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Background Following the invasion of eukaryotic cells, Salmonella enterica serovar Typhimurium replaces PBP2/PBP3, main targets of β-lactam antibiotics, with PBP2SAL/PBP3SAL, two homologue peptidoglycan synthases absent in Escherichia coli. PBP3SAL promotes pathogen cell division in acidic environments independently of PBP3 and shows low affinity for β-lactams that bind to PBP3 such as aztreonam, cefepime, cefotaxime, ceftazidime, ceftriaxone, cefuroxime and cefalotin. Objectives To find compounds with high affinity for PBP3SAL to control Salmonella intracellular infections. Methods An S. Typhimurium ΔPBP3 mutant that divides using PBP3SAL and its parental wild-type strain, were exposed to a library of 1520 approved drugs in acidified (pH 4.6) nutrient-rich LB medium. Changes in optical density associated with cell filamentation, a read-out of blockage in cell division, were monitored. Compounds causing filamentation in the ΔPBP3 mutant but not in wild-type strain—the latter strain expressing both PBP3 and PBP3SAL in LB pH 4.6—were selected for further study. The bactericidal effect due to PBP3SAL inhibition was evaluated in vitro using a bacterial infection model of cultured fibroblasts. Results The cephalosporin cefotiam exhibited higher affinity for PBP3SAL than for PBP3 in bacteria growing in acidified LB pH 4.6 medium. Cefotiam also proved to be effective against intracellular Salmonella in a PBP3SAL-dependent manner. Conversely, cefuroxime, which has higher affinity for PBP3, showed decreased effectiveness in killing intracellular Salmonella. Conclusions Antibiotics with affinity for PBP3SAL, like the cephalosporin cefotiam, have therapeutic value for treating Salmonella intracellular infections.

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.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.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.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.

Introduction The aim of this study was to monitor the development of drug-resistant bacteria isolated from acute uncomplicated cystitis (AUC) and to evaluate methodology of the survey conducted by collecting only clinical data. Methods We enrolled female patients at least 16 years of age diagnosed with AUC in 2018. Patient information including age, menopausal status, and results of bacteriological examination were collected and analyzed regardless of bacterial identification, antimicrobial susceptibility testing or extended-spectrum β-lactamase (ESBL) detection method. Results A total of 847 eligible cases were collected. Escherichia coli (E. coli) was the most frequently isolated bacterial species at about 70%, with proportions of fluoroquinolone-resistant E. coli (QREC) and ESBL-producing E. coli isolates at 15.6% and 9.5% of all E. coli isolates, respectively. The proportion of Staphylococcus saprophyticus (S. saprophyticus) was significantly higher in premenopausal women. Regarding the drug susceptibility of E. coli, isolates from Eastern Japan had significantly higher susceptibility to cefazolin, cefotiam and cefpodoxime and lower susceptibility to levofloxacin in postmenopausal women. ESBL-producing E. coli isolates had a high susceptibility to tazobactam-piperacillin, cefmetazole, carbapenems, aminoglycosides, and fosfomycin. In S. saprophyticus, the susceptibility to β-lactams including carbapenems was 40–60%. Conclusions The proportions of QREC and ESBL-producing E. coli were increasing trends and lower susceptibility to LVFX in postmenopausal women was observed. Such surveillance, consisting of the collecting only clinical data, could be conducted easily and inexpensively. It is expected to be continuously performed as an alternative survey to conventional one collecting bacterial strains.

In the current study, we used 7922 FDA approved small molecule drugs as well as compounds in clinical investigation from NIH's NPC database in our drug repurposing study. SARS‐CoV‐2 main protease as well as Spike protein/ACE2 targets were used in virtual screening and top‐100 compounds from each docking simulations were considered initially in short molecular dynamics (MD) simulations and their average binding energies were calculated by MM/GBSA method. Promising hit compounds selected based on average MM/GBSA scores were then used in long MD simulations. Based on these numerical calculations following compounds were found as hit inhibitors for the SARS‐CoV‐2 main protease: Pinokalant, terlakiren, ritonavir, cefotiam, telinavir, rotigaptide, and cefpiramide. In addition, following 3 compounds were identified as inhibitors for Spike/ACE2: Denopamine, bometolol, and rotigaptide. In order to verify the predictions of in silico analyses, 4 compounds (ritonavir, rotigaptide, cefotiam, and cefpiramide) for the main protease and 2 compounds (rotigaptide and denopamine) for the Spike/ACE2 interactions were tested by in vitro experiments. While the concentration‐dependent inhibition of the ritonavir, rotigaptide, and cefotiam was observed for the main protease; denopamine was effective at the inhibition of Spike/ACE2 binding.

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.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.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.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.

Osteomyelitis remains one of the most challenging disorders for orthopedic doctors despite the advancement of therapeutic techniques. The purpose of this study was to investigate the feasibility of local antibiotic administration using hydroxyapatite/collagen (HAp/Col) as a drug delivery system. We hypothesized that higher adsorbability of antibiotics onto HAp/Col will result in more efficacious activity and therefore, treatment of osteomyelitis. Eight antibiotics were examined in this study: amikacin, cefazolin, cefotiam, daptomycin, minocycline, piperacillin, teicoplanin, and vancomycin. Aligning with their adsorbability onto HAp/Col, minocycline, teicoplanin, and vancomycin showed antibacterial effects up to 14 days after subcutaneous implantation in Wistar rats; while antibiotics with reduced adsorbability (cefazolin, cefotiam, piperacillin) had diminished antibacterial effects. Furthermore, when implanted into a rat femur, vancomycin levels from the Hap/Col were detected in the medullary space above the minimum inhibitory concentration for Staphylococcus aureus for 7 days, while cefazolin levels were undetectable. Aligning with these results, implantation of Hap/Col impregnated with vancomycin to the femur in an acute osteomyelitis rat model had a greater therapeutic effect than cefazolin, as measured by the number of bacteria, the extent of bone destruction, and bone regeneration. These results indicated that the adsorbability of antibiotics onto their carrier is important when locally administered and that HAp/Col scaffolds might be a useful antibiotic delivery system for osteomyelitis. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 38:843‐851, 2020, This study aimed to investigate the feasibility of local antibiotic administration using hydroxyapatite collagen (HAp/Col) composite as a drug delivery system. Minomycin, teicoplanin, and vancomycin showed antibacterial effects up to 14 days after subcutaneous implantation in rats with HAp/Col owing to their adsorbability. The implantation of HAp/Col impregnated with vancomycin for an acute osteomyelitis model revealed a significant therapeutic effect because of longitudinal antibacterial activity. These results indicated that the adsorbability of antibiotics onto the carrier is important when locally administered.

Background Tissue adhesive injection is the first‐line treatment for gastric varices rebleeding. Available studies are focused on antibiotic usage in emergency endoscopy, while the use of antibiotics in selective endoscopic tissue adhesive treatment remains controversial. Methods This is a randomized controlled study conducted in a tertiary referral hospital. Consecutive patients were enrolled from February 16, 2016, to November 19, 2016, and blindly randomized into two treatment groups. Patients in the prophylactic group received 2 g of cefotiam during endoscopic injection of tissue adhesive. All the subjects were observed for rebleeding, fever, and changes in laboratory indicators in hospital and post‐discharge. Result One hundred and seven patients who received endoscopic therapy for gastroesophageal varices were included. Fifty‐three patients were allocated to the antibiotic prophylactic group and 54 patients to the on‐demand group. The two groups had similar baseline characteristics. The incidence of fever in hospital was 2/53 (3.8%) vs 9/54 (16.7%) (P = 0.028). Perioperative and postoperative clinical events were significantly lower in the antibiotic prophylactic group (5.7% vs 24.1%, P = 0.018; 7.5% vs 20.4%, P = 0.050). Inflammation indices were elevated on the first day after endoscopic therapy; however, no significant difference was observed between the two groups. The cumulative rebleeding free rate within 2 months was lower in the antibiotic prophylactic group (1.9% vs 9.3%, P = 0.100). Conclusion Our study illustrated that prophylactic use of antibiotics in selective endoscopic injection of tissue adhesive reduced the incidence of the total clinical events in perioperative period and had a trend towards lower rebleeding in 2 months.

Background: The objective of this study was to characterize individual case safety reports (ICSRs) and adverse drug reactions (ADRs) related to second-generation cephalosporins and resulting in hepatobiliary disorders, in VigiBase, WHO global database. Methods: All second-generation cephalosporins hepatobiliary ADRs reported up to July 2019 were included. Characteristic of cephalosporins and ADRs, aside from disproportionality data were evaluated. Results: A total of 1343 ICSRs containing 1585 ADRs were analyzed. Cefuroxime was suspected to have caused hepatobiliary disorders in most cases—in 38% of adults and in 35% of elderly. Abnormal hepatic function was the most frequent ADR, followed by jaundice and hepatitis. For 49% of the ADRs reported in the elderly and 51% in the adult population, the outcome was favorable, with fatal outcome for 2% of the adults and 10% of the elderly. Higher proportional reporting ration (PRR) values were reported in the elderly for cefotetan-associated jaundice, cefuroxime-associated acute hepatitis and hepatitis cholestatic as well as for cefotiam and cefmetazole-associated liver disorder. Conclusion: Hepatobiliary ADRs were reported for 2nd generation cephalosporins, with over 50% of cases in adults, without gender differences. Cholestatic hepatitis was predominately reported in the elderly and this category was more prone to specific hepatic reactions.

Excreted antibiotics into intestine after parenteral administration may be unwanted and can disrupt the indigenous microbiota and cause some adverse clinical consequences. To mitigate this adverse effect, we developed BL, a recombinant beta-lactamase formulated into enteric-coated pellets, to degrade the excreted beta-lactam antibiotics. Herein, we reported its preclinical efficacy evaluation in rats, using ampicillin and cefotiam as model antibiotics. In one study, animals were assigned to receive oral vehicle or different dosage of BL(24∼144μg/dose) three times around one intravenous dose of antibiotics, blood and intestinal samples were collected, and antibiotics concentration were determined. In the second study, animals received daily intraperitoneal antibiotics concurrently with vehicle or different dosage of BL(72∼216μg/dose) 3 times per day , or no treatment, for three consecutive days, fecal samples were collected before and after the antibiotics treatment and cultured for bifidobacterium/lactobacillus counting. Herein we showed that orally administered BL significant decreased the antibiotics intestinal concentration with no noticeable influence to the serum concentration. Antibiotics’ treatment induced a 5-6 order of magnitude decrease in bifidobacterium/lactobacillus count, and BL intervention could prevent gut from such damage and maintain the counts similar to the no treatment group. These preclinical studies demonstrated that BL could degrade the excreted beta-lactam antibiotics and protect against its damage to gut probiotic bacteria.

BACKGROUND: To investigate the clinical values of the common biomarkers including blood routine (B-Rt), C-reactive protein (CRP), serum amyloid A (SAA) and procalcitonin (PCT) for efficacy monitoring of antibiotics in early-onset neonatal sepsis (EONS). METHODS: The clinical and laboratory data of 78 neonates with confirmed EONS in the neonatal intensive care unit (NICU) of our center from July 1, 2019 to June 30, 2020 were retrospectively analyzed. All the subjects were treated with cefotiam (50 mg/kg q12h) and augmentin (30 mg/kg q12h) within 12 hours after birth. Blood samples were collected 0–12 hours after birth for blood culture, measurements of B-Rt, CRP and SAA. Subsequently, blood sampling was performed at intervals of 12–24, 24–48, 48–96, and 96–144 hours for measurements of B-Rt, CRP, SAA and PCT. Statistical analyses were performed in the SPSS 20.0 software package. P value of 0.8551), respectively. CONCLUSIONS: WBC count, NEU% and CRP showed no clinical significance for any intervals for efficacy monitoring of antibiotic treatment. SAA and PCT had similar monitoring values at 12–24 and 24–48 hours. SAA is thus more valuable than PCT for efficacy monitoring of antibiotics at the 48–96 and even at the 96–144 hours intervals in EONS.

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.

BACKGROUND Cefotiam, a second-generation cephalosporin, is a broad-spectrum antibiotic with good antibacterial action against both gram-negative and gram-positive bacteria. It is used widely in clinical practice, although bacterial drug resistance makes its clinical use problematic. The authors hypothesized that subtherapeutic concentrations of cefotiam leads to bacterial resistance. The present study was conducted to evaluate whether the standard cefotiam dosing regimen resulted in a subtherapeutic concentrations in children. METHOD Data were prospectively collected from pediatric patients with suspected or confirmed community-acquired pneumonia who were receiving cefotiam at the standard dosing regimen (40-80 mg/kg, 2 or 3 times daily). A blood sample was collected after 70%-100% of the dosing interval, and plasma concentrations were determined by high-performance liquid chromatography using an ultraviolet detector. RESULTS The data from 88 patients (age, 3.0 ± 2.8 years; weight, 15.4 ± 8.3 kg) were used for analysis. The average of cefotiam concentrations was 0.06 mcg/mL (range

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.

Objective: To analyze the related substances in Cefotiam Hydrochloride for Injection. Methods: HPLC-IT-TOF, the HPLC condition: C18 (250 mm伊4.6 mm, 5 μm); temp: 30 ℃; mobile phase: A) 0.02 mol/L ammonium acetic; B) methanol; flow tate: 1.0 mL/min; postcoiumn split ratio: 1:1; detection: UV254; elute by linear gradient. MS parameter: ion source: ESI(+); 100-1 000 m/z; ionization voltage: 3.0 kV; dry gas (N2); temp: 200 ℃; emale cone voltage 30 V[1]. Result: Eight related substances were separated in products, of which three were elucidated in the production, Others are degradation impurities. Conclusion: There were several related substances during production of Cefotiam． LCMS-IT-TOF provided an effective method to determine the related substances and ensure the quality and safety of the product．

Objective: To analyze the related substances in Cefotiam Hydrochloride for Injection. Methods: HPLC-IT-TOF, the HPLC condition: C18 (250 mm伊4.6 mm, 5 μm); temp: 30 ℃; mobile phase: A) 0.02 mol/L ammonium acetic; B) methanol; flow tate: 1.0 mL/min; postcoiumn split ratio: 1:1; detection: UV254; elute by linear gradient. MS parameter: ion source: ESI(+); 100-1 000 m/z; ionization voltage: 3.0 kV; dry gas (N2); temp: 200 ℃; emale cone voltage 30 V[1]. Result: Eight related substances were separated in products, of which three were elucidated in the production, Others are degradation impurities. Conclusion: There were several related substances during production of Cefotiam． LCMS-IT-TOF provided an effective method to determine the related substances and ensure the quality and safety of the product．

Objective: To investigate the long-term antibiotic susceptibility of group B Streptococcus (GBS) present in the vagina. Materials and methods: A population-based retrospective cohort study was performed. A total of 19,899 women who underwent vaginal swab examination between 2005 and 2017 was enrolled. Specimens were cultured on modified Drigalski agar, blood agar, and chocolate agar media. Antibiotic susceptibilities of GBS were assessed using eight antibiotics, namely penicillin-G (PC-G), cefotiam (CTM), cefditoren (CDTR), ceftriaxone (CTRX), meropenem (MEPM), chloramphenicol (CP), levofloxacin (LVFX), and azithromycin (AZM), by the broth microdilution method when GBS was positive in the culture. The main outcome was antibiotic sensitivity based on the culture results. Results: GBS was 100% susceptible to PC-G, CTM, CTRX, CDTR, and MEPM. However, the susceptibility trend showed a considerable decrease for CP (99%–81%), LVFX (91%–70%), and AZM (87%–57%). Conclusions: Our study demonstrated a significant decrease in the antibiotic sensitivity of GBS in Japan in the past 13 years. Based on these results, current policies on antibiotic resistance of GBS in maternal and neonatal care may need to be reassessed. Keywords: Group B Streptococcus, Penicillin, Resistance, Streptococcus agalactiae, Susceptibility

Natural lipopeptide antibiotic tripropeptin C (TPPC) revitalizes and synergistically potentiates the activities of the class of β-lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA) but not against methicillin-sensitive S. aureus in vitro; however, the mode of action remains unclear. In the course of the study to reveal its mode of action, we found that TPPC inhibited the β-lactamase production induced by cefotiam. This prompted us to focus on the β-lactam-inducible β-lactam-resistant genes blaZ (β-lactamase) and mecA (foreign penicillin-binding protein), as they are mutually regulated by the blaZ/I/R1 and mecA/I/R1 systems. Quantitative reverse-transcription polymerase chain reaction analysis revealed that TPPC reversed β-lactam resistance by reducing the expression of the genes blaZ and mecA, when treated alone or in combination with β-lactam antibiotics. In a mouse/MRSA septicemia model, subcutaneous injection of a combination of TPPC and ceftizoxime demonstrated synergistic therapeutic efficacy compared with each drug alone. These observations strongly suggested that reverse β-lactam resistance by TPPC may be a potentially effective new therapeutic strategy to overcome refractory MRSA infections.The Journal of Antibiotics advance online publication, 26 July 2017; doi:10.1038/ja.2017.88.

Summary A 26-year-old woman presented with recurrent attacks of widespread urticaria and systemic symptoms. The patient was a nurse, and the attacks occurred only in her workplace, without an apparent trigger. A patch test to cefotiam (CTM) induced an immediate skin reaction. ELISA detected the patient's serum IgE antibody binding to CTM conjugated with human serum albumin (CTM-HSA), and her basophils released histamine in response to CTM-HSA in a histamine release assay (HRA). Both reactions in ELISA and HRA were inhibited by pretreatment of the patient’s serum or basophils with cefotiam. No crossreactivity in skin tests or in vitro assays was observed against other antibiotics, even those containing a beta-lactam ring and/or side chains similar to CTM. Certain antibiotics including CTM may cause extremely sensitive and specific contact urticaria syndrome, which is mediated by IgE and evoked even without apparent skin contact with the culprit drug and in the absence of any history of an allergic reaction against other antibiotics with similar structures.

IntroductionThe common treatment for toxoplasmosis was pyrimethamine. In recent years, it has been found that this parasite is getting resistant to this treatment, therefore urgent alternative treatments are needed.Material and MethodsIn this study, by using drug repurposing and in silico methods we tried to make a selective treatment by inhibiting the Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii which doesn’t exist in mammalians. We screened the FDA approved drugs by molecular docking and after ranking them by their binding energies and inspecting the top scored ones, we chose Cefpiramide, Ceftriaxone and Cefotiam as the hit compounds. After that, we used molecular dynamics simulations to test the hit compounds in a much more realistic environment.ResultsBy analyzing the results, we found that all of the hit compounds and good and can bind strongly to the active site of the protein. Therefore, they can be potential candidates for inhibiting Calcium-Dependent Protein Kinase 1 from Toxoplasma gondii.ConclusionMoreover, because the predicted compounds are FDA approved drugs, their toxicity profiles are well known and their newly predicted use can be tested in clinical trials.

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.

Two structural isomers of cefotiam in cefotiam hydrochloride for injection were observed, and the structures of the isomers were determined by mass spectrometry and various 1D and 2D NMR techniques. The thermo-isomerization mechanism of cefotiam was also discussed. Thermo-isomerization occurred not only in cefotiam but also in cephalosporins containing a 1-alkyl-1H-tetrazole-5-thiol side chain at C-3. Furthermore, the toxic effects of the two impurities of cefotiam hydrochloride were predicted and it is thought that they could be more toxic than cefotiam. The results reported in this article may be important for quality control and stability studies of this class of drugs.

Background Few studies have investigated the incidence of anaphylaxis induced by individual or structurally similar cephalosporins. The aims of the study were to assess the incidence of cephalosporin-induced anaphylaxis and evaluate the clinical efficacy of screening skin tests. Methods In this retrospective cohort study, we obtained information on total cephalosporin use and cephalosporin-induced anaphylaxis in intravenous cephalosporin recipients in 12 general hospitals between 2013 and 2015. Cephalosporins were divided into 4 groups according to similar side-chain structures. The incidence of cephalosporin-induced anaphylaxis was assessed for each cephalosporin, cephalosporin generation, and side-chain group. To verify the efficacy of screening intradermal tests (IDT) with cephalosporin, the 12 hospitals were assigned to the intervention or control group depending on whether they performed screening IDT before the administration of cephalosporins. Results We identified 76 cases of cephalosporin-induced anaphylaxis with 1 123 345 exposures to intravenous cephalosporins (6.8 per 100 000 exposures), and the incidence of fatal anaphylaxis by cephalosporin was 0.1 cases per 100 000 exposures. The highest incidences of anaphylaxis occurred in the ceftizoxime (13.0 cases per 100 000 exposures) and side-chain group 1 (cefepime, cefotaxime, ceftizoxime, ceftriaxone, and cefuroxime; 9.3 per 100 000). There was no case of anaphylaxis induced by cefoxitin, cefmetazole, cefminox, and cefotiam. The clinical effectiveness of routine screening IDT was not significant (P = .06). Conclusions The incidence of cephalosporin-induced anaphylaxis differed according to individual drugs and side-chain structure. Screening IDT showed no clinical efficacy at a population level.

Junichi Yoshida, Yukiko Harada, Tetsuya Kikuchi, Ikuyo Asano, Takako Ueno, Nobuo Matsubara Infection Control Committee, Shimonoseki City Hospital, Shimonoseki, Japan Abstract: The aim of this study was to elucidate risk factors, including ward antimicrobial use density (AUD), for central line-associated bloodstream infection (CLABSI) as defined by the Centers for Disease Control and Prevention in a 430-bed community hospital using central venous lines with closed-hub systems. We calculated AUD as (total dose)/(defined daily dose × patient days) ×1,000 for a total of 20 drugs, nine wards, and 24 months. Into each line day data, we inputed AUD and device utilization ratios, number of central line days, and CLABSI. The ratio of susceptible strains in isolates were subjected to correlation analysis with AUD. Of a total of 9,997 line days over 24 months, CLABSI was present in 33 cases (3.3 ‰), 14 (42.4%) of which were on surgical wards out of nine wards. Of a total of 43 strains isolated, eight (18.6%) were methicillin-resistant Staphylococcus aureus (MRSA); none of the MRSA-positive patients had received cefotiam before the onset of infection. Receiver-operating characteristic analysis showed that central line day 7 had the highest accuracy. Logistic regression analysis showed the central line day showed an odds ratio of 5.511 with a 95% confidence interval of 1.936–15.690 as did AUD of cefotiam showing an odds ratio of 0.220 with 95% confidence interval of 0.00527–0.922 (P=0.038). Susceptible strains ratio and AUD showed a negative correlation (R2=0.1897). Thus, CLABSI could be prevented by making the number of central line days as short as possible. The preventative role of AUD remains to be investigated. Keywords: bloodstream infection, central line, antimicrobial use density

The pharmacokinetics of cefotiam were investigated after intravenous administration of 1 g to 2 healthy volunteers with normal renal function and to 16 patients whose creatinine clearance ranged from 4.7 to 0.1 l/h (78 to 1.66 ml/min). The elimination half-life varied from 1.1 h in normal subjects to 13 h in patients and the total plasma clearance from 21 to 0.6 l/h (350 to 10 ml/min). The urinary recovery decreased from 62% of the dose in normal subjects to 1.1% in patients, and the renal clearance from 15 to 0.01 l/h (250 to 0.5 ml/min). Plasma and renal clearances of cefotiam correlated well with the creatinine clearance. The dosage schedule for cefotiam in patients with normal renal function can be used in the presence of renal failure when the creatinine clearance is equal to or greater than 1 l/h (16.6 ml/min). For patients whose creatinine clearance is less than 1 l/h, the dose must be decreased to 75% of that for a patient with normal renal function only when it is given every 6 or 8 h.

Background: Minimal inhibitory concentration (MIC) measurements are usually conducted using the agar plate dilution test or the microdilution test. Methods for rapid evaluation of antimicrobial susceptibility using ATP measurements with luciferin-luciferase reagents and a tetrazolium salt have been reported. Material and methods: We recently measured the minimal inhibitory concentrations (MICs) of various antimicrobial agents against 96 strains of Escherichia coli (1 standard strain and 95 clinically isolated strains) with Cell Counting Kit-8 containing a tetrazolium salt and an electron carrier using the Dry Plate Eiken for MIC measurement and compared the results with that obtained using the standard method. Results: Agreement exceeded 90% for ampicillin, cefotiam, ceftazidime, flomoxef, aztreonam, imipenem, meropenem, gentamicin, and levofloxacin, and complete agreement exceeded 90% for cefotiam, ceftazidime, flomoxef, aztreonam, imipenem, meropenem, and levofloxacin. Agreement was in the range of 78.1- 86.5% for piperacillin, cefazolin, cefpodoxime, amikacin, and minocycline with complete agreement in the range 55.2-78.1%. Cefaclor had the lowest agreement and complete agreement (42.7% and 38.5, respectively). For the antimicrobial agents with low agreement (piperacillin, cefaclor, cefazolin, amikacin and minocycline), MICs measured by the short-time method were often below onehalf or one-fourth of that measured by the standard method, and regrowth of the bacteria appeared to occur 6 hours after the start of the short-time method. Conclusion: The results of this study indicate that measuring absorbance with Cell Counting Kit-8 enables counting of viable bacteria. The use of this method for measuring MICs (short-time method) allowed the results of the susceptibility testing to be obtained in 6 hours, and the results correlated well with the results obtained using the standard method. Therefore, this method appears useful for the early detection of drug-resistant bacteria.

Routine perioperative intravenous antimicrobial agents are administered as surgical prophylaxis. However, whether balanced ultrafiltration during extracorporeal circulation has substantial effect on the concentration of antimicrobial agents remains unclear. The concentrations of antimicrobial agents in plasma and ultrafiltrate samples were measured in this pseudo-extracorporeal circulation model. Extracorporeal circulation consisted of cardiotomy reservoir, membrane oxygenator, and pediatric arterial line filter. A hemoconcentrator was placed between the arterial purge line and oxygenator venous reservoir. Fresh donor human whole blood was added into the circuit and mixed with Ringer's solution to obtain a final hematocrit of 24-28%. Two kinds of antimicrobial agents, cefotiam (320 mg) and cefmetazole (160 mg), were bolus added into the circuit. After 30 min of extracorporeal circulation, zero-balanced ultrafiltration was initiated and arterial line pressure was maintained at approximately 100 mm Hg with a Hoffman clamp. The rate of ultrafiltration (12 mL/min) was controlled by ultrafiltrate outlet pressure. An identical volume of Plasmalyte A was dripped into the circuit to maintain stable hematocrit during 45 min of experiment. Plasma and ultrafiltrate samples were drawn every 5 min, and concentrations of antimicrobial agents (including cefotiam and cefmetazole) were measured with high performance liquid chromatography. Both antimicrobial agents were detected in ultrafiltrate, demonstrating hemoconcentration may remove antimicrobial agents. The concentrations of plasma antimicrobial agents decreased linearly with the increase of ultrafiltrate volume. At end of balanced ultrafiltration, the concentration of plasma cefotiam was 104.96 ± 44.36 mg/L, which is about 44.38% ± 7.42% of the initial concentration (238.95 ± 101.12 mg/L) (P < 0.001); the concentration of plasma cefmetazole decreased linearly to 25.76 ± 14.78 mg/L, which is about 49.69% ± 10.49% of the initial concentration (51.49 ± 28.03 mg/L) (P < 0.001). The total amount of cefotiam in ultrafiltrate is 27.16% ± 12.17% of the total dose administered, whereas cefmetazole in ultrafiltrate is 7.74% ± 4.17%. Balanced ultrafiltration may remove antimicrobial agents from plasma and has a prominent influence on plasma concentration of antimicrobial agent. The strategy of surgical prophylaxis should consider this unique technique during extracorporeal circulation.

Pneumatosis intestinalis (PI) is a comparatively rare disease characterized by the presence of intramural gas in the gastrointestinal tract. PI is known to be associated with several clinical conditions, such as pulmonary diseases, gastrointestinal diseases, and traumatic injury, as well as autoimmune disorders. In particular, PI is commonly seen in systemic sclerosis (SSc) but rarely in systemic lupus erythematosus and dermatomyositis (DM). In this report, we present three cases of PI presenting in autoimmune diseases, including DM, Sjögren's syndrome, and limited SSc, and further discuss its background characteristics.

β-Lactam antibiotics have cerebral and peripheral adverse effects. Multidrug resistance-associated protein 4 (MRP4) has been reported to transport several β-lactam antibiotics, and its expression at the blood-brain barrier also serves to limit their distribution to the brain. Therefore, the purpose of this study was to clarify the structure-activity relationship of MRP4-mediated transport of β-lactam antibiotics using MRP4-expressing Sf9 membrane vesicles. The transport activity was evaluated as MRP4-mediated transport per MRP4 protein [nL/(min·fmol MRP4 protein)] based on measurement of MRP4 protein expression by means of liquid chromatography-tandem mass spectrometry. Cefotiam showed the greatest MRP4-mediated transport activity [8.90 nL/(min·fmol MRP4 protein)] among the β-lactam antibiotics examined in this study. Measurements of differential transport activity of MRP4 for various β-lactam antibiotics indicated that (i) cephalosporins were transported via MRP4 at a greater rate than were penams, β-lactamase inhibitors, penems, or monobactams; (ii) MRP4-mediated transport activity of anionic cephalosporins was greater than that of zwitterionic cephalosporins; and (iii) higher-molecular-weight anionic β-lactam antibiotics showed greater MRP4-mediated transport activity than lower-molecular-weight ones, whereas zwitterionic β-lactam antibiotics did not show molecular weight dependency of MRP4-mediated transport. These quantitative data should prove useful for understanding MRP-related adverse effects of β-lactam antibiotics and their derivatives.

A simple, rapid and precise LC method has been developed to determine the total concentrations of cefotiam (reported protein-binding ratios of 40–62%) in human serum. New procedures were incorporated in which proteins denatured by acetonitrile were dissociated from cefotiam. Macromolecular impurities above 30 kDa were entirely removed using an ultrafiltration membrane. The assay can be applied to therapeutic drug monitoring of cefotiam in serum and to pharmacokinetic studies in patients.

We studied the effect of the addition of the bacteriostatic agent, netilmycin, to cefotiam treatment as prophylactic antibiotics against infection for grade III open tibial fractures. From 45 eligible cases, assigned randomly to a control group that receive only cefotiam, and the treatment group that receive netilmycin in addition to cefotiam. We observed that the clearing of infection occurred earlier in the cefotiam /netilmycin group. We found that 3-day administration of cefotiam-netilmycin is superior to 3-day administration of cefotiam only. It is equivalent to 5-day treatment with cefotiam alone.

The present study aimed to examine the peritoneal pharmacokinetics and pharmacodynamic exposure of intravenous cefotiam. One gram of cefotiam was administered to eight patients before abdominal surgery. Venous blood and peritoneal fluid (PF) samples were obtained at the end of infusion (0.5 h) and 1, 2, 3, 4, 5, and 6 h afterwards. The drug concentrations in the plasma and PF were determined, analyzed pharmacokinetically, and used for a stochastic simulation with minimum inhibitory concentration (MIC) data. Cefotiam penetrated well into the PF with the area under the drug concentration-time curve ratio of 0.88 +/- 0.18 (mean +/- SD, n = 8). Regarding the pharmacodynamic exposures against Escherichia coli and Klebsiella species, the probabilities of attaining the bacteriostatic target (40% of the time above MIC) in the PF using 0.5 g every 12 h, 1 g every 12 h, and 2 g every 12 h were 88.3-93.6%. However, 1 g every 8 h was needed for 89.7 and 91.6% probabilities of attaining the bactericidal target (70% of the time above MIC). These results should help us to understand better the peritoneal pharmacokinetics of cefotiam while also helping us to choose the appropriate dosage for intra-abdominal infections.

The method for predicting the fraction absorbed (Fa) of the PEPT1 substrates was established based on the in vitro uptake into Caco-2 cells. Uptake of a drug into Caco-2 cells was measured, and the carrier-mediated initial uptake clearance (ΔCLuptake) was calculated as the difference between the uptake clearance in the absence of glycyl-sarcosine (Gly-Sar) and that in the presence of 30 mM Gly-Sar. The ΔCLuptake of each drug was then divided by that of cephradine to obtain Δ C L uptake ∗ , which was a normalized parameter to correct for inter-day and/or inter-cell variability. Then, cephradine (CED), cefixime (CFIX), and cefotiam (CTM) were selected as marker compounds having excellent, medium and poor absorption, respectively. The Δ C L uptake ∗ and Fa values for CED, CFIX and CTM were fitted to the equation derived from the complete radial mixing (CRM) model, and the scaling factor (A′) was obtained. Using the A′ value, Fa was predicted from the Δ C L uptake ∗ value of each drug. Good correlation was observed between the predicted and reported Fa values, which demonstrated that Fa of PEPT1 substrates can be predicted based on the in vitro uptake in Caco-2 cells.

A 19-year-old girl developed a fever of up to 40 degrees C and, during an episode of high fever, generalized seizures. Physical examination on admission was unremarkable, except for several small lymph nodes. Differential blood count showed a leukopenia (1700/microliters) with 14% stab and 7% segmented neutrophils. After initial clinical improvement she again became feverish and the differential count now showed agranulocytosis with a total white cell count of 1400/microliters. Because of the time of year and the geographic location borreliosis was now considered in the differential diagnosis. The antibody titre against Borrelia was raised to 1:64 (IgM) and 1:256 (IgG). Her condition and the differential blood count rapidly improved on intravenous antibiotic treatment with cefotiam (2 g two times daily) and gentamicin (120 mg two times daily), as well as filgrastim (granulocyte-colony stimulating factor) subcutaneously. Antibiotic treatment was continued after 6 days with oral ampicillin (1 g three times daily) for 3 weeks. Follow-up examination six weeks later found the patient to be symptom-free.

A 51-year-old man, known to have chronic-aggressive hepatitis B, HIV infection and exertional dyspnoea, was hospitalized because of acute physical deterioration, cough with whitish exudate and dyspnoea at rest. Despite a CD4/CD8 ratio of 0.16 no prophylactic measures against Pneumocystis carinii had been taken. On examination the lungs were unremarkable, but the liver was enlarged and there were petechiae over all parts of the body. Laboratory tests showed impaired liver functions and a rise in lactate dehydrogenase activity (538 U/l). Chest radiogram demonstrated small to very small infiltrates in the lung. As Pneumocystis carinii pneumonia was suspected but bronchoscopy was too risky, he was at first treated with trimethoprim/sulphamethoxazole (four times 320/1600 mg/24 h intravenously). When this failed, he received pentamidine (4 mg/kg, after 4 days 2 mg/kg intravenously), and finally cefotiam (twice 2 g daily), tobramycin (three times 40 mg daily) and corticoids (100 mg). Despite this treatment he died after 10 days from respiratory failure. Autopsy revealed interstitial pneumonia throughout the lung as well as focal mucor infiltrations in the wall of middle-calibre lung veins. Mucor is a ubiquitous, facultatively pathogenic mold fungus.

Ten days after starting military service in a police barracks a 25-year-old man developed left middle and lower lobe pneumonia which did not respond to ampicillin (8 g daily) and gentamycin (120 mg daily). Parenteral administration of doxycycline (100 mg daily) was equally ineffective. However, the fever fell on administration of cefotiam (4 g daily). Antibody tests demonstrated Legionella pneumophila serogroup 1 as the causative organism. Because of the confined accommodation of the conscripts the source of the infection was thought to be the hot water system in the barracks. In two other policemen the demonstration of antibodies and of urine antigens confirmed Legionella infection as cause of an acute respiratory illness (Pontiac disease). Legionella pneumophila serogroup 1 subtype Philadelphia, 1-8 colony-forming units per ml, was isolated from six of 14 hot water samples in the barracks. This subtype possesses a virulence-associated antigen which is found in the majority of patient isolates of Legionella pneumophila serogroup 1.

The problem of an allergy to penicillins and the possibility of related allergies to other betalactams is very common and relevant in clinical practice. These antibiotics are often used to treat bacterial infection and to prevent endocarditis. Unlike allergic determinants derived from penicillin, the cephalosporin determinants have not been clearly identified yet. The question of a group allergy to betalactams versus cross reactivity to single or all cephalosporins rises after IgE-mediated anaphylaxis to a β-lactam antibiotic, so further investigations are needed. We present an immediate type hypersensitivity confirmed by positive in-vitro diagnostic and skin tests in a 18 year-old woman who suffered from severe intraoperative anaphylaxis and generalized urticaria and angioedema within few minutes after intravenous administration of cefazolin. For premedication the patient had received amoxicillin before the elective surgery of talocrural join but hypersensitivity to this drug, in addition to latex, could be excluded. Prior to this anaphylaxis cefazolin was well tolerated, it was given several times during several heart catheterizations due to congenital atrioventricular septal defect. Allergologic investigations demonstrated additional sensitizations to cefotiam, cefuroxim and cefuroximaxetil, but tolerance to penicillin and amoxicillin in skin tests as well as in the oral challenge test. This case nicely demonstrates the complexity and need of a detailed allergologic work-up in suspected betalactam hypersensitivity.

In a meta-analysis of 5 randomized controlled trials involving 1030 adults, the likelihood of bacteriologic eradication in the treatment of group A beta-hemolytic streptococcal (GAS) tonsillopharyngitis with 5 days of select cephalosporins (cefpodoxime, cefuroxime, cefotiam, and cefdinir) was noninferior to 10 days of penicillin (odds ratio, 1.46; 95% confidence interval, 0.96-2.22, P = 0.08).

Objective: The standard protocol of antibiotic prophylaxis in radical prostatectomy remains to be established. We retrospectively compared the occurrence of perioperative infections following radical prostatectomy between two different protocols of antibiotic prophylaxis. Methods: This study included 106 cases of radical retropubic prostatectomy managed on the clinical pathways. Two different protocols of antibiotic prophylaxis were used in otherwise identical pathways. Between January and December 2004, 50 patients received a second generation cephem, cefotiam, for 4 days, beginning 30 min before surgery (4-day group), whilst between December 2004 and July 2005, only two doses of cefotiam were given on the day of operation in 56 patients (1-day group). The incidence of surgical site infection (SSI) and remote infection (RI) was retrospectively investigated. Results: Superficial incisional SSI occurred in one (1.8%) patient in the 1-day group, whereas no patient in the 4-day group developed SSI. No RI was observed in either the 1-day or 4-day group. Intravenous antibiotics were administered besides the pathway in a patient in the 1-day group because unexplained fever more than 38°C continued postoperative day (POD) 2 through POD 4 without signs of SSI or RI. Excluding this case, postoperative more than 38°C was rare and transient after POD 2. Conclusion: The incidence of SSI and RI was low and not significantly different between the 1-day and 4-day groups. Therefore, the 1-day protocol of prophylactic antibiotic treatment seems adequate for preventing perioperative infections in radical prostatectomy.

We examined the substrate specificity of human organic anion transporter (hOAT) 1 and hOAT3 for various cephalosporin antibiotics, cephaloridine, cefdinir, cefotiam, ceftibuten, cefaclor, ceftizoxime, cefoselis and cefazolin by using HEK293 cells stably transfected with hOAT1 or hOAT3 cDNA (HEK-hOAT1, HEK-hOAT3). Additionally, we examined the uptake of various compounds by these transfectants. The mRNA level of hOAT3 in HEK-hOAT3 was about three-fold that of hOAT1 in HEK-hOAT1. Functional expression of hOAT1 and hOAT3 was confirmed by the uptake of p-[14C]aminohippurate and [3H]estrone sulfate, respectively. p-[14C]Aminohippurate, [3H]estrone sulfate, [14C]captopril, [3H]methotrexate, [3H]ochratoxin A, [3H]leucovorin and [3H]cimetidine were shown to be substrates for hOAT1 and hOAT3, and [3H]dehydroepiandrosterone sulfate was shown to be a substrate for hOAT3. All cephalosporin anitibiotics tested were shown to inhibit the uptake of p-[14C]aminohippurate and [3H]estrone sulfate via hOAT1 and hOAT3, respectively, in a dose-dependent manner, and the IC50 values of these antibiotics, except for cefaclor, for the hOAT1-mediated uptake of p-[14C]aminohippurate were within four-fold of those for the hOAT3-mediated uptake of [3H]estrone sulfate. The uptake of cephaloridine, cefdinir and cefotiam by HEK-hOAT3 was 35-50-fold greater than that by control cells. Moreover, the accumulation of the other cephalolsporin antibiotics was significantly greater in HEK-hOAT3 than in control cells. In contrast, the uptake of these antibiotics by HEK-hOAT1 was within two-fold of that by control cells. In conclusion, hOAT3 plays a more important role than hOAT1 in the renal secretion of cephalosporin antibiotics.

It is widely accepted that antimicrobial prophylaxis is useful for the prevention of surgical wound infection, especially in colorectal surgery. While many reports support the finding that the first dose should be administered immediately before surgery, there is less evidence concerning the ideal timing for the second dose. The purpose of this study is to examine the significance of intraoperative repeated dosing. A surgical series of 131 patients with primary colorectal cancer was retrospectively analyzed for 14 parameters, including the protocols of antimicrobial administration to determine the clinical risk factors for surgical wound infection. The overall surgical wound infection rate of the 131 patients was 16.0% (21/131). When the operation finished within 4 h after the first dose (n = 29), wound infection was observed in only one patient (3.4%). In a prolonged operation exceeding 4 h after the first dose, the surgical wound infection rates were 8.5% and 26.5%, respectively, for those with (n = 47) and without (n = 49) intraoperative repeated dosing, which were significantly different based on both a univariate analysis (P = 0.031) and a multivariate analysis (P = 0.0079). Intraoperative repeated antimicrobial dosing is therefore recommended to prevent the surgical wound infection for prolonged colorectal surgery.

We examined the alterations in vitamin A metabolism as a result of flupenthixol or cefotiam administration. The impact of these drugs on indices of vitamin A status was evaluated in Brown Norway and Long–Evans rats. Intramuscular drug administration for 28 d resulted in a decline in systemic retinol. Changes in circulating retinol with time for chronic dosing showed drug treatment (PPP=0·33) was not a significant factor. Flupenthixol was the most active retinol-lowering compound (PPP

Background: Differing factors may alter the effects of antibody to tumor necrosis factor (TNF) in infection and sepsis. The authors tested whether bacteria type or treatment route alters antibody to TNF in a rat model of bacterial pneumonia. Methods: Rats (n 231) received similarly lethal doses of either intratracheal Escherichia coli or Staphylococcus aureus followed by treatment with either intratracheal or intraperitoneal antibody to TNF or control serum. Animals received antibiotics (cefotiam daily dose, 100 mg/kg) starting 4 h after inoculation and were studied for up to 96 h. Results: Compared with S. aureus, E. coli increased serum TNF and interleukin-6 concentrations, lung lavage TNF concentrations, neutrophil counts, and alveolar-to-arterial oxygen gradients and decreased circulating neutrophils and lymphocytes (P > 0.05 for all). Compared with controls, with both bacteria, except for lung lavage TNF concentrations (which decreased with intratracheal but not with intraperitoneal antibody to TNF), treatment route did not alter the effects of antibody to TNF on any parameter (P not significant for all). Antibody to TNF reduced mortality rates (relative risk of death SEM) with both E. coli (1.6 0.6; P 0.006) and S. aureus (0.5 0.04; P 0.185), but these reductions were greater with E. coli than with S. aureus in a trend approaching statistical significance (P 0.09). Compared with controls, similarly (P not significant) with both bacteria, antibody to TNF decreased lung lavage and tissue bacteria concentrations (both P < 0.05) and serum TNF concentration (P < 0.09) and increased circulating neutrophils and lymphocytes (both P < 0.01). Compared with S. aureus, with E. coli antibody to TNF decreased alveolar-to-arterial oxygen gradients (P 0.04) and increased serum interleukin-6 concentrations (P 0.003). Conclusion: Antibody to TNF improved host defense and survival rates with both lethal E. coli and S. aureus pneumonia, but protection was greater with E. coli, where TNF concentrations were higher than with S. aureus. The efficacy of antiinflammatory agents in sepsis may be altered by bacteria type. AN excessive host inflammatory response has been closely associated with the organ injury and lethality related to sepsis and septic shock. 1 Of the mediators activated and released during this response, tumor necrosis factor (TNF) was one of the first to be directly associated with these pathogenetic events during sepsis. 2 On the basis of this, over the past decade several different agents were developed to specifically inhibit TNF in patients with sepsis. Although these therapies were very beneficial in published animal models of sepsis, 2–25 none showed individual benefit in 10 clinical trials enrolling more than 5,000 patients. 26 –37 A review of this experience however shows that although these agents were tested almost exclusively in animal models using Gram-negative infectious challenges, patients in clinical trials presented with sepsis related to differing types of underlying infection, including Gram-negative, Gram-positive, and mixed bacterial infections. 2–37 Thus, variability in the release or activity of TNF with differing types of bacteria might provide one basis for the disparate effects antibody to TNF agents had in comparing preclinical and clinical trials. 38 Although TNF may be a central host mediator in tissue injury during Gram-negative bacterial infection, other mediators may play a more important role with other bacteria types. In several different studies, the TNF response with Grampositive bacterial challenge has been shown to be either diminished or retarded when compared with Gram-negative bacterial challenges. 39 –4 1 Consistent with this possibility, we showed before that similarly lethal doses of Escherichia coli and Staphylococcus aureus administered intratracheally in rats resulted in significantly greater TNF concentrations with the former than with the latter bacteria type. 42 Furthermore, administration of granulocyte colony-stimulating factor to augment host defense function with these challenges, although increasing circulating neutrophils and survival rates with S. aureus, caused a paradoxical reduction in circulating neutrophils and worsened lung injury and survival rates with E. coli. Thus, in this preclinical model, stimulating the neutrophil, a cellular component in the inflammatory response, had very different effects comparing similarly lethal E. coli and S. aureus pneumonia. This differential effect of granulocyte colony-stimulating factor with Gram-positive bacterial pneumonia has now been observed in clinical trials testing this agent. 43

OBJECTIVE The purpose of this study was to investigate the efficacy of perioperative antibiotic administration in the prophylaxis of wound infection in lumbar disc surgery. METHODS In 1989, 541 conventional lumbar discectomies were performed to treat nucleus pulposus prolapse in 533 patients at the neurosurgical department of the Benjamin-Franklin-Hospital (Free University of Berlin). Each patient received 2 g of the antibiotic Cefotiam intravenously at induction of anesthesia. During the previous year no antibiotic was administered in 636 similar operations (in 628 Patients). Acquisition of data was performed retrospectively. After statistical stratification there remained 492 procedures in 461 patients in the prophylaxis group and 538 procedures in 475 patients in the control group. Regarding patients age, duration of the surgical procedure and distribution of individual surgeons there were no significant differences between these two groups. RESULTS The rate of infection was 0.2 % (n=1) in operations performed after antibiotic administration versus 2.8 % (n=15) in procedures without antibiotic prophylaxis. This difference is statistically significant (p < 0.0001). CONCLUSION In accordance with the reviewed literature, this study confirms that one preoperative intravenous ('single shot') administration of Cefotiam is effective in decreasing the rate of postoperative wound infections in lumbar disc surgery.

Most cephalosporin antibiotics are excreted into urine via glomerular filtration and active tubular secretion by renal organic anion transporters. In this study, we investigated the interaction of cephalosporins with rat organic anion transporter rOAT1, mainly expressed at the basolateral membrane of the renal proximal tubules, using Xenopus laevis oocytes, to assess the roles of rOAT1 in renal excretion of cephalosporin antibiotics. The expression of rOAT1 significantly stimulated the uptake of cefazolin, cefotiam and cephalexin into oocytes, but not of cefoperazone. The inhibition constants of these cephalosporins to rOAT1-mediated p-aminohippurate (PAH) uptake were 72 microM for cefazolin, 298 microM for cefoperazone, 718 microM for cefotiam and 6 mM for cephalexin. Eadie-Hofstee plot analysis revealed that cefoperazone as well as cefotiam inhibited rOAT1-mediated PAH uptake competitively. These results suggest that rOAT1 mediates basolateral uptake of cephalosporin antibiotics in the renal tubules. Furthermore, it is suggested that a minor contribution of the kidney to cefoperazone excretion could be related to the finding that cefoperazone is a poor substrate of rOAT1.

The pharmacokinetics of cefuroxime, cefotiam, clamandole, and ampicillin/sulbactam were randomly measured in 40 patients undergoing major orthopedic surgery associated with high blood and volume turnover and intraoperative blood salvage. Serum and bone concentrations and the pharmacokinetics occurring in the context of these procedures were measured. No changes in elimination half-life relative to a normal population occurred with cefuroxime, cefotiam, and ampicillin. Serum and tissue concentrations were slightly lower with cefamandole and sulbactam, but reapplication of the initial dose was required with all antibiotics 4 hours after the first application.

A 75-year-old female patient presented with late stage cutaneous radiation syndrome, following postoperative combined radiotherapy for cervical carcinoma administered 32 years ago. She was hospitalized because of a deep abscess in the radiation-exposed area on the sacrum. Extension into the subcutaneous fibrosis was verified by 7,5-MHz-sonography and nuclear magnetic resonance imaging. With intravenous cefotiam (Spizef) 2.0 g three times daily, the inflammation decreased, as seen clinically and with nuclear magnetic resonance imaging. As a secondary finding, an unusual distinctive subcutaneous calcification was diagnosed in the radiation-exposed area by means of 7,5-MHz-sonography, as well as computer- and nuclear magnetic resonance imaging. These subcutaneous calcifications are most likely to have been radiation-induced.

A questionnaire survey on the theory of postoperative infection prophylaxis was conducted to obtain the consensus on perioperative antimicrobial use among orthopedists in Japan in the period from April to September 2000. Fifty of the 91 orthopedists replied, and the following consensus was obtained. An antimicrobial prophylaxis (AMP) agent should be chosen based on their efficacy against the pathogens expected to be contaminants, such as Staphylococcus spp., and Streptococcus spp., Use an AMP agent that achieves a bactericidal concentration in both the serum and operating site. Use an AMP agent that has little unfavourable side effects. Use an AMP agent that affects minimally the normal bacterial flora. The most commonly used agents are the penicillins and first and second generation cephalosporins. The optimal strategy for most commonly used agents entails infusion of the first dose between approximately 30 minutes pre and post-skin incision and the therapeutic levels should be maintained throughout the operation. The AMP agents having no cross-resistance to the prophylactic agents should be used, if postoperative infection is suspected or developed. The most commonly used agent for both clean operations with or without foreign implants and dirty operations is cefazolin (CEZ), followed by cefotiam (CTM) and flomoxef (FMOX).

This report describes two infants who had neutropenia develop after treatment with beta-lactam antibiotics. The first patient, a 9-month-old girl, was administered flomoxef (FMOX); the second patient, a 14-month-old boy, was administered cefotiam (CTM). Both infants were found to have neutropenia 4 to 5 days after they were placed on respective antibiotics, and neutropenia had persisted despite antibiotics withdrawal for 1 to 3 months. Drug-induced lymphocyte stimulation test (DLST), granulocyte-bound antibodies, serum granulocyte antibodies, and immunoblotting analysis indicated that beta-lactam antibiotics possibly triggered production of granulocyte autoantibody with resultant autoimmune neutropenia.

Background Cancer surgery is known to lead to a deterioration in host defence mechanisms and an increase in susceptibility to infection after operation. Filgrastim enhances important antimicrobial functions of neutrophils including chemotaxis, phagocytosis and oxidative killing mechanisms. Methods The effects of additional (all patients received perioperative 3 ′ 25 mg kg−1 cefotiam and 1 ′ 20 mg kg−1 metronidazole) preoperative prophylaxis with filgrastim (5 μg kg−1 12 h prior to surgery plus 5 μg kg−1 0 h prior to surgery) on neutrophil phagocytosis and reactive oxygen radical production and postoperative infections in 24 patients undergoing cancer neck dissection were studied. Phagocytic capacity was assessed by measuring the uptake of fluorescein isothiocyanate-labelled Escherichia coli and Staphylococcus aureus by flow cytometry. Reactive oxygen generation after phagocytosis was estimated by determining the amount of dihydrorhodamine 123 converted to rhodamine 123, intracellularly. Results In the filgrastim-treated patients a higher neutrophil phagocytic capacity was seen intraoperatively, and 1–5 days postoperative, but not prior to surgery. Reactive oxygen radical production was significantly higher in filgrastim-treated patients prior to surgery, intraoperative and postoperative (1–5 days). 2/12 (17%) patients had postoperative infections in the filgrastim group and 9/12 (75%) patients had infections in the placebo group (P