A Novel Antibiotic, Rhodomyrtone: Pharmacokinetic Studies in a Murine Model and Optimization and Validation of High-Performance Liquid Chromatographic Method for Plasma Analysis.

Rhodomyrtone has indisputable and undeniable potential as a new antibiotic for antibiotic-resistant Gram-positive bacteria. Therefore, the main objective of this study was to determine the pharmacokinetics profiles of orally administered rhodomyrtone in rats. A reverse-phase HPLC-UV method was developed, optimized and validated for the analysis of rhodomyrtone concentrations in rat plasma. The retention time of papaverine and rhodomyrtone was 3.928 and 5.937 min, with no interference with the excipients used. The lower limit of quantification (LLOQ) of rhodomyrtone in the plasma sample was 0.04 µg/mL, the accuracy of rhodomyrtone at the LLOQ level ranged from 93.64 to 106.36%, precision was 6.59%, 80-120% for accuracy and <20% CV for precision. The calibration curve was linear at concentrations ranging from 0.04 to 128 µg/mL with a correlation coefficient (r) value of equal to or greater than 0.999. Sprague Dawley rats received a single dose of rhodomyrtone at 50 and 100 mg/kg. Blood samples were collected from tail veins. The peak plasma concentration was observed at 2 h, and the area under the curve of rhodomyrtone at 50 mg/kg and 100 mg/kg was 3.41 ± 1.04 and 7.82 ± 1.53 µg·h/mL, respectively. The results demonstrated linear pharmacokinetics characteristics at the studied dosage range. The plasma concentration of rhodomyrtone was above the minimal inhibition concentrations of several common pathogenic bacteria of medical importance. The proposed HPLC-UV method is fast, cost-effective, reliable and reproducible, and it is proposed for the routine analysis of rhodomyrtone.

Vasorelaxing effect of Garcinia cowa leaf extract in rat thoracic aorta and its underlying mechanisms.

Background and aim: The leaves of Garcinia cowa (G. cowa) are used in Thai traditional medicine to improve blood circulation. However, there is no scientific evidence to confirm this therapeutic claim. Here, we investigated the vasorelaxing effect and its underlying mechanisms of an aqueous extract of G. cowa leaves in rat thoracic aortic rings. Materials and methods: Dried leaves of G. cowa were extracted with water, followed by phytochemical analysis. Vascular reactivity experiments were performed in isolated rat thoracic aortic rings using an organ bath system. The results were recorded using the data acquisition system Power Lab. Results: Phytochemical analysis showed that the leaves of G. cowa are rich in polyphenols and flavonoids, especially kaempferol, vitexin, and isovitexin. The G. cowa leaf extract caused a concentration-dependent relaxation of aortic rings. This effect was attenuated by denudation of the endothelium, or by pre-treatment of the aortic rings with l-NAME, ODQ, indomethacin, or glibenclamide, but not with TEA. Conclusion: This study indicates that G. cowa leaf extract induces vasorelaxation through both endothelium-dependent and endothelium-independent manners. Its mechanism of action mainly involves the production of nitric oxide and prostanoids, as well as opening ATP-sensitive K+ channels. The vasorelaxing effect of G. cowa leaf extract is probable promoted by the action of flavonoids.

Seasonal and Geographic Variation in Alkaloid Content of Kratom (Mitragyna speciosa (Korth.) Havil.) from Thailand.

The objective of this study was to obtain data on the distribution of alkaloids in kratom plants grown in Thailand. Two collections were performed, covering the southern, central, and northern regions of Thailand and different seasons. The contents of alkaloids, including mitragynine (MG), paynantheine (PAY), and speciogynine (SG), were determined using the validated HPLC method. The 134 samples in the first collection were collected from Nam Phu subdistrict, Ban Na San, Surat Thani, Thailand, during June and October 2019 and January 2020. The maximum mitragynine content was 4.94% w/w in June (late summer), and the minimum content was 0.74% w/w in October (rainy season). To expand the study area after kratom decriminalization, 611 samples were collected in June-August 2021, October-December 2021, and January-April 2022. The accumulation of MG ranged from 0.35 to 3.46% w/w, 0.31 to 2.54% w/w, and 0.48 to 2.81% w/w, respectively. The meteorological data supported the climate's effect on alkaloid production. Soil analysis revealed the importance of Ca and Mg in promoting alkaloid production. Geographical locations played a role in the variation of MG in kratom leaves, but did not affect the color of leaf veins. In conclusion, the present study suggested that the alkaloid content in kratom diverges based on seasonal and geographical origin.

(-)-Kusunokinin inhibits breast cancer in N-nitrosomethylurea-induced mammary tumor rats.

Natural and synthetic (-)-kusunokinin inhibited breast cancer, colon cancer and cholangiocarcinoma cells at the G2/M phase and induced apoptosis. However, there is no report on the action and adverse effects of (-)-kusunokinin in animal models. In this study, we investigated the cytotoxic effect of (-)-kusunokinin from Piper nigrum on cancer cells. NMU-induced rat mammary tumors, an ER positive breast cancer model, were treated with (-)-kusunokinin. Proteins of interest related to cell cycle, angiogenesis, migration and signaling proteins were detected in tumor tissues. Results showed that (-)-kusunokinin exhibited strong cytotoxicity against breast, colon and lung cancer cells and caused low toxicity against normal fibroblast cells. For in vivo study, 7.0 mg/kg and 14.0 mg/kg of (-)-kusunokinin reduced tumor growth without side effects on body weight, internal organs and bone marrow. Combination of (-)-kusunokinin with a low effective dose of doxorubicin significantly inhibited tumor growth and provoked cell death in cancer tissues. Mechanistically, 14.0 mg/kg of (-)-kusunokinin decreased cell proliferation (c-Src, PI3K, Akt, p-Erk1/2 and c-Myc), cell cycle (E2f-1, cyclin B1 and CDK1), and metastasis (E-cadherin, MMP-2 and MMP-9) proteins in tumor tissues, which supports its anticancer effect. We further confirmed the antimigration effect of (-)-kusunokinin; the results show that this compound inhibited breast cancer cell (MCF-7) migration in a dose-dependent manner. In conclusion, the results suggest that 14 mg/kg of (-)-kusunokinin inhibited tumors through the reduction of signaling proteins and their downstream molecules. Therefore, (-)-kusunokinin becomes an intriguing candidate for cancer treatment as it provides a strong potency in cancer inhibition.

Pharmacokinetics of Imipenem in Critically Ill Patients with Life-threatening Severe Infections During Support with Extracorporeal Membrane Oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) has become increasingly used for lifesaving respiratory and/or cardiac failure support in critically ill patients, including those with life-threatening severe infections. This cardiopulmonary bypass device has been shown to enhance the profound pathophysiological changes in this patient population, resulting in an alteration of the pharmacokinetics of antimicrobial agents. OBJECTIVE: The aim of this study was to determine the effect of ECMO on the pharmacokinetics of imipenem in critically ill patients supported by this cardiopulmonary bypass device. METHODS: The study was conducted in critically ill patients with respiratory and/or cardiac failure and severe infections who were supported by ECMO. All patients received a 1-h infusion of 0.5 g of imipenem every 6 h and imipenem pharmacokinetics studies were carried out on the fourth dose of drug administration. RESULTS: Ten patients were enrolled in this study. The pharmacokinetics parameters of imipenem were found to be highly variable. The volume of distribution, total clearance, elimination half-life and the area under the concentration-time curve between 0 and 6 h were 33.38 ± 13.89 L, 9.99 ± 10.47 L/h, 12.01 ± 29.63 h and 88.93 ± 54.07 mg∙h/L, respectively. CONCLUSIONS: Pathophysiological changes in critically ill patients with severe infections during support with ECMO had a greater impact on altered pharmacokinetic patterns of imipenem than those that occur in critically ill patients without ECMO support. Therefore, the largest licensed dose, 1 g every 6 h, of imipenem, may be required to maintain adequate drug concentrations to achieve the pharmacokinetic/pharmacodynamic targets for effective antimicrobial therapy in this patient population.

(-)-Kusunokinin and piperloguminine from Piper nigrum: An alternative option to treat breast cancer.

Several studies have reported that active compounds isolated from Piper nigrum possess anticancer properties. However, there are no data on anticancer activity of (-)-kusunokinin and piperlonguminine. The purposes of this study were to isolate active compounds from P. nigrum and identify the molecular mechanisms underlying growth and apoptosis pathway in breast cancer cells. Two bioactive compounds, (-)-kusunokinin and piperlonguminine, were isolated from P. nigrum. Cytotoxicity and the molecular mechanism were measured by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry and Western blot analysis. We found that the active compounds, which effect cancer cell lines were (-)-kusunokinin and piperlonguminine. These compounds have potent cytotoxic effects on breast cancer cells (MCF-7 and MDA-MB-468) and colorectal cells (SW-620). (-)-Kusunokinin demonstrated a cytotoxic effect on MCF-7 and MDA-MB-468 with IC50 values of 1.18 and 1.62µg/mL, respectively. Piperlonguminine had a cytotoxic effect on MCF-7 and MDA-MB-468 with IC50 values of 1.63 and 2.19µg/mL, respectively. Both compounds demonstrated lower cytotoxicity against normal breast cell lines with IC50 values higher than 11µg/mL. Cell cycle and apoptotic analysis using flow cytometry, showed that the (-)-kusunokinin and piperlonguminine induced cell undergoing apoptosis and drove cells towards the G2/M phase. Moreover, both compounds decreased topoisomerase II and bcl-2. The increasing of p53 levels further increased p21, bax, cytochrome c, caspase-8, -7 and -3 activities, except caspase-9. These results suggest that the (-)-kusunokinin and piperlonguminine have been shown to have potent anticancer activities through extrinsic pathway and G2/M phase arrest.

Anti-cancer effects of Piper nigrum via inducing multiple molecular signaling in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Piper nigrum is widely used as a folk medicine including usage for pain relief, fevers, as well as an anti-cancer agent. However the crude extract of piperine free P. nigrum (PFPE), which inhibits breast cancer, and its mechanisms are still being kept secret. This research aims to elucidate the anti-cancer effects of PFPE and its mechanisms. MATERIALS AND METHODS: Anti-cancer effects of PFPE were investigated in N-nitroso-N-methylurea (NMU)-induced mammary tumorigenesis rats and breast cancer cell lines MCF-7 and ZR-75-1. Furthermore, the cancer prevention effects of PFPE were investigated in rats. Western blotting was employed to study protein levels induced by PFPE. RESULTS: PFPE was found to up-regulate p53, and down-regulate estrogen receptor (ER), E-cadherin (E-cad), matrix metalloproteinase 9 (MMP-9), matrix metalloproteinase 2 (MMP-2), c-Myc, and vascular endothelial growth factor (VEGF) levels in breast cancer rats. Moreover, PFPE decreased protein levels of E-cad, c-Myc, and VEGF in MCF-7 cells. These results suggest that PFPE can enhance breast cancer cell response to phytochemicals, then induce cell cycle arrest, and inhibit cancer cell proliferation resulting in tumor size decrease in the PFPE treated group. It further suggests that PFPE may suppress tumor cell invasion, migration, and angiogenesis. In addition, PFPE possessed cancer prevention effects through generation of reactive oxygen species (ROS) to higher cancer cell cellular stress. CONCLUSIONS: PFPE may possess anti-cancer and cancer prevention effects; hence, it deserves further investigation as a novel candidate for breast cancer treatment.

Anticancer and Cancer Prevention Effects of Piperine-Free Piper nigrum Extract on N-nitrosomethylurea-Induced Mammary Tumorigenesis in Rats.

Piper nigrum (P. nigrum) is commonly used in traditional medicine. This current study aimed to investigate the anticancer and cancer preventive activity of a piperine-free P. nigrum extract (PFPE) against breast cancer cells and N-nitrosomethylurea (NMU)-induced mammary tumorigenesis in rats. The cytotoxic effects and the mechanism of action were investigated in breast cancer cells using the MTT assay and Western blot analysis, respectively. An acute toxicity study was conducted according to the Organization for Economic Co-operation and Development guideline. Female Sprague-Dawley rats with NMU-induced mammary tumors were used in preventive and anticancer studies. The results showed that PFPE inhibited the growth of luminal-like breast cancer cells more so than the basal-like ones by induction of apoptosis. In addition, PFPE exhibited greater selectivity against breast cancer cells than colorectal cancer, lung cancer, and neuroblastoma cells. In an acute toxicity study, a single oral administration of PFPE at a dose of 5,000 mg/kg body weight resulted in no mortality and morbidity during a 14-day observation period. For the cancer preventive study, the incidence of tumor-bearing rats was 10% to 20% in rats treated with PFPE. For the anticancer activity study, the growth rate of tumors in the presence of PFPE-treated groups was much slower when compared with the control and vehicle groups. The extract itself caused no changes to the biochemical and hematologic parameters when compared with the control and vehicle groups. In conclusion, PFPE had a low toxicity and a potent antitumor effect on mammary tumorigenesis in rats.

Pharmacokinetic interactions between ciprofloxacin and itraconazole in healthy male volunteers.

OBJECTIVE: To investigate the pharmacokinetic interaction between ciprofloxacin and itraconazole in healthy male volunteers. METHODS: Ten healthy male volunteers were assigned into a 2-sequence, 3-period pharmacokinetic interaction study. In phase 1, all subjects were randomly assigned to receive 500 mg of ciprofloxacin alone and 200 mg of itraconazole alone twice daily for 7 days with a 14 day wash-out period in a crossover design. Phase 2 was performed 14 days after finishing phase 1, all subjects received 500 mg of ciprofloxacin in combination with 200 mg of itraconazole twice daily for 7 days. Ciprofloxacin and itraconazole pharmacokinetics were studied and adverse effects noted. RESULTS: Ciprofloxacin significantly increased the C(max) and AUC(0 - ∞) of itraconazole by 53.13% and 82.46%, respectively. The half-life and CL of itraconazole were not changed significantly. The combination of itraconazole and ciprofloxacin could therefore result in an increase in adverse drug reactions. Conversely, itraconazole had no significant effect on the pharmacokinetics of ciprofloxacin. CONCLUSION: Ciprofloxacin decreases the metabolism of itraconazole, most likely through inhibition of CYP3A4. The dosage of itraconazole should be reduced and its therapeutic outcome should be monitored closely when these two agents are concomitantly administered.

Development of an analytical method for cefpirome in plasma by simplified HPLC technique and its applications.

The objective of this study was to develop a rapid and simplified, reliable high-performance liquid chromatography (HPLC) method for quantification of cefpirome (CAS 98753-19-6) in plasma. After precipitation of the plasma containing the internal standard, hydrochlorothiazide, with 5% trichloroacetic acid (TCA), the analysis of the cefpirome level in the plasma samples was carried out using a reverse-phase C18 column with the ultraviolet detector set at a wavelength of 258 nm. The chromatographic separation was accomplished with an isocratic mobile phase consisting of acetonitrile-acetate buffer pH 5. The proposed method was specific and sensitive with a lower limit of quantitation (LLOQ) of 0.5 microg/ml. This HPLC method was validated by examining the precision and accuracy for inter- and intra-day analysis in the concentration range 0.5-64.0 microg/ml. The relative standard deviation in the inter- and intra-day validation was less than 3%. Analytical recovery was more than 84%, and cefpirome was found to be stable in human plasma during both the storage and assay procedures. A satisfactory pharmacokinetic study of cefpirome was carried out in rabbits using the devised procedure.

Pharmacokinetic study of the interaction between itraconazole and nevirapine.

OBJECTIVE: To investigate the drug interaction potential between itraconazole and nevirapine. METHODS: Our study was conducted in 12 healthy volunteers in two phases. In phase 1 (from days 1-28), all subjects were randomly assigned to a two-way crossover study of a nevirapine regimen (nevirapine 200 mg once daily for 7 days) and an itraconazole regimen (itraconazole 200 mg once daily for 7 days) with a 14-day wash-out period between. Phase 2 (from days 43-49) was performed 14 days after phase 1 ended, and all subjects received a combination regimen (nevirapine 200 mg combined with itraconazole 200 mg once daily for 7 days). Nevirapine pharmacokinetic studies were carried out starting with the seventh dose of nevirapine in the nevirapine regimen (on days 7-10 or 28-31) and the combination regimen (on days 49-52). Itraconazole pharmacokinetic studies were carried out starting with the seventh dose of itraconazole in the itraconazole regimen (on days 7-10 or 28-31) and the combination regimen (on days 49-52). RESULTS: There was no significant difference in nevirapine pharmacokinetic parameters between the nevirapine and combination regimens. Itraconazole plasma concentrations were lower when it was administered in the combination regimen than when it was administered in the itraconazole regimen. The mean C(max), AUC(0-96) and t (1/2) of itraconazole were significantly reduced by 38, 61 and 31%, respectively. CONCLUSION: Nevirapine had a strong inducing effect on the metabolism of itraconazole, but there was no significant effect of itraconazole on the pharmacokinetics of nevirapine. However, a higher daily dosage of itraconazole might have an inhibitory effect.

Effect of efavirenz on the pharmacokinetics of ketoconazole in HIV-infected patients.

OBJECTIVE: To investigate the effect of efavirenz on the ketoconazole pharmacokinetics in HIV-infected patients. METHODS: Twelve HIV-infected patients were assigned into a one-sequence, two-period pharmacokinetic interaction study. In phase one, the patients received 400 mg of ketoconazole as a single oral dose on day 1; in phase two, they received 600 mg of efavirenz once daily in combination with 150 mg of lamivudine and 30 or 40 mg of stavudine twice daily on days 2 to 16. On day 16, 400 mg of ketoconazole was added to the regimen as a single oral dose. Ketoconazole pharmacokinetics were studied on days 1 and 16. RESULTS: Pretreatment with efavirenz significantly increased the clearance of ketoconazole by 201%. C(max) and AUC(0-24) were significantly decreased by 44 and 72%, respectively. The T ((1/2)) was significantly shorter by 58%. CONCLUSION: Efavirenz has a strong inducing effect on the metabolism of ketoconazole.

Pharmacokinetics of imipenem in healthy volunteers following administration by 2 h or 0.5 h infusion.

OBJECTIVES: The aim of this study was to demonstrate the t > MIC of 0.5 and 1 g of imipenem when administered by 2 h infusion every 6 h compared with 0.5 g of imipenem when administered by 0.5 h infusion every 6 h. METHODS: The study was a randomized three-way crossover study with a 30 h wash-out period in eight healthy volunteers. Each subject received imipenem in three regimens: (i) a 0.5 h infusion of 0.5 g every 6 h for three doses; (ii) a 2 h infusion of 0.5 g every 6 h for three doses; and (iii) a 2 h infusion of 1 g every 6 h for three doses. RESULTS: Following 0.5 h infusion of 0.5 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 21.5 +/- 2.2%, 38.6 +/- 3.5% and 57.5 +/- 4% of a 6 h interval, respectively. For the 2 h infusion of 0.5 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 26.9 +/- 8.5%, 48.0 +/- 3.5% and 65.4 +/- 3.2% of a 6 h interval, respectively. For the 2 h infusion of 1 g, the percentages of time above four times an MIC of 4, 2 and 1 mg/L were 51.6 +/- 5.4%, 67.8 +/- 4.5% and 87.8 +/- 5.6% of a 6 h interval, respectively. CONCLUSIONS: A 2 h infusion resulted in a greater t > MIC than those after a 0.5 h infusion and intermittent infusion may be a useful mode of administration of imipenem in tropical countries.

Comparison of the pharmacodynamics of meropenem in patients with ventilator-associated pneumonia following administration by 3-hour infusion or bolus injection.

The time that concentrations in serum are above the MIC (T>MIC) is the pharmacokinetic/pharmacodynamic parameter correlating with the therapeutic efficacy of beta-lactam antibiotics. The aim of this study was to demonstrate the T>MIC of meropenem when administered by a 3-h infusion compared with that when administered by bolus injection. The study was conducted with nine patients with ventilator-associated pneumonia. Each subject received meropenem in three regimens consecutively: (i) bolus injection of 1 g every 8 h for 24 h; (ii) 3-h infusion of 1 g every 8 h for 24 h; and (iii) 3-h infusion of 2 g every 8 h for 24 h. Following bolus injection, the percentages of the T>MICs of 16, 8, 4, and 1 microg/ml were 28.33% +/- 11.67%, 45.89% +/- 22.90%, 57.00% +/- 24.82%, and 74.67% +/- 17.94% of an 8-h interval, respectively. For the 3-h infusion of 1 g of meropenem, the percentages of the T>MICs of 16, 8, 4, and 1 microg/ml were 37.78% +/- 20.57%, 58.11% +/- 24.38%, 72.67% +/- 21.97%, and 93.56% +/- 6.84% of an 8-h interval, respectively. For the 3-h infusion of 2 g of meropenem, the percentages of the T>MICs of 16, 8, 4, and 1 microg/ml were 57.89% +/- 24.26%, 72.89% +/- 22.40%, 85.56% +/- 16.42%, and 98.56% +/- 3.28% of an 8-h interval, respectively. In conclusion, a 3-h infusion resulted in greater T>MICs than those after a bolus injection. For the treatment of infections caused by pathogens with intermediate resistance, a 3-h infusion of 2 g of meropenem every 8 h can provide concentrations in serum above the MIC of 16 microg/ml for almost 60% of an 8-h interval.

Comparison of the pharmacodynamics of meropenem in healthy volunteers following administration by intermittent infusion or bolus injection.

OBJECTIVES: The aim of this study was to compare the pharmacokinetics and pharmacodynamics of meropenem when administered by 3 h infusion or bolus injection regimens. PATIENTS AND METHODS: The study was a randomized three-way crossover study with a 1 week wash-out period in 12 healthy volunteers. Each subject received a single dose of meropenem in three regimens: (i) bolus injection of 1 g meropenem; (ii) 3 h infusion of 1 g meropenem; and (iii) 3 h infusion of 0.5 g meropenem. RESULTS: Following bolus injection of 1 g meropenem, the mean +/- s.d. percentages of the t > MIC of 4, 2 and 1 mg/L were 42.50 +/- 6.20%, 54.38 +/- 7.64% and 67.04 +/- 8.47% of an 8 h dosing interval, respectively. For the 3 h infusion of 1 g meropenem, the percentages of the t > MIC of 4, 2 and 1 mg/L were 59.27 +/- 7.34%, 71.97 +/- 8.63% and 86.07 +/- 9.41% of an 8 h dosing interval, respectively. For the 3 h infusion of 0.5 g meropenem, the percentages of the t > MIC of 4, 2 and 1 mg/L were 47.27 +/- 5.34%, 59.36 +/- 6.60% and 71.44 +/- 8.45% of an 8 h dosing interval, respectively. CONCLUSIONS: We conclude that a 3 h infusion of 0.5 g or 1 g of meropenem both give greater values for t > MIC than a 1 g bolus and that intermittent infusion may be a useful mode of administration in tropical countries where drug instability may prevent the use of continuous infusion.

Stability of meropenem in normal saline solution after storage at room temperature.

The bactericidal activity of meropenem is determined by the time that concentrations in tissue and serum are above the MIC for the pathogens during the dosing interval. Thus, the most effective mode of administering of meropenem is continuous infusion. However, the stability of meropenem reconstituted in solution is influenced by the storage temperature. Until now we have had no data to evaluate the stability of this drug during continuous infusion in a tropical country. The objective of this study was to provide such data. Meropenem 0.5 g and 100 ml normal saline solution were mixed together and stored at room temperature for 8 hours. Half of the solution was stored in a room with air conditioning at 20 degrees C and the other half of the solution was stored in a room without air conditioning at 32 degrees-37 degrees C. The concentrations of meropenem in the solution were measured at 0, 1, 2, 3, 4, 6 and 8 hours after the drug was reconstituted. Twelve lots of (0.5 g meropenem in normal saline) solution were evaluated in each temperature condition. The mean meropenem concentrations reconstituted in normal saline solution decreased 1.66%, 3.31% and 5.80% after 2, 4 and 8 hours storage at 20 degrees C, respectively. Drug concentrations decreased 3.14%, 5.86% and 11.85% after 2, 4 and 8 hours storage at 32 degrees-37 degrees C, respectively. Therefore, we conclude that this agent should not be administered by 8-hour continuous infusion at room temperature in a tropical country.

Continuous infusion versus intermittent administration of cefepime in patients with Gram-negative bacilli bacteraemia.

The objective of this study was to compare the pharmacokinetics of cefepime administered by continuous infusion and intermittent injection regimens. A prospective, randomized, cross-over study of ten patients with Gram-negative bacilli bacteraemia was conducted. All patients were randomized to receive cefepime either as a 4-g continuous infusion over 24 h for 48 h or a 2-g bolus administered intermittently intravenously every 12 h for 48 h. After 48 h the patients received the alternative dose regimen. Cefepime pharmacokinetic studies were carried out during hours 36-48 after the start of both regimens. All of the pathogens isolated from the blood in 7 patients had a minimum inhibitory concentration (MIC) < 1 microg mL(-1). In both regimens, the serum cefepime concentrations at all time points were higher than the MIC for the pathogens isolated from this study. For the continuous infusion arm, the highest steady-state concentration was 49.80+/-18.40 microg mL(-1) and the lowest steady-state concentration was 41.42+/-16.48 microg mL(-1). The steady-state concentrations were greater than 4 times the MIC of 8 microg mL(-1). For the intermittent injection regimen, the mean trough concentration was 4.74+/-3.99 microg mL(-1). The mean serum cefepime concentration was above 8 microg mL(-1) for 81.66% of the dosing interval. Therefore, we conclude that either continuous infusion or intermittent injection can be used as an effective mode of cefepime administration to achieve bactericidal activity.