Ampicillin/sulbactam in elderly patients with community-acquired pneumonia.

PURPOSE: Age-related physiological changes affect body systems, altering pharmacokinetics, which may potentiate or alter the effects of drugs. The aim of this study was to assess the influence of age on the steady-state pharmacokinetics and pharmacokinetic/pharmacodynamic parameters of ampicillin/sulbactam in the population of elderly patients (age ≥65 years) with community-acquired pneumonia (CAP). PATIENTS AND METHODS: The pharmacokinetics and pharmacokinetic/pharmacodynamic parameters of ampicillin/sulbactam were determined at steady state in a total of 13 elderly patients with CAP following the administration of multiple intravenous doses of 2 g ampicillin + 1 g sulbactam (Unacid(®), Pfizer), each over 15 min thrice a day. RESULTS: A reduced C max, AUC0-8 h and total clearance, a prolonged half-life, and an increased steady-state volume of distribution were observed for ampicillin. The mean estimated free C min of 1.8 mg/L for ampicillin was higher than that predicted to be effective against Streptococcus pneumoniae. Based on an MIC90 of 1 mg/L for Streptococcus pneumoniae, the calculated T > MIC and T > 4 × MIC for ampicillin was 75-100 % (median 100 %) and 12.5-100 % (median 50 %), respectively. A T > 4 × MIC of at least 50 % was achieved in 7 of 13 elderly patients with CAP. CONCLUSIONS: Age and, probably, pneumonia did affect the pharmacokinetics of ampicillin and sulbactam. Despite the reduced C max, adequate free C min/MIC90 ratios due to impaired renal function were observed in elderly patients with CAP. In elderly patients without renal impairment and/or in severe infection with less susceptible pathogens, more frequent dosing of ampicillin 2 g/sulbactam 1 g can be necessary to avoid the risk of underdosing in CAP.

[Hydrogelexpander as drug delivery system for antibiotics]. / Hydrogelexpander als Medikamentenabgabe-System für Antibiotika.

PURPOSE: The suitability of a high-hydrophilic osmotic self-inflating hydrogel expander consisting of a co-polymer of N-vinylpyrolidone and methyl methacrylate as a drug delivery system for antibiotics to prevent a postoperative infection was investigated in a laboratory setting. METHODS: The dry expanders were incubated in a 0.3 % solution of Ofloxacin or Tobramycin for 24 hours. The completely swollen expander had increased in volume from 0.3 mL to almost 3 mL (adsorbing 2.7 mL of the 0.3 % solution, i. e.,8.1 mg of Ofloxacin or Tobramycin, respectively). Addressing the elimination of both antibiotics, the concentrations in 15 mL elution medium (simulating the volume of the orbit in a newborn baby) were measured after 0.25, 1, 2, 6, 24, 48 and 72 hours of elution. 0.9 % sodium chloride (B. Braun Melsungen, Germany) was used as elution medium. To imitate fluid exchange due to blood perfusion in the surrounding tissue the medium was renewed after every sampling. For each substance 10 expanders were tested. Concentrations of antibiotic were determined by HPLC/UV for Ofloxacin and by using a specific fluorescence-polarisation immunoassay (Abbott TDx) for Tobramycin. RESULTS: Mean concentrations of Ofloxacin at 0.25, 1, 2, 6, 24, 48 and 72 hours after beginning of the elution were 50.2, 46.8, 41.2, 75.4, 88.2, 46.2 and 19.1 µg/mL, respectively. The cumulative amount of Ofloxacin eluted after 72 hours reached 68 % of the loading dose. The corresponding mean concentrations of Tobramycin were 38.8, 48.5, 40.5, 69.8, 88.7, 119.3 and 71.6 µg/mL. The cumulative eluted amount was 88 %. CONCLUSIONS: The investigated hydrogel expanders soaked in 0.3 % antibiotic solution can store and later on release sufficient amounts of Ofloxacin or Tobramycin to produce antimicrobial effective concentrations in vitro in the surrounding environment. This principle, when used in a clinical setting, might help to eliminate post-implantation infection which is one of the major complications in clinical use.

In vitro kinetics of delivery of tobramycin and ofloxacin from osmotic hydro gel expanders.

OBJECTIVE: High-hydrophilic osmotic self-inflating hydro gel expanders are well-accepted for implantation to achieve tissue expansion in defined parts of the body like skin, breast and orbital soft tissue. To prevent post-implantation infections effective antibiotic prophylaxis might be helpful. The suitability of this hydro gel consisting of a co-polymer of N-vinyl-pyrolidone and methyl-methacrylate as a drug delivery system for antibiotics was investigated in a laboratory setting simulating the orbit in a newborn. METHODS: In a first setting the dry expanders were incubated in a 0.3% solution (5 ml) of tobramycin and ofloxacin for 24 h (n = 10 for each substance, adsorbing 2.4 ml of the 0.3% solution, i.e. 7,200 µg antibiotic). Addressing the release of both antibiotics, the concentrations in 15 ml elution medium (0.9% sodium chloride, renewed after every sampling) were measured after 0.25, 1, 2, 6, 24, 48 and 72 h of elution. To simulate the clinical use in a second setting the expanders were dried after incubation in a 0.3% and 0.03% solution of tobramycin (n = 5 for each concentration) before measuring the release. RESULTS: The cumulative amount of tobramycin released after 72 h reached 7,157 µg, i.e. 99% of the initially loaded antibiotic. The cumulatively released amount of ofloxacin was 5,505 µg (76% of loading dose). Main fraction of release (about two thirds) was detected for both antibiotics for a elution period 0 - 24 h. In the periods 24 - 48 and 48 - 72 h the released amount of tobramycin was significantly higher than for ofloxacin. The release from expander dried after loading tobramycin was comparable: The cumulatively released amount of 0.3% and 0.03% incubation solution was 99% and 79% of loading dose, respectively. CONCLUSIONS: The investigated hydro gel expanders soaked in antibiotic solution can store and further on release sufficient amounts of tobramycin or ofloxacin to produce antimicrobial effective concentrations in vitro in the surrounding environment according to the breakpoints reported by EUCAST [14]. This principle, when used in a clinical setting, might help to eliminate post-implantation infection, which is one of the major complications in clinical use.

Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation.

Mycophenolate mofetil (MMF) has been used successfully in solid organ transplantation (SOT) and more recently in nonmyeloablative hematopoietic stem cell transplantation (HSCT) for prophylaxis of graft rejection and acute graft-versus-host disease. However, the pharmacokinetics of MMF seem to differ when applied in HSCT compared to SOT. Here, we analyzed pharmacokinetics of mycophenolic acid (MPA), the active metabolite of MMF, in a nonmyeloablative canine HSCT model. Dogs received nonmyeloablative TBI for conditioning followed by leukocyte antigen-identical littermate HSCT and immunosuppression containing cyclosporin A (CsA) and different doses of MMF. Pharmacokinetics were performed on days 2, 14 and 27. Dose escalation of MMF from 10 to 30 mg/kg tended to increase area under the curve (AUC) and the apparent oral clearance by 45 and 110%, respectively. Doses applied had no linear association with MPA concentration or blood trough level. No significant drug accumulation occurred over time. Using a twice daily MMF regimen, we conclude that an AUC of 30-60 mug/ml h as recommended for SOT cannot be reached in HSCT. Toxicities did not permit single doses higher than 30 mg/kg. Thus, if larger AUCs are desired in order to assure sufficient immunosuppression in HSCT, MMF might have to be administered at least three times daily.

Pharmacokinetics and penetration of linezolid into inflamed soft tissue in diabetic foot infections.

OBJECTIVE: Physiological changes and local and systemic inflammation may affect plasma and tissue pharmacokinetics of antimicrobial agents in diabetics. The aim of the study was to investigate the penetration of linezolid into inflamed areas of infected diabetic foot wounds and the pharmacokinetics in the risk population of diabetics. METHODS: Pharmacokinetics and tissue penetration of linezolid into inflamed diabetic foot infection (DFI) tissue were determined at steady state in 15 patients with diabetes type 2 and DFI following administration of multiple oral doses of 600 mg given every 12 h. Second debridement was performed on days 4-6, 3 h after linezolid administration. Linezolid concentrations were determined in perinecrotic wound tissue of inflamed diabetic foot by high-performance liquid chromatography (HPLC). RESULTS: A mean maximum plasma concentration (C(max)) in plasma of 14.3 mg/L was attained at a median of 2.0 h [time to reach C(max) (T(max)) range 0.5-6.0 h). Area under the concentration time curve from zero to 12 h (AUC(0-12 h)) with a mean of 114.1 mgh/L and C(min) of 5.4 mg/L were achieved in patients with diabetes mellitus type 2. Penetration of linezolid into inflamed areas of DFI with tissue/plasma ratios of mean 101.7% [95% confidence interval (CI) 56; 148%] produced a mean concentration of 9.6 microg/g (95% CI 7.4; 11.8 microg/g) greater than those predicted to be effective against methicillin-resistant staphylococci [minimum concentration that inhibits 90% of organisms (MIC(90)) of 4 mg/L]. Tissue/plasma ratios correlated positive with systemic inflammation. CONCLUSION: Plasma pharmacokinetics of linezolid in diabetics and adequate levels in inflamed areas of diabetic foot wound suggest that an oral dose of 600 mg bd of linezolid provides effective concentrations for treating methicillin-resistant Staphylococcus aureus (MRSA) in DFI.

Preventable ADRs leading to hospitalization - results of a long-term prospective safety study with 6,427 ADR cases focusing on elderly patients.

BACKGROUND: Studies evaluating the impact of age and potentially inappropriate medication (PIM) on avoidable adverse drug reactions (ADRs) are scarce. METHODS: In this prospective, multi-center, long-term (8.5 years) observational study, we analysed ADRs leading to hospitalization in departments of internal medicine. ADRs causality and preventability were assessed using standardised algorithms. PIM was defined based on the PRISCUS-list. Multivariate analyses and estimation of ADR incidence rates were conducted. RESULTS: Of all 6,427 ADR patients, a preventable ADR was present in 1,253 (19.5%) patients (elderly patients ≥70 years: 828). Risk factors for preventable ADRs in elderly patients were multimorbidity, two to four ADR-causative drugs, and intake of particular compounds (e.g. spironolactone) but not sex, PIM usage, or the total number of drugs. Regarding particular compounds associated with preventable ADRs, highest incidence rates for preventable ADRs were found for patients aged ≥70 years for spironolactone (3.3 per 1,000 exposed persons (95% CI: 1.4-6.6)) and intermediate-acting insulin (3.3 per 1,000 exposed persons (95% CI: 1.6-6.1)). CONCLUSION: Avoiding PIM usage seems to be of limited value in increasing safety in elderly patients whereas our results underline the importance of an individualized medication review of the most commonly implicated drugs in preventable ADRs (supported by BfArM FoNr: V-11337/68605/2008-2010).

Clearance of levofloxacin by an in vitro model of continuous venovenous hemodialysis (CVVHD).

Information about the elimination and the adequate dosing of levofloxacin during renal replacement therapy is scarce. The aim of this study was to characterize in vitro the elimination of levofloxacin during continuous venovenous hemodialysis (CVVHD) and to investigate whether the CVVHD clearances of creatinine and urea are correlated with the levofloxacin clearance in order to facilitate dosage adjustments. An in vitro model of CVVHD was established using five dialyzer membranes at varying dialysate flow rates applied in the clinical setting (8, 16, 25, 33 and 41 ml/min). Plasma and dialysate samples were drawn for determination of levofloxacin, creatinine and urea concentrations to evaluate clearances by CVVHD. During CVVHD, the clearance of levofloxacin varied between 9.02 and 33.30 ml/min, depending on the chosen setup. Positive correlations (p<0.001) were received for: dialysate flow rate (QD) and creatinine/ urea clearances (R(2)>0.93); QD and levofloxacin clearance (R(2) 0.59-0.71); levofloxacin and creatinine clearance (R(2) 0.69-0.75); and levofloxacin and urea clearance (R(2) 0.56-0.75) as well. When dosing critically ill patients, therefore, extracorporeal as well as total clearance of levofloxacin should be considered.

Pharmacokinetic profiling of cyclosporine microemulsion during the first 3 weeks after simultaneous pancreas-kidney transplantation.

The optimal effect of therapy with cyclosporine (CsA) seeks to minimize undesirable side effects while maximizing immunosuppression. This balance, depends on CsA exposure, which may be characterized by the area under the concentration-time-curve (AUC). Therefore, we tested the pharmacokinetic profile of microemulsion CsA as a superior approach to guide clinical immunosuppression after de novo simultaneous pancreas-kidney transplantations. We examined 10 consecutive pancreas-kidney recipients with type 1 diabetes and end-stage renal disease. All patients were treated with a regimen consisting of CsA, mycophenolate mofetil (MMF), and prednisone. Full (9-point) pharmacokinetic studies (C0, C1, C2, C3, C4, C6, C8, C10, C12) were performed on week 1 and during week 3 to examine CsA pharmacokinetic profiles. Mean AUC0-12 of 4431 +/- 2400 microg x h/L at week 1 remained stable at week 3 (5119 +/- 1190 microg x h/L). The C6 sampling time displayed the best correlation with AUC0-12 (r2 = 0.881), followed by C3 (r2 = 0.758). Our preliminary data after simultaneous pancreas-kidney transplantation support the hypothesis that C3 or C6 sampling is a more accurate predictor of the AUC0-12 than C0. The combination of two samplings, namely C3 + C6 (r2 = 0.938) or C2 + C6 (r2 = 0.955) proved excellent prediction of exposure after simultaneous pancreas-kidney transplantation.

Prediction of in vivo drug interaction from in vitro systems exemplified by interaction between verapamil and cimetidine using human liver microsomes and primary hepatocytes.

Emphasis on drug safety is increasing as newly developed drugs become more potent. Interest in the prediction and description of drug interactions is growing accordingly. The study of potential interactions at a very early stage of drug development requires suitable in vitro models that describe drug interactions both qualitatively and quantitatively. The purpose of the work described here was to help assess the predictive value of in vitro drug interaction tests with liver microsomes and hepatocytes by means of the interaction between verapamil and cimetidine. The in vitro inhibition of verapamil metabolism by cimetidine observed during the studies was quantitatively similar to the results reported in published clinical studies after intravenous application. Studies using liver microsome fractions showed that the intrinsic clearances for the formation of various metabolites could be used to predict drug interactions. In addition, work with hepatocyte cultures revealed that an in vitro system covering both phase I and phase II reactions should be included in such studies to permit quantitative prediction of the various metabolic pathways. Both human hepatocyte cultures and human microsomes offer certain advantages for predicting the degree of drug metabolism and interactions in humans at the biotransformation level. Therefore, it seems likely that the simultaneous application of both systems will yield conclusions that most closely approximate the situation in humans.

Pharmacokinetics and bioavailability of quercetin glycosides in humans.

Due to its potentially beneficial impact on human health, the polyphenol quercetin has come into the focus of medicinal interest. However, data on the bioavailability of quercetin after oral intake are scarce and contradictory. Previous investigations indicate that the disposition of quercetin may depend on the sugar moiety of the glycoside or the plant matrix. To determine the influence of the sugar moiety or matrix on the absorption of quercetin, two isolated quercetin glycosides and two plant extracts were administered to 12 healthy volunteers in a four-way crossover study. Each subject received an onion supplement or quercetin-4'-O-glucoside (both equivalent to 100 mg quercetin), as well as quercetin-3-O-rutinoside and buckwheat tea (both equivalent to 200 mg quercetin). Samples were analyzed by HPLC with a 12-channel coulometric array detector. In human plasma, only quercetin glucuronides, but no free quercetin, could be detected. There was no significant difference in the bioavailability and pharmacokinetic parameters between the onion supplement and quercetin-4'-O-glucoside. Peak plasma concentrations were 2.3 +/- 1.5 microg x mL(-1) and 2.1 +/- 1.6 microg x mL(-1) (mean +/- SD) and were reached after 0.7 +/- 0.2 hours and 0.7 +/- 0.3 hours, respectively. After administration of buckwheat tea and rutin, however, peak plasma levels were--despite the higher dose-only 0.6 +/- 0.7 microg x mL(-1) and 0.3 +/- 0.3 microg x mL(-1), respectively. Peak concentrations were reached 4.3 +/- 1.8 hours after administration of buckwheat tea and 7.0 +/- 2.9 hours after ingestion of rutin. The terminal elimination half-life was about 11 hours for all treatments. Thus, the disposition of quercetin in humans primarily depends on the sugar moiety. To a minor extent, the plant matrix influences both the rate and extent of absorption in the case of buckwheat tea administration compared with the isolated compound. The site of absorption seems to be different for quercetin-4'-O-glucoside and quercetin-3-O-rutinoside. The significance of specific carriers on the absorption of quercetin glycosides, as well as specific intestinal beta-glucosidases, needs to be further evaluated.

Up-regulation of cytochrome P450 1A2, 2C9, and 2E1 in chronic pancreatitis.

The oxidative metabolism of xenobiotics is effected mainly by cytochrome P450 enzymes (CYP), which are expressed as a family of genetically related enzymes primarily in hepatocytes. The pancreas is among the extrahepatic tissues expressing CYP, and it has been suggested that intermediates generated by them might be of pathogenetic significance for diseases of the pancreas such as chronic pancreatitis. We studied 10 surgical resection specimens by immunohistochemistry with polyclonal antibodies against recombinant human CYP 1A1, 1A2, 2C9, 2E1, and 3A and used tissues from 11 normal pancreata as controls. In addition, we assayed microsomal preparations for their capacity to metabolize verapamil. In normal pancreata weak to moderate expression of all enzymes was demonstrated immunohistochemically in up to 50% of duct epithelia, acinar cells, and islet cells. In contrast, in chronic pancreatitis an up-regulation was observed, with immunohistochemical positivity in some cases in up to 100% of duct epithelia and acinar cells. The oxidative capacity of microsomal preparations from chronic pancreatitis was higher than that of preparations obtained from control tissues; compared to liver microsomes, however, it was low. The up-regulation of CYP may have pathogenetic significance for chronic pancreatitis. Yet considering the pancreas' capacity for conjugation reactions, conceivably low levels of reactive intermediates could effectively undergo inactivation.

Expression and function of beta-glucuronidase in pancreatic cancer: potential role in drug targeting.

Improvement of non-surgical strategies is a pivotal task in the treatment of pancreatic cancer. Response to treatment with most anticancer agents has been very poor, probably due to insufficient drug concentration in tumor tissue. Increased response rates during chemotherapy might be achieved by dose escalation; however, this approach is often hampered by severe side effects. One strategy to overcome these adverse effects is application of nontoxic glucuronide prodrugs from which the active moiety is released by beta-glucuronidase within or near the tumor. The use of glucuronide prodrugs in pancreatic cancer requires increased expression of the enzyme in the diseased tissue, a problem that has not been addressed so far. We therefore investigated function and expression of beta-glucuronidase in tissue samples from human healthy pancreas (n=7) and pancreatic adenocarcinoma (n=8), respectively. Comparing the ability of tissue homogenates to cleave the standard substrate 4-methylumbelliferyl-beta-D-glucuronide, we found a significantly increased specific beta-glucuronidase activity (P<0.05) in pancreatic cancer (median: 133; 75% percentile: 286; 25% percentile: 111 nmol/mg per h) as compared to healthy pancreas (median: 74; 75% percentile: 113; 25% percentile: 71 nmol/mg per h). Enzyme kinetic experiments with the model prodrug N-[4-beta-glucuronyl-3-nitrobenzyloxycarbonyl] doxorubicin (HMR 1826) demonstrated bioactivation of HMR 1826 by pancreatic beta-glucuronidase. Enzymatic activity was found to be closely related to enzyme contents (r=0.87) as assessed by Western blot analysis. Our data indicate that increased beta-glucuronidase activity in pancreatic cancer seems to be due to an elevated steady-state level of the protein. This may be the basis for new therapeutic strategies in treatment of pancreatic carcinoma by using glucuronide prodrugs of anticancer agents.

Perioperative antibiotic prophylaxis in maxillofacial surgery: penetration of clindamycin into various tissues.

Although clindamycin is recommended for prophylactic use in oral and maxillofacial surgery, there is little data available regarding its ability to provide sufficient tissue concentrations at the operative site. We investigated tissue samples from 31 patients, who had to undergo oral and maxillofacial surgery and who received at least one dose of 600 mg clindamycin i.v. preoperatively, to determine clindamycin tissue concentrations in muscle, oral mucosa, fatty tissue, skin and bone between 15 min and 8 h after administration. After homogenization, clindamycin concentration was determined by bioassay. It was demonstrated that clindamycin concentrations above the MIC90 of those pathogens most likely to cause contamination were reached in all kinds of tissues investigated. Already 15 min after administration, tissue concentrations above the MIC90 were reached and were still detectable in the last samples taken between 4 and 8 h after the last clindamycin administration. From the pharmacokinetic point of view, clindamycin is suitable for perioperative prophylaxis during oral and maxillofacial surgery providing sufficient tissue concentrations with no intraoperative additional dosage necessary unless procedures exceed 4 h duration.

Primary or established liver cells for a hybrid liver? Comparison of metabolic features.

It is currently in discussion whether or not established liver cell lines can be used for an extracorporeal liver assist device. Thus, metabolic features of primary hepatocytes, immortalized hepatocytes, and hepatoma cells were compared. The ability of these cells to process toxic blood of patients with hepatic failure was investigated by testing their viability in toxin enriched medium that was obtained by toxin separation from patients' blood via a molecular adsorbents recirculating system (MARS). In addition, glucose metabolism, urea synthesis, P450 dependent verapamil metabolism using high performance liquid chromatography, and interleukin-6 induced "acute phase" reaction by sulfodesoxysalicylic acid-polyacrylamide gel electrophoresis detected changes of albumin synthesis were determined in primary hepatocytes and in established liver cells. The viability of hepatoma cells after contact with the toxic compounds coming from the patients' blood was significantly decreased in comparison to that of immortalized hepatocytes and primary hepatocytes. Immortalized hepatocytes and hepatoma cells showed a significantly higher consumption of glucose associated with a significantly higher lactate synthesis. A basic urea synthesis rate could be measured in immortalized hepatocytes and hepatoma cells, but it was significantly lower than that of primary cells. P450 with its subenzyme CYP2C was inducible only in primary hepatocytes and in immortalized cells, but in the latter the enzymatic activity was lower than that of primary cells. The incubation with acute phase mediators resulted in a decrease of albumin synthesis in primary hepatocytes and in hepatoma cells, but it increased the albumin synthesis in immortalized hepatocytes. Summarizing these data, partially beneficial effects can be assumed if established cells are used in an extracorporeal liver assist device. These might include synthesis of some compounds and basic metabolic activities, such as urea synthesis. However, established liver cells showed clearly altered metabolic characteristics. The sufficient removal of toxic compounds requires additional strategies for detoxification by primary hepatocytes in sufficient amounts.

Rapid HPLC assay for verapamil and its metabolites: use for application to in vitro studies.

An improved method using isocratic reversed phase HPLC is presented for the extraction and rapid determination of verapamil and its main metabolites in microsomal preparations and cell culture media. Possibilities for using the method to estimate cytochrome P450 enzymes in microsomal test systems and hepatocyte cultures are described. The studies show that primary hepatocyte cultures are suitable for studying the metabolism and interactions of pharmaceuticals in vitro and could be superior to microsomal systems in many cases.

[Pancreatic penetration of antibiotics]. / Die Pankreasgängigkeit von Antibiotica.

Antibiotic therapy is indicated in acute pancreatitis because the most common complication and the mean reason for mortality is a bacterial infection. Concentrations of nine antibiotics from various classes were studied in the pancreatic tissue and pancreatic juice of patients and dogs. The volume of distribution is the most valuable parameter for predicting the potential pancreatic penetration of a substance. As a result of our pharmacokinetic studies mezlocillin and cefotiam, especially ciprofloxacin, have the most antiinfectious potential in treatment of acute pancreatitis. Metronidazole is suitable for combination in cases of pancreatic infections covering anaerobic bacteria.

Antibiotic prophylaxis in cerebrospinal fluid shunting: reassessment of Cefotiam penetration into human CSF.

OBJECTS: Shunt infection is a major complication of shunt implantation. Numerous clinical studies give evidence that antibiotic prophylaxis is efficacious in preventing infections after cerebrospinal fluid shunting. In CSF shunting, antibiotics need to reach sufficient concentrations not only in the blood shielding the operative field but also in tissues and the CSF compartment. Cefotiam is widely used for prophylaxis in neurosurgery. Some clinical trials report that this beta-lactam is able to penetrate considerably into the CSF. However, these studies include disease patterns which are most likely to be associated with a pathological permeability of the blood-brain barrier. Therefore, this study was designed to investigate the extent of penetration of Cefotiam into human CSF in patients without morphological disruption of the blood-brain barrier. METHODS: The penetration of Cefotiam into human CSF was investigated in 23 patients without morphological disruption of the blood-brain barrier undergoing CSF shunt surgery. 2 g Cefotiam was administered prior to surgery as a short-term infusion for a period of 15 min. Samples of blood and CSF were collected intraoperatively. The concentrations of Cefotiam were determined by bioassay. RESULTS: All patients (n=23) showed moderate to high plasma levels of Cefotiam (range: 19.8-146.2 mg/L); the pharmacokinetic profiles in blood accorded well with published data. In contrast to earlier studies, no Cefotiam was detected in CSF. CONCLUSION: This study clearly demonstrates that Cefotiam does not penetrate through an intact blood-brain barrier into human CSF. Although Cefotiam has been shown to be valuable for the perioperative prophylaxis of shunt infection, other antibiotics might be superior if they are capable of entering the CSF. Further studies are required to address this assumption.