30 ml of water was used twice to rinse the remaining drug from the tube and was then administered to the patients to ensure delivery of the entire dose. Enteral feedings were interrupted only at the time of dosing and were resumed immediately after dosing.
The bioavailability of ciprofloxacin after oral administration varies from 64% to 85% (Davis et al., 1985; Bergan et al., 1986; Borner et al., 1986; Tartaglione et al., 1986). Its absorption from the gastrointestional tract has been reported to be passive and variable, possibly due to the intestinal pH that influences the ionization and dissolution of the tablet (Wingender et al., 1986). The variability in bioavailability reported is greater with larger doses (100 vs. 750 mg) and is partially attributed to more variable disintegration and dissolution rates of the tablet (Plaisance et al., 1987). In this study, there was a tendency for greater absorption when ciprofloxacin was administered directly into the duodenum, as compared with its administration into the stomach, suggesting that there may be a possible degradation of ciprofloxacin w h e n it is exposed to the gastric environment. This difference may also be explained by the fact that the stomach, compared with the small intestine, has a small absorptive area in the GI tract due to the lack of villus-type membrane and the presence of tight junctions between the epithelial cells. Only a few highly lipid-soluble substances or weak acids, such as alcohol and aspirin, can be absorbed at the site in small quantities. Because the stomach delivers its contents into the small intestine, the overall absorption should be equal when a drug is delivered into the stomach rather than the duodenum. The en-
Sample Collection and Assay Blood samples were obtained just before and at 0.5, 1, 2, 3, 6, 9, and 12 hr after the fourth dose. Samples were allowed to clot; sera were removed and stored frozen at -70°C until the time of assay. Samples were assayed using a modified high-performance liquid chromatography (HPLC) assay (Jehl et al., 1985, 1987).
RESULTS The data from four patients with ND tubes and three with NG or G tubes are summarized in Table 2.
A b s o r p t i o n via Enteral Feeding Tubes
101
TABLE 1.
Patient D e m o g r a p h i c s
Patient No.
Feeding Tube
Age
Sex
Weight (kg)
Height (cm)
1 2 3 4 5 6 7b
ND NG ND G ND ND NG
76 61 72 47 76 71 74
M M M M M M M
80 79 110 55 72 65 46
173 170 179 175 185 183 183
Enteral Feeding (ml/hr)" Jevity FS 80 Jevity FS 75 Jevity FS 100 Jevity FS 100 Jevity FS 75 Jevity FS 70 Osmolite FS 60
Underlying Diseases c s/p CABG s/p lobectomy Respiratory failure Hypoglycemic coma s/p AVR s/p AVR s/p urosepsis
=FS, full strength. bNon-lCU patient. CCABG, coronary artery bypass graft; s/p, status post; and AVR, aortic valve replacement.
51
~
4, Mean NG ( A U C = 11.27 mcg.hr/ml) ----o-- Mean ND ( A U C = 25.35 mcg-hr/ml)
4-
::L-J
.o "o =,.
N
E~
2
3- ~
~.
5
10
15
Time (hour)
FIGURE 1. Mean serum concentration versus time curve from patients with ND tubes (open square) and patients with NG or G tubes (solid diamond). Concentrations were corrected for weight by dividing by expected LBW of 70kg male patient's calculated LBW.
TABLE 2.
Area U n d e r the S e r u m C o n c e n t r a t i o n vs. Time C u r v e (AUC)
Feeding Tube
Patient No.
AUC a (~g.hr/ml)
ND ND
1 3
20.52 37.72
ND ND
5 6
20.81 22.36
NG G NG c
2 4 7
10.88 6.09 16.84
Mean AUC _+ SDb (Izg.hr/ml)
25.35 + 8.28
Volunteer data a
11.27 + 5.39 15.26 --- 3.90
"AUC divided by LBW expected in 70-kg male patient's calculated LBW. bMean AUC (normalized by LBW) __-standard deviation (SD). CNon-ICU patient. eData obtained from six healthy male volunteers who received ciprofloxacin through an NG tube with concurrent enteral feeding (Yuk et al., 1989).
h a n c e d absorption of ciprofloxacin t h r o u g h N D tube administration c o m p a r e d with that given t h r o u g h an N G tube is consistent with the postulate that an unfavorable condition exists in the stomach for its absorption. The differences in the rate of a b s o r p t i o n can theoretically affect the AUC if there is a capacitylimited metabolism process. We d o not believe this to be the case, as changes in elimination rates of ciprofloxacin w e r e not observed. The difference observed in our s t u d y is opposite that expected based on n o r m a l physiology. W h e n ciprofloxacin was delivered in a s u s p e n s i o n form, the disintegration step that contributes to the variability after oral administration was circumv e n t e d and this was not responsible for the differences observed. H o w e v e r , the effect of the gastric e n v i r o n m e n t might also have b e e n a u g m e n t e d in our s t u d y with the s u s p e n s i o n form of administration, w h i c h allows m o r e ciprofloxacin to be in direct contact with the gastric e n v i r o n m e n t as c o m p a r e d to the administration of an intact tablet. The slightly greater absorption of ciprofloxacin with enteral feeding in our v o l u n t e e r s t u d y (Yuk et al., 1989) is consistent with this postulate; it might also be explained as a result of the mitigation of the gastric environm e n t b y c o n c u r r e n t enteral feeding. The data from a non-ICU patient, patient 7, is intriguing (see Tables 1 a n d 2) a n d implies a n o t h e r factor that could affect the overall a b s o r p t i o n of ciprofloxacin. This patient h a d a smaller b o d y mass t h a n expected d u e to his p o o r nutritional status (46 kg; ideal b o d y weight, 78 kg); this could have led to a smaller volume of distribution and resulted in falsely elevated concentrations a n d AUC. W h e n the AUC was corrected, taking the difference in b o d y w e i g h t into consideration, the AUC achieved was consistent but slightly h i g h e r t h a n those from other N G or G tube patients. H o w e v e r , this patient was in relatively stable condition (non-ICU patient with urosepsis) compared to the other patients studied, which could have led to a different gastric e n v i r o n m e n t
102
(e.g., less acidity). A l t h o u g h this patient also received a different enteral feeding formula, which might have affected the results, it is not likely due to the overall similarity of the feeding formulas.
J.H. Yuk et al.
A l t h o u g h the n u m b e r of subjects is small, examination of Table 1 reveals a bias in the age of patients; the ND patients are s o m e w h a t older, indicating a possible effect of age on the observed AUC.
REFERENCES
Ashby J, Piddock LJV, Wise R (1985) An investigation of the hydrophobicity of the quinolones. J Antimicrob Chemother 16:805-810. Bergan T, Thorsteinsson SB, Kolstad IM, Jognsen S (1986) Pharmacokinetics of ciprofloxacin after intravenous and increasing oral doses. Eur J Clin Microbiol 5:187-192. Borner K, Hoffken G, Lode H, Koeppe P, Prinzing C, Glatzel P, Wiley R, Olschewski P, Stevens B, Reinitz D (1986) Pharmacokinetics of ciprofloxacin in healthy volunteers after oral and intravenous administration. Eur J Clin Microbiol 5:179-186. Davis RL, Koup JR, Williams-Warren J, Weber A, Smith AL (1985) Pharmacokinetics of three oral formulations of ciprofloxacin. Antimicrob Agents Chemother 18:74-77. HaUynck TH, Soep HH, Thomis JA (1981) Should clearance be normalized to body surface area or to lean body mass? Br J Clin Pharmacol 11:523-526. Hoffken C, Borner K, Glatzel PD, Koeppe P, Lode H (1985) Reduced enteral absorption of ciprofloxacin in the presence of antacids. Eur J Clin Microbiol 4:345. Jehl F, Gallion C, Debs J, Brogard JM, Monteil H, Minck R (1985) High-performance liquid chromatographic method for detection of ciprofloxacin in biological fluids. J Chromatogr 339:347-357. Jehl F, Adloff M, Monteil H, Brogard JM (1987) Ciprofloxacin biliary disposition in cholecystectomized patients with special references to HPLC and bioassay data. Eur J Drug Met Pharmacokin 12:115-122.
Parpia SH, Nix DE, Hejmanowski LG, Goldstein HR, Wilton JH, Shentag JJ (1989) Sucralfate reduces the gastrointestinal absorption of norfloxacin. Antimicrob Agents Chemother 33:99-102. Plaisance KI, Drusano GL, Forrest A, Bustamante CI, Standiford HC (1987) Effects of dose size on bioavailability of ciprofloxacin. Antimicrob Agents Chemother 31:956958. Preheim LC, Cuevas TA, Roccaforte JS, MeUencamp MA, Bittner MJ (1986) Ciprofloxacin and antacids. Lancet 2:48. Stein GE (1988) The 4-quinolone antibiotics: past, present, and future. Pharmacotherapy 8:301-314. Tartaglione TA, Raffalovich AC, Pognor WJ, EspineMngroff A, Kerkerig TM (1986) Pharmacokinetics and tolerance of ciprofloxacin after sequential increasing oral doses. Antimicrob Agents Chemother 29:62-66. Wingender W, Beerman D, Forster D, Graefe K-H, Kuhlmann J (1986) Interaction of ciprofloxacin with food intake and drugs. In First International Ciprofloxacin Workshop, Leverkusen, FRG, 1985. Eds. HC Neu and H Weuta. Amsterdam: Excerpta Medica, pp 136-140. Yuk JH, Nightingale CH, Sweeney KR, Quintiliani R, Lettieri JT, Frost RW (1989) Relative bioavailability of ciprofloxacin administered through a nasogastric tube with and without enteral feeding in healthy volunteers. Antimicrob Agents Chemother (in press).
