Search

Background: In 2019, the shortage of cefazolin led to the demand for cefotiam and cefmetazole exceeding the supply. The Department of Nephro-urology at Nagoya City University Hospital used fosfomycin as a substitute for perioperative prophylaxis. This retrospective preliminary study evaluated the efficacy of fosfomycin and cefotiam for preventing infections following ureterorenoscopy., Methods: The study included 182 patients who underwent ureterorenoscopy between January 2018 and March 2021). Perioperative antibacterial treatment with fosfomycin (n = 108) or cefotiam (n = 74) was administered. We performed propensity score matching in both groups for age, sex, preoperative urinary catheter use, and preoperative antibiotic treatment., Results: The fosfomycin and cefotiam groups (n = 69 per group) exhibited no significant differences in terms of patients' median age, operative duration, preoperative urine white blood cell count, preoperative urine bacterial count, and the rate of preoperative antibiotic treatment. In the fosfomycin and cefotiam groups, the median duration of postoperative hospital stay was 3 and 4 days, respectively; the median maximum postoperative temperature was 37.3 °C and 37.2 °C, respectively. The fosfomycin group had lower postoperative C-reactive protein levels and white blood cell count than the cefotiam group. However, the frequency of fever > 38 °C requiring additional antibiotic administration was similar., Conclusions: During cefotiam shortage, fosfomycin administration enabled surgeons to continue performing ureterorenoscopies without increasing the complication rate., (© 2024. The Author(s).)

Rationale: Antibiotics can cause central nervous system disturbances, manifesting as dizziness, confusion, headache, and seizures. Seizures due to antibiotic administration are related to increased excitatory neurotransmission because antibiotics act as competitive antagonists of the γ-aminobutyric acid type A receptor., Patient Concerns and Clinical Findings: All 5 patients, comprising 4 females and one male and aged 45 to 72 years, underwent open craniotomy with additional surgical maneuvers according to their specific disease. All patients presented American Society of Anesthesiologists Physical Status grades 1 to 2. There were no specific underlying diseases, except hepatitis C and hypertension. However, seizures developed sequentially in the 5 patients after neurosurgery., Diagnoses, Interventions, and Outcomes: Early postcraniotomy seizures (PCS) developed in the patients after neurosurgery. Prophylactic antibiotics were administered in all cases to prevent infection due to open craniotomy. This included the administration of 10 g and 2 g of an antibiotic (cefotiam HCL; Jetiam Intravenous Injection 1g®) an hour before the surgery in the ward and half an hour before the surgery in the operating room, respectively. After surgery, cefotiam HCL 2 g was administered in all patients on the day of surgery. Five patients had myoclonic seizure or generalized tonic-clonic seizure several times at emergence or in the intensive care unit., Lessons: Early PCS occurred in every patient when an overdose of the prophylactic antibiotic was administered. This report showed that the preoperative prophylactic antibiotic cefotiam administered in double doses evoked early PCS within a few hours of drug administration. Furthermore, such experiences caution that preoperative intravenous cephalosporins, including cefotiam, should be administered carefully in open craniotomy., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: In March 2019, cefazolin was unavailable owing to difficulty in procuring the active ingredient. Furthermore, the supply of alternative drugs, such as cefotiam and cefmetazole, was limited. In the Department of Nephro-Urology, fosfomycin-based drugs are used as substitutes for cefazolin, which is a perioperative prophylactic antibacterial drug. Herein, we investigated the effectiveness of fosfomycin sodium and cefotiam in preventing infection after endoscopic combined intrarenal surgery as a retrospective preliminary study., Methods: A total of 200 patients who underwent endoscopic combined intrarenal surgery at our department between August 2017 and January 2021 were included. The patients were administered cefotiam (n = 95) or fosfomycin (n = 105) as perioperative antibacterial agents. There were no significant differences in the median age or surgery time between the cefotiam and fosfomycin groups. Propensity score matching was performed to match the preoperative urine bacterial counts of both groups. Sixty-eight patients were selected from each group., Results: The median postoperative hospital stay duration was 4 days for the two groups. The median maximum postoperative temperatures were 37.5 and 37.4°C, respectively. There were no significant differences between the maximum postoperative temperatures in both groups. Furthermore, there were no differences between the groups regarding the white blood cell counts, C-reactive protein levels, and aspartate aminotransferase and alanine aminotransferase levels postoperatively, as well as in terms of postoperative fever requiring additional antibiotics., Conclusions: During a period of difficulty in acquiring cefazolin and cefotiam, the use of fosfomycin allowed us to continue with the procedure without increased clinical complications., (© 2022 The Japanese Urological Association.)

Introduction: In March 2019, cefazolin availability was limited owing to the contamination of the drug substance. In addition, there was a difficulty in supplying drugs alternative to cefazolin, such as cefotiam and cefmetazole. In our Department of Nephro-urology, we used fosfomycin-based drugs to substitute cefazolin as perioperative preventive antibacterial drugs. In this study, we aimed to evaluate the usage status of perioperative prophylactic antibacterial drugs before and after the period of limited cefazolin supply and to investigate the efficacy and safety of fosfomycin sodium in preventing infections following transurethral resection of bladder tumor., Methods: We enrolled 346 patients who underwent transurethral resection of bladder tumor in our department from April 2018 to August 2020. The patients received the following perioperative antibacterial agents: cefotiam (n = 146), fosfomycin (n = 166), and other antibacterial agents (n = 34). There was no significant difference in the median age or surgery time., Results: The median length of hospital stay was 6, 5, and 5 days in the cefotiam, fosfomycin, and other antibacterial groups, respectively, with significant difference. The median maximum postoperative temperature was 37.1 °C in all groups, with no significant difference. There were no differences in C-reactive protein, aspartate aminotransferase, and alanine aminotransferase levels determined by postoperative blood tests; preoperative and postoperative urinary white blood cell counts; preoperative urine bacterial counts; and surgery-related infection requiring additional antibiotic treatments among the groups., Conclusions: The use of fosfomycin-based agents helped overcome the limited supply of cefazolin without worsening clinical outcomes., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Bacteremia is often caused by gram-negative bacteria (represented by EKP; Escherichia coli, Klebsiella species, and Proteus mirabilis), and the excessive use of cefazolin, as the first-line antimicrobial in its treatment, has been a source of concern in the emergence of resistant strains. As an antimicrobial, cefotiam may be an alternative to cefazolin; however, little evidence is available for its use in the treatment of bacteremia. The purpose of this non-inferiority study was to retrospectively compare the therapeutic efficacy of cefotiam with some antimicrobials of narrow spectrum (cefazolin, cefmetazole, and flomoxef) in the treatment of EKP-induced bacteremia. The number of patients recruited was 32 in the cefotiam group and 29 in the control group. In the primary endpoint, the survival rate on day 28 for the cefotiam group and the control group was 93.5% and 89.3%, respectively (relative risk at day 28, 1.048; 95% confidence interval, 0.894-1.227). In the secondary end point, treatment success rate in the two groups was 71.9% and 69.0%, respectively (relative risk, 1.042; 95% confidence interval, 0.752-1.445). Intensive care unit admission, low body weight, hypoalbuminemia, and infections unassociated with the urinary tract were identified to be the risk factors responsible for treatment failure. We demonstrated cefotiam may be non-inferior to other antimicrobials of similar spectrum, in terms of survival rate, in EKP-induced bacteremia., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

The pharmacokinetics in patients with cystic fibrosis (CF) has long been thought to differ considerably from that in healthy volunteers. For highly protein bound β-lactams, profound pharmacokinetic differences were observed between comparatively morbid patients with CF and healthy volunteers. These differences could be explained by body weight and body composition for β-lactams with low protein binding. This study aimed to develop a novel population modeling approach to describe the pharmacokinetic differences between both subject groups by estimating protein binding. Eight patients with CF (lean body mass [LBM]: 39.8 ± 5.4kg) and six healthy volunteers (LBM: 53.1 ± 9.5kg) received 1027.5 mg cefotiam intravenously. Plasma concentrations and amounts in urine were simultaneously modelled. Unscaled total clearance and volume of distribution were 3% smaller in patients with CF compared to those in healthy volunteers. After allometric scaling by LBM to account for body size and composition, the remaining pharmacokinetic differences were explained by estimating the unbound fraction of cefotiam in plasma. The latter was fixed to 50% in male and estimated as 54.5% in female healthy volunteers as well as 56.3% in male and 74.4% in female patients with CF. This novel approach holds promise for characterizing the pharmacokinetics in special patient populations with altered protein binding.

We performed a survey of clinical experience of cefotiam (CTM: Pansporin) as postmarketing surveillance (PMS), and evaluated the efficacy and safety of CTM in 10,499 cases of data which were collected during the first 2 years after approval. The following results were obtained. The efficacy rate of CTM in the treatment of various infections was 83.2%, which was equal or superior to the clinical results obtained before approval. A total of 472 adverse drug reactions was reported by 10,499 patients (4.50%). The commonest adverse drug reactions was liver function abnormality (230 cases), followed by dermal symptoms (103 cases), gastrointestinal symptoms (53 cases) and renal function abnormality (20 cases) in the order mentioned. All of these adverse drug reactions had already been known for cephem antibiotics, and no remarkable adverse drug reactions specific to CTM was found. The above PMS results indicate the same efficacy of CTM that obtained from premarketing studies. As regards safety, there was no remarkable unexpected adverse drug reaction and their profile was also the same as that found in premarketing studies. Thus, the utility of CTM was confirmed.

In 12 patients undergoing operation, 1 g of cefotiam (CTM) was administered intravenously and CTM levels in gallbladder tissue and gallbladder bile were examined. CTM concentration in gallbladder bile was high in patients with patent cystic duct, while very low in those with cystic duct obstruction. CTM concentration in gallbladder tissue was low in patients with chronic inflammatory gallbladder. CTM activities of T-tube bile were compared with those of CMZ by cross over method in 2 cases. CTM showed extremely higher concentration in bile than CMZ. In a case with excessive output of bile, CTM activity, total bile acids concentration and canalicular flow/ductal flow ratio were low. It can be presumed that CTM was diluted by increased ductal secretion.

CTM was administered at dose levels of 1 to 3 g a day to 77 cases of otorhinolaryngological infections, and the following results were obtained: The effect of the drug was determined in 75 cases. The responders were 3 out of 5 (60.0%) in acute suppurative otitis media, 4 out of 11 (36.4%) in chronic suppurative otitis media, 39 out of 43 (90.7%) in tonsillitis and peritonsillar abscess and 12 out of 16 (75.0%) in other diseases, a total of 58 out of 75 cases (77.3%). The bacteriological effect of CTM was evaluated in 53 cases, and bacterial eradication was demonstrated in 41 cases (77.4%). Also, its antibacterial potency was 2 to 4 times superior in comparison to that of CEZ against isolated bacteria in which MICs were measurable. Side effects which were neither severe nor specific were recognized in 3 out of 77 cases (3.9%). In the cases with abnormal laboratory values, none was determinable to be attributed to CTM.

Clinical trial of cefotiam was made in children and the following results were obtained. 1. Pharmacodynamic studies of the drug in CSF of experimental staphylococcal meningitis in rabbits showed a CSF/serum ratio of T 1/2 of 3.52, which was relatively high, but a percentage of CSF/serum ratio of AUC of only 3.42% up to 3 hours, suggesting a low efficiency of passage of the drug into CSF. 2. Blood concentrations of the drug were determined in children after an intravenous bolus injection of 20 mg/kg and were 46 mcg/ml (15 min.) and 26 mcg/ml (30 min.), T 1/2 being 40.8 min., Urinary recovery rate was 91.3% up to 4 hours in one patient and 61.9% up to 6 hours in another, respectively. 3. Thirteen patients with the following 14 episodes of infections were treated with cefotiam; urinary tract infection (5 cases), pneumonia (5), empyema (1), tonsillitis (1) and suspected sepsis (2). An overall efficacy rate was 100%, i. e., excellent in 12, good in 2 and no failure. No adverse reactions were clinically discernible and only laboratory abnormalities were transient or slight elevations of transaminase levels in 2 patients. 4. Based on the above results, it was concluded that cefotiam is a potent new antibiotic in the treatment of bacterial infections. Spectrum and antibacterial activity of the drug suggest that the drug particularly indicated for pneumonia.

In 20 patients undergoing heart surgery, concentrations of cefotiam (Halospor) in plasma, heart valves, muscles and subcutaneous tissue were determined after intravenous injection of 2 g. Within 5 h cefotiam serum concentration declined from 18 micrograms/ml to 7 micrograms/ml, the concentrations in heart valves declined from 22 micrograms/g to 4 micrograms/g. In heart valves the concentrations during heart surgery were high enough to inhibit most Staphylococcus aureus, E. coli and Klebsiella strains.

The renal excretory mechanism of cefmenoxime in rabbits was compared with that of 6 other cephalosporins (cefotaxime, deacetylcefotaxime, cefotiam, cefazolin, cephaloridine, and cefsulodin). The clearance ratios (Cf-Drug/CInulin=CRf) of cefmenoxime (337) and cefazolin (73) were considerably higher than those of the 5 other cephalosporins (0.9-20). When p-amino-hippurate (PAH) was administered concurrently with each of the cephalosporins, the CRf values of the cephalosporins except for cefsulodin were significantly decreased. These findings indicate that cefmenoxime and the 5 other cephalosporins except cefsulodin are actively incorporated in the proximal tubular cells and secreted into the tubular lumen. In the case of cefotiam and cefsulodin, glomerular filtration tended to exceed urinary excretion with highest dose of PAH (40 mg/kg/minute), suggesting the possibility of tubular reabsorption of these drugs. On the other hand, glomerular filtration of cefmenoxime and the 4 other cephalosporins did not exceed urinary excretion. The drug concentration ratio of the cortex to medulla indicated that the tubular cell level of cefmenoxime was lower than, higher than, and similar to those of cephaloridine, cefotaxime, and the remaining cephalosporins, respectively. These results demonstrate that the renal excretory mechanisms of cefmenoxime is similar to that of cefazolin but not to that of the remaining cephalosporins.

Clinical investigation of cefotiam and aminoglycosides combination use against infections complicated by acute leukemia was performed, and the results obtained were as follows. 1) Sixteen patients were treated with cefotiam in doses 4--6 grams per day parenterally. The clinical effectiveness were excellent 47.6%, good 14.3%, fair 9.5% and poor 28.6%. No significant differences in therapeutic efficacy was observed between the patients given CTM 4 g/day and CTM 6 g/day. 2) It was considered that the clinical effectiveness of CTM has not been influenced by the difference of a number of maturation granulocyte. CTM has showed a certain, though not distinctive, efficacy compared with CFX. 3) As side effects with CTM, eruption appeared in 1 case, and no remarkable laboratory findings was observed. Cefotiam is thus considered to be a useful drug for the treatment of infections complicated by acute leukemia.

A clinical study on cefotiam (CTM) was performed in the field of pediatric infection, and the following results were obtained: The number of cases studied were six including 2 cases of U.T.I., 1 case of vaginitis and vulvitis, 1 cervical lymphadenitis, 1 absence of thigh and coxitis. Clinical responses to CTM were excellent in 3 cases, good in 1 cases but there was 1 exception who dropped out because of concurrent use of other antibiotics. As for bacteriological responses, CTM eliminated the pathogens E. coli and P. mirabilis from U.T.I., Staph. epidermidis and P. morganii, from vaginitis and vulvitis, H influenzae and Str. pneumoniae from cervical lymphadenitis and Staph. aureus from abscess of thigh. No side effect was observed except 1 case who showed an elevation of GOT, GPT and LDH. It is uncertain, however, wether this abnormality was resulted from the use of CTM or not, because the other antibiotics were used also.

The concentration of cefotiam (CTM), a newly synthesized cephem derivative antibiotic in serum and cerebrospinal fluid after single intravenous treatment was determined and its utility in the field of cerebral neurosurgery was studied. 1. One gram or 2 g of CTM was intravenously administered for 1 time to 10 patients admitted to our department. Dose dependency was observed in the progress of the mean serum concentration. There was no difference in the specific rate of constant, and the ratio of AUC between the group treated with 1 g and the one with 2 g was 1:1.9. The biological half-lives of the elimination phase for both dose levels were about 1.1 hours. 2. Disparity was recognized in the cerebrospinal fluid concentration in spite of the dose dependency. Although a case with comparatively high value of 1.37 micrograms/ml at 60 minutes after administration were seen in the 1 g treatment group, generally the migration concentration was low. Good cerebrospinal fluid concentration was attained in all of the cases in the 2 g treatment group, and the peak values ranged from 0.59 to 10.16 micrograms/ml. 3. The concentration ratio of cerebrospinal fluid to serum in the 2 g treatment group elevated till 360 minutes after administration, and the maximum values ranged from 15.8 to 89.8%. 4. The migration to the cerebrospinal fluid was faster in cases with slight inflammation than those without inflammation in the 2 g treatment group. 5. It was assumed that the prophylactic effect of CTM 2 g administration against staphylococci, streptococci and Klebsiella pneumoniae which are the major causative organisms can be expected in postoperative infection in the field of cerebral neurosurgery.

Studies on the antibacterial activity, absorption and excretion and also clinical investigation in the field of pediatrics have been carried out with cefotiam (SCE-963, CTM), a new cephalosporin antibiotic. 1) The MICs of CTM against the following clinical isolates were measured and compared with those of CEZ: S. aureus (81 strains), E. coli (27) and K. pneumoniae (27), with CTM being inferior by 1 tube in S. aureus, being superior by 2 to 3 tubes in E. coli and by about 2 - 3 tubes in K. pneumoniae. 2) Absorption and excretion. After intravenous one shot injection at dose levels of 10 mg/kg and 20 mg/kg, the peak in the serum concentration was shown in the 15-minute value with 18.1 and 36.6 mcg/ml for 10 mg/kg and 20 mg/kg, respectively. The half-life in ;the serum was 1.14 and 0.61 hours, respectively. In the case of 1-hour intravenous drip infusion at a dose level of 10 mg/kg, it was 14.3 mcg/ml, with 0.98-hour half-life in the serum. The recovery rates from the urine within 0 to 6 hours were 50.6% and 66.2% in the case of intravenous one shot injection at dose levels of 10 mg/kg and 20 mg/kg, respectively, with 71.1% in the case of the 1-hour intravenous drip infusion. 3) Two to 3 hours after intravenous one shot injection of CTM in H. influenzae-meningitis every 4 hours at a dose level of 62.5 mg/kg at one time, the cerebrospinal fluid concentration of CTM was only 2.12 to 10.0 mcg/ml, and this fact suggests that CTM is a useful cephalosporin for treating purulent meningitis. 4) CTM was administered in 19 clinical cases, with the results being: excellent in 4 out of 4 cases of bronchitis; excellent in 5 and good in 1 out of 6 cases of pneumonia; excellent in 3 cases of pyelitis; good in purulent parotitis, purulent meningitis and bacterial pericarditis; and excellent in peritonsillar abscess, purulent osteomyelitis and staphylococcal scalded skin syndrome (S.S.S.S.). No side effects have been observed in all cases. As for abnormal laboratory findings, 3 cases of eosinophilia were seen.

Cefotiam of 1 to 2 g was intravenously given during 15 to 60 minutes in 10 cases, and blood levels and cerebrospinal fluid (CSF) levels were studied. Following the drip infusion of cefotiam, maximum blood levels of 25.2 to 305 micrograms per ml was an average of 101.2 micrograms per ml were achieved at 15 to 60 minutes in 9 cases. Half life of cefotiam in serum was from 20 to 50 minutes, and mean time was 39.4 minutes. In contrast, maximum CSF levels of cefotiam were ranged 1.4 to 17.2 micrograms per ml and mean value was 5.7 micrograms per ml in 8 cases. The ratios of CSF levels to blood levels were calculated from 1.7 to 6.6% with an average of 4.6%. The CSF levels of cefotiam showed long delay and long decay. The period between the drip infusion and peak levels of cefotiam in CSF showed 60 to 420 minutes and mean time was 194 minutes. Half life varied between 45 and 270 minutes with an average of 178 minutes. No side effects were found in all cases.

A new synthetic cephalosporin, cefotiam (CTM) was studied from the basic and clinical aspects, and the following results were obtained: 1. Bacteriological study: The bacterial activities of CTM against the clinical isolates of S. aureus, S. pyogenes, E. coli, Klebsiella sp. and Proteus sp. were compared with those of CEZ, CER, ABPC and GM. (1) As for S. aureus and S. pyogenes, the antibacterial actions of the conventional cephalosporins were slightly more potent than those of CTM. (2) However, CTM had the antibacterial actions which were most potent Proteus sp. among the above 4 antibiotics and more potent against E. coli and Klebsiella sp. than the above 2 conventional cephalosporins. 2. Pharmacokinetic study: The peak serum levels of CTM were comparatively low with 19.30 +/- 1.66 mcg/ml 30 minutes after a bolus injection of 20 mg/kg and 25.85 +/- 4.32 mcg/ml just after a drip infusion of 20 mg/kg. The half-life of the serum levels was 0.98 hrs. and 0.87 hrs., respectively. The 4 hours urinary excretions in six patients ranged from 38.6 to 64.9%, showing a slightly wide variance. 3. Clinical study: The clinical response was good in 23 out of total 25 cases, i.e. 14 cases with respiratory tract infection, 7 with urinary tract infection and 4 with skin and soft tissue infection. The response rate was 92%. Also, neither side effects nor abnormal laboratory findings was observed.

The variation of granulocyte phagocytosis after antibiotic treatment has been studied. The conclusion is drawn that cephalosporins, piperacillin and aztreonam cause an increase of phagocytosis, while rifampicin and gentamicin induce a decrease of this activity.

Pharmacokinetics and clinical studies on cefotiam (CTM) in pediatric surgery were performed and the results obtained are summarized below. In neonates without congenital heart disease (CHD), serum levels of CTM were rapidly increased following injection of CTM (20 mg/kg, one shot intravenous administration) and the peak values were found at 15 minutes. Six hours later, CTM almost disappeared from the blood. In the patient with CHD, however, CTM was retained in the serum and the urinary excretion was poor. The CTM was administrated prophylactically to prevent postoperative infections in 10 patients. Eight of 10 had no episodes during postoperative period. Wound infection, however, was found in 2 patients. No clinical and laboratory side effects were caused by CTM.

The fundamental and clinical studies on cefotiam (CTM) were performed in the field of pediatrics, and the following results were obtained: 1. The peak MIC's of CTM against Gram negative rods such as E. coli, Klebsiella, Salmonella, Proteus were 1.56 mcg/ml. The MIC distribution against S. aureus was almost equal to the conventional cephalosporin antibiotics. The MICs against P. pseudomonas and Serratia were over 400 mcg/ml. 2. The mean serum levels of CTM after bolus intravenous injection of 25 mg/kg were 59.9 mcg/ml after 15 min., 30.0 mcg/ml after 30 min., 15.6 mcg/ml after 1 hour. 3. Administration of CTM to 6 pediatric patients produced the clinical responses which were good in all 6 cases and the bacterial effects of eradication in 3 cases and superinfection in the 2 cases in the 5 cases from whom the organism were isolated. No side effect was observed. From the above results, it is considered that a bolus injection of CTM 25 mg/kg t.i.d. to q.i.d. is a safe and useful treatment for pediatric cases.

Change in external appearance, pH values and residual antimicrobial potency of cefotiam dihydrochloride (CTM) upon combination with infusion solutions and other injections was investigated. The combinations of CTM with bromhexine hydrochloride 2 mg/ml, 2 ml, dipyridamole 5 mg/ml, 2 ml and gabexate mesilate 100 mg/vial respectively were found to be incompatible on account of turbidity produced. As for 34 other combinations, no change in their appearance, pH and potency was observed.

The treatment of the patients with ruptured cerebral aneurysm in acute stage is performed by direct neck clipping and cisternal drainages for preventing vasospasm. The cisternal drainage is carried out for 1 to 2 weeks' duration. The cisternal drainage has higher risk for bacterial infections in the cerebrospinal fluid (CSF). In this paper, penetration characteristics of cefotiam (CTM) in CSF were studied. CTM concentrations in CSF were measured at 1, 3 and 6 hours after intravenous drip infusion of CTM (2 g). CTM concentration in cisternal CSF was higher than that of ventricular CSF. The peak concentration in CSF was higher than 0.78 micrograms/ml and obtained at 3 hours after intravenous drip infusion. Our data suggest that CTM is a useful cephalosporin for treatment of meningitis (Staphylococcus aureus, Streptococcus pneumoniae et al.). Apart from meningitis, the higher concentration of CTM in CSF was obtained in the cases with the vasospasm. The result may support that the breakdown of blood brain barrier is induced by the peroxidative substance from the cisternal subarachnoid clots which has the vasospastic activity.

Clinical investigation with cefotiam (CTM) was performed, the following results were obtained. CTM was administered to 18 cases of infectious diseases in the otorhinolaryngologic field. Clinical results were excellent in 7 cases, good in 5 cases, fair in 4 cases and poor in 2 cases. Clinical efficacy was 66.7%. No side reactions were noted in any cases.

To evaluate the antibacterial potency of cefotiam (CTM) clinical and laboratory studies were carried out and the results were as follows. Clinical evaluation and adverse reaction CTM was given to total of 23 patients, 10 with bronchopneumonia, 10 with bronchitis and one each with cystitis, enteritis and suspected sepsis. Overall efficacy rate was 78.3% (18/23) (excellent 9, good 9, fair 3, poor 2). Only 1 case showed a side effect of slightly elevated GOT and GPT. Antibacterial activities MIC of CTM against isolates from sputum was investigated on those patients mentioned above and was compared with MIC of CEZ and CMZ. CTM showed superior antibacterial activity against almost all strains. Especially on Haemophilus and Klebsiella antibacterial activity of CTM was impressive. Organisms in sputum Four out of 8 causative bacteria disappeared and 1 out of 8 decreased after administration of CTM. Thus CTM is considered to be the useful drug for the treatment of respiratory infection.

Cefotiam (SCE 963), a new, broad-spectrum, third generation cephalosporin was used in the treatment of 136 patients suffering from respiratory tract infections, urinary tract infections, septicemia, meningitis, biliary tract infections and osteoarthritis infections. Cefotiam was administered in monotherapy to 98 patients at the mean posology of two grams per day (extreme doses: 1 to 6 g). The following clinical effectiveness was noted: 83 successes and 18 failures on 101 available clinical reports. The general, biological tolerance and renal tolerance was good in all patients.

Basic and clinical studies in 37 patients with biliary tract disease on comparison between cefmenoxime (CMX) and cefotiam (CTM) were studied and the following results were obtained. In vitro antibacterial activities of CMX and CTM against 25 strains (15 organisms) isolated from bile of patients with biliary tract disease were stronger than that of cefazolin (CEZ). In cholecystectomized patients, CMX (2 g) or CTM (2 g) was injected intravenously, followed by determination of concentration in bile and gallbladder tissue about 2 hours after administration. In CMX administration, the mean concentration in gallbladder bile was 812.1 micrograms/ml, and the mean concentration in duct bile was 1,050.6 micrograms/ml, and the mean concentration in gallbladder tissue was 100.7 micrograms/g. In CTM administration, the mean values were, 1,092.5 micrograms/ml, 1,287.8 micrograms/ml, 28.5 micrograms/g, respectively. The concentration of CMX and CTM were almost similarly. The bile concentration of CMX (i.v.) was compared with CTM (i.v.) by cross-over method in cases of T-tube drainage. The peak bile concentrations of CMX and CTM were as high as 172.4 micrograms/ml and 182.2 micrograms/ml, respectively, 1 approximately 2 hours after 2 g intravenous administrations. Furthermore, the concentration of them were highly gained, 16.1 micrograms/ml of CMX and 33.8 micrograms/ml of CTM, even at 5 approximately 6 hours. In choledochostomized patients, CMX (4 g/day) was injected intravenously, followed by determination of concentration in intraperitoneal exudate. The mean concentration of CMX was 15.3 micrograms/ml on the first day after the operation, and 6.0 micrograms/ml even on the third day after the operation. Those results suggest that the high antibacterial activity of CMX against organism in bile and, the high penetration of CMX to bile, gallbladder tissue and intraperitoneal exudate will promise its important role in treatment of biliary tract infections.

The preoperative administration of cefotiam (CTM) 1 g by intravenous drip infusion for 30 minutes was performed. And the concentration of CTM in peripheral blood, bone marrow fluid and bone tissue was investigated. CTM was smoothly transmigrated from blood to bone tissue, and kept on the concentration in bone tissue over MIC values for several hours. These preliminary results encourage us to think that CTM may be as useful in prophylaxis against postoperative infections.

Cefotiam (CTM) was administered to female patients suffering from acute cystitis to examine its clinical efficacy and changes in form of the bacteria in urine. CTM was administered to 15 female patients with acute cystitis once a day for three consecutive days (1 g/time in 13 cases, and 0.5 g/time in 2 cases). The overall clinical efficacy was 100%. Bacteriological examination, revealed 13 cases of single infection by E. coli, and one case of E. coli and S. epidermidis (MIC: 0.78 micrograms/ml). MIC of E. coli ranged from 0.05 to 0.78 micrograms/ml. All of the strains were eradicated, the eradication efficacy being 100%. The forms of bacteria in the urine after the administration of CTM were examined in 8 cases (all due to E. coli). Bacteria in urine disappeared or formed a spherical form 5 minutes after the administration of CTM. Disappearance of E. coli was observed in 7 cases at 15 or 30 minutes after drug administration, and with the disappearance, improvements were also observed in the urinary findings. Of these cases, the urinary concentration of CTM was measured in 4 cases. It ranged from 296 to 6,893 micrograms/ml at 5 minutes after the administration. In one case of deficient excretion in urine, filamentation was observed, and with the rise in CTM concentration in urine, granular changes were observed in the shape of bacteria. CTM's excellent clinical efficacy was substantiated by the changes in the form of bacteria in urine.

Cefotiam is clearly more active against Neisseria gonorrhoeae in vitro than penicillin. This applies especially to strains producing beta-lactamase but also to those which do not. No strain requires more than 0.25 micrograms/ml for inhibition. 1 g of cefotiam dissolved in 3 ml of 1% lidocaine solution cures 90.0% of patients suffering from uncomplicated genital gonorrhoea if injected once intramuscularly. Tolerance of this regimen is very good, no major side-effect being found.

Cefotiam (CTM) was intravenously given to 12 patients with infectious diseases in the field of otorhinolaryngology including 10 cases with chronic suppurative otitis media. Daily doses of CTM were 1 to 4 g. Clinical responses were excellent in 3 patients, good in 5, fair in 1 and poor in 3. The rate of overall clinical effectiveness was 67%. Staphylococcus species were most frequently isolated from the patients and all of them were eradicated by the CTM treatment. No side effects and no abnormal laboratory findings relating to the drug administration were observed.

Bacteriological evaluation was made on cefotiam (CTM), a new broad-spectrum cephalosporin antibiotic, and the following results wer obtained. 1) CTM has shown very potent antibacterial activities against Staphylococcus aureus, Escherichia coli, Edwardsiella tarda, Citrobacter intermedius, Salmonella, Klebsiella, Proteus mirabilis, Proteus rettgeri, Proteus inconstans, Yersinia enterocolitica, Aeromonas hydrophila, Plesiomonas shigelloides and Pseudomonas putrefaciens. 2) Streptococcus faecalis, Enterobacter and Proteus morganii isolated from urine, Serratia and glucose non fermentative Gram-negative bacilli except Pseudomonas putrefaciens, were almost insusceptible to cefotiam.

Distributions of cefsulodin (CFS) and cefotiam (CTM), new parenteral cephalosporins, to human aqueous humor and cornea were studied in comparison with those of sulbenicillin (SBPC) and cefazolin (CEZ), and pharmacokinetic analysis was made by theory of compartment model, to obtain the following results. 1. Maximum aqueous humor levels of CFS and CTM were noticed at 2.5 hours after the start of 1 g CFS or CTM administration by 30 minute intravenous drip infusion, with the levels of 3.6 micrograms/ml and 4.2 micrograms/ml respectively. On the other hand, in case of 5 g SBPC or 2 g CEZ administration maximum aqueous humor levels were 12.5 micrograms/ml and 5.2 micrograms/ml respectively. 2. The ratios of maximum aqueous humor level to plasma level of the same time in CFS, CTM, SBPC and CEZ were 15.0, 16.8, 6.4% and 5.5%. Distribution of CFS or CTM was 2 to 3 times better than that of SBPC or CEZ. 3. From the result of pharmacokinetic analysis, ratios of aqueous humor to plasma levels in area under curves (AUC) of CFS, CTM, SBPC and CEZ were 25.6, 29.9, 16.4% and 7.9% respectively. Maximum aqueous humor levels of CFS, CTM, SBPC and CEZ were 2.9, 3.6, 11.4 micrograms/ml and 4.3 micrograms/ml and biological half life of gamma-phase were 2.57, 2.31, 2.77 hours and 2.24 hours respectively. 4. Cornea levels of CFS or CTM at one hour after the start of 1 g CFS or CTM administration by 30 minutes intravenous drip infusion were 2.9 micrograms/g and 5.2 micrograms/g, and their ratios to plasma level were 7.5% or 14.3% respectively. In case of 5 g SBPC or 2 g CEZ administration, the cornea levels were 26.7 micrograms/g and 5.0 micrograms/g, and the ratios were 9.4% and 3.4% respectively. 5. From the above, the distribution of CFS or CTM to human aqueous humor and cornea is better than that of SBPC or CEZ, and it is considered that clinical usefulness of both CFS and CTM by parenteral administration is expected in intraocular infections.

The ability of ceftizoxime to penetrate the outer membrane was compared with those of five other new cephalosporins: cefotiam, cefuroxime, cefotaxime, cefmetazole and cefoxitin, using a clinical isolate of Enterobacter cloacae as a test strain. Estimation of permeability was performed by a method utilizing the inhibitory activities of the cephalosporins against beta-lactamase located in the periplasm. Of the cephalosporins tested, both ceftizoxime and cefmetazole gave remarkably high concentrations in the periplasm, several times higher than those of cefotaxime and cefoxitin and ten or more times higher than those of cefuroxime and cefotiam. The approximate permeability coefficient of ceftizoxime was also several times higher than those of cefotiam and cefmetazole and over ten times higher than those of cefoxitin, cefuroxime and cefotaxime.

The influence on bowel flora of CTM was studied in 5 children who were taking normal diet. 1) In the cases following no diarrhea, administration of CTM caused no significant changes in bowel flora. In the cases following diarrhea, administration of CTM caused a fall in coliform, BEP group, Lactobacillus and Peptostreptococcus. However, after the administration was discontinued, the reduced bowel flora was returned to the normal range within a few days. 2) No overgrowth of bowel flora by Pseudomonas, Clostridium difficile or Candida was observed. 3) One strain of nontoxigenic Clostridium difficile was observed in the case of following no diarrhea. 4) As for the side effects, diarrhea was observed in 2 cases. BEP group: Nonspore making anaerobic Gram positive rods of Bifidobacterium, Eubacterium, Propionibacterium.

The clearance approach was used in the evaluation of the role of renal and biliary excretion in the total elimination of cephothiam from organism of patients after cholecystectomy. Six patients with inserted T-like drain into the choledochus duct and urinary catheter after gall bladder operation received I g cephothiam by stream intravenously during the early postoperative period. The value of renal clearance (= 132.86 +/- 27.35 ml/min) was with one order higher than that of biliary clearance (= 11.54 +/- 9.67 ml/min) and revealed glomerular filtration as the basic mechanism for elimination of cephothiam from the organism of those patients. The value for the sum Clr + Clb = 144.40 ml/min. kre + keb + 1.51 h1-resp. corresponded to the value of the clearance from the central (plasma) compartment, that for kle resp. suggesting that the kidneys and liver were part of that compartment. The high degree of positive correlation between the biliary clearance and biliary flow (r = 0.94, p less than or equal to 0.02) as well as the positive dependence of the biliary excretory rates, biliary excretory rate constants resp X 80, (r = 0.81, r = 0.83 resp) from the biliary flow revealed that the elimination of the drug from the live depends on the volume of the biliary flow. The negative correlation (r = -0.87, p less than 0.05) between the half-life for biliary excretion and the volume of the biliary flow support that presumption.

240 and 183 strains of non-PPNG and PPNG isolated in 1981 were studied for their susceptibility to ceftriaxone and cefotaxime respectively. All the strains were susceptible to 0.016 microgram/ml of either antibiotic. PPNG from males were less susceptible to cefotaxime than non-PPNG or PPNG from females. PPNG isolated in 1979 were less susceptible to gentamicin than non-PPNG. The relatively high MIC values of cotrimoxazole may account for the high treatment failure rate encountered with the drug.

Clinical evaluation of cefotiam (panspolin), a new cephem antibiotics, was performed in the infectious disease associated with hematological disorders and in the respiratory system. In hematological dis orders, 40% of good and 25% of fair results were obtained in clinical effects. In respiratory infections, however, 92% of good results were obtained. Opportunistic infection due to Gram-negative bacilli are often experienced in patients with leukemia. Since cefotiam has sufficient bacteriocidal effects in broad spectrum, it would be a good therapeutic agent against infectious diseases associated with hematological disorders.

Prophylactic antimicrobial therapy for the prevention of infection during total joint arthroplasty or spinal surgery was investigated using cefotiam (CTM) and cefmenoxime (CMX), which are cephems having broad antimicrobial spectrum. Seven patients received 2 g of CTM, and 12 patients 2 g of CMX, by intravenous drip infusion over 15 minutes. Blood, bone marrow and osseous tissue samples were obtained at the end of the infusion, and 30, 60, 90 and 120 minutes after the beginning of the infusion. The concentrations of CTM and CMX were detected by the agar-well method. CTM and CMX were smoothly distributed from blood to bone marrow and osseous tissue, and kept on the effective concentrations for prophylaxis against postoperative infections. The primary wound healing was obtained in all cases, and no side effects were also recognized.

All subjects were patients with malignant tumors on the gastroenterological system and in whose cases there were marked ascites (Table 1). In the study, each patient was subjected to the intravenous drip infusion of CTM 1 g for a period of 1 hour. Samples of peripheral venous blood and ascites were taken 4 times, at 1 hour after completion of infusion, and at 2, 3 and 4 hours. The test samples were kept at -80 degrees C until the CTM contents were determined (Fig. 1). Determination results 1. Blood concentrations of CTM decreased with the passage of time (Fig. 2). 2. There was hardly any difference in the concentration of CTM in ascites between the 1 hour and 4 hour samples. Furthermore, the concentration was maintained which exceeded the MIC against intestinal flora, including Escherichia coli, without Pseudomonas and Bacteroides (Fig. 3, Table 2). 3. The higher serum creatinine levels were the greater the concentration of CTM in blood (Fig. 5). 4. The maximum blood and ascites concentration of CTM indicated a correlation coefficient of 0.809, P less than 0.01 (Fig. 6). These results led to the following conclusions: 1. If 1 hour intravenous drip infusion of CTM 1 g/100 ml is to be carried out against postoperative peritoneal infection, such administration at interval less than 5-hours would not be reasonable. 2. The peritoneal invasion of malignant tumor is not a factor in the inhibition of CTM transition from blood to ascites.

The pharmacokinetic behaviour of cephalosporin antibiotic, second generation after intravenous administration to patients during the early post-operative period was characterized as well as after cholecystectomy. The data suggest a two-compartment distribution with elimination from the central compartment, realized on account of the renal way of clearance. In one of the patients, with one-compartment distribution of the drug, the presence of the theoretical determining factors in "the collapse" of one two-compartment open model to one-compartment is shown, associated with clinical characteristics of that patient.

The in vivo antibacterial activity of cefoperazone (CPZ) against systemic infections was studied in comparison with that of cefotiam (CTM) using beta-lactamase non-producing bacteria and producing bacteria. In vitro antibacterial activity of CPZ against Gram-positive bacteria was slightly inferior to that of CTM, but there was no significant difference between their in vivo activities. On the other hand, the therapeutic effect of CPZ against Gram-negative bacteria was nearly parallel to in vitro antibacterial activity and particularly was superior to that of CTM against cephalosporinase (CSase) producing bacteria. The ascitic levels of CPZ in mice infected with CSase producing bacteria were persisted longer, but those of CTM disappeared quickly after administration. This result appeared to reflect on the therapeutic effects of both drugs.

Cefotiam (CTM) were clinically applied to 6 cases and the following results were obtained: 1. The patients were aged 1 year in 5 cases and 7 years in 1 case. They comprised three cases of acute tonsillitis and 1 case each of phlegmon, bronchopneumonia and cervical abscess. CTM was administered in a daily dose of 50-115 mg/kg t.i.d. by an 1-hour intravenous drip infusion for 4 to 8 days. 2. The causative bacteria were S. aureus in 3 cases and H. parainfluenzae, K. pneumoniae and unknown pathogen in each 1 case. The organisms were eradicated in all cases except for only 1 case of S. aureus. 3. Overall responses were good in 4 cases and fair in 2 cases. 4. As for the abnormal laboratory findings, slight increase of GOT and GPT was observed in 1 case. Any other side effects were not observed.

The basic and clinical studies of cefotiam (CTM) in pediatric infections were carried out, and the following results were obtained: 1. The antibacterial activity of CTM against S. aureus was equal or slightly less than that of cefazolin (CEZ). Those of CTM against E. coli and K. pneumoniae were eight times more active than those of CEZ. 2. CTM 20 mg/kg was administered wither by 30 minutes or 1 hour intravenous drip infusion. The peak serum levels were obtained at the end of each drip infusion, with the mean peak levels being 44.8 and 41.4 mcg/ml respectively. The serum levels at 1.5 and 2 hours after drip infusion were 2.8 and 2.2 mcg/ml respectively, and at 3.5 and 4 hours after drip and 4 hours after drip infusion were 0.3 and 0.7 mcg/ml respectively. The half lives were 0.62 and 1.15 hours, respectively. The mean urinary excretion over 6 hours were 52.8% in ;the 30 minutes drip infusion group and 42.6% in the 1 hour drip infusion group. 3. Clinical efficacy was evaluated in sixteen cases suffering from tonsillitis (4 cases), pneumonia (4), bronchitis (2), cervical lymphadenitis (2), purulent meningitis (2), suppurative arthritis (1) and suspected sepsis (1). Good and excellent responses were obtained in 15 of 16 cases (93.8%). Bacteriological response in the form of eradication was noted in 4 of 6 cases. Side effect observed was rash in 1 case, and laboratory abnormalities were elevation of BUN in 1 case and elevation of GPT in 2 cases.

MIC determinations with the dilution method using DST-agar show that 7 beta-[2-amino-thiazol-4-yl)acet-amido-3-less than ([1-(2-dimethylaminoethyl)-1H-tetrazol-5-yl]thio)methyl greater than-ceph-3-em-4-carboxylic acid (cefotiam) is approximately ten times more active than cefoxitin or cefuroxime against non-selected bacterial isolates. Cefotiam is also significantly more active than cefoxitin or cefoperazone against mezlocillin- and piperacillin-resistant cultures. The determination of susceptibility to cefotiam gives reliable results with 30 microgram discs. Inhibition zones of up to 12 mm (corresponding to MIC superior or equal to 64 microgram/ml) should be considered as resistance and zones larger or equal to 18 mm (corresponding to MIC inferior or equal to 8 microgram/ml) as susceptibility.

Cefotiam, a second generation cephalosporin and cefoperazone, a third generation cephalosporin have a broad spectrum of activity against a majority of organisms commonly found in the bile. Although cefoperazone is excreted into the human bile to a greater extent than is cefotiam, there are no comparative data available that cefoperazone prophylaxis is safer and more effective than cefotiam for patients undergoing biliary tract surgery. A prospective randomized study was performed to compare the safety and efficacy of cefotiam with those of cefoperazone for prophylaxis in patients undergoing elective biliary tract surgery. The incidence of postoperative infection was not significantly different between the cefotiam group (n = 86) and the cefoperazone group (n = 86). The rate of side effects, however, was significantly different. In the cefotiam group, only one patient had diarrhea whereas in the cefoperazone group, eight had diarrhea and one skin eruption. Clostridium difficile cytotoxin was nil in those with diarrhea. Diarrhea in all patients was mild and recovery was rapid. Cefotiam is thus safer and as effective as cefoperazone in preventing postoperative infections following biliary tract surgery. We suggest that cefotiam is the first choice antibiotic for prophylaxis in biliary tract surgery.