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There have been few coherent reports on extraintestinal infection or bacteremia caused by Campylobacter jejuni (C. jejuni) or C. coli in Japan. To clarify the clinical and microbiological characteristics of invasive infections caused by these two species, we retrospectively analyzed the records of patients from whom these pathogens had been isolated from sterile sites between 2000 and 2015. During this study period, we identified 9 patients. The clinical syndrome of all of these patients was bacteremia. Three patients had underlying diseases with both liver cirrhosis and malignant neoplasm, and all of these patients were aged 60 years or older. The remaining 6 patients were immunocompetent and younger than 40 years of age. All 9 patients had a fever of 38.5 degrees C or higher. The proportion of patients with gastrointestinal symptoms was lower for the 3 patients with underlying diseases, compared with the 6 patients without underlying diseases (1/3 cases vs, 4/6 cases). Of the 8 strains evaluated for antimicrobial susceptibility, all were susceptible to imipenem/cilastatin, kanamycin and erythromycin, and 2 were resistant to levofloxacin. Antimicrobial treatment was administered to 8 patients, but one spontaneously recovered without any treatment. We were able to follow the outcomes of 8 patients, and all of these patients completely recovered without relapses. We also reviewed 14 Japanese patients reported in the Japanese and English literature and found similar clinical features consisting of a high-grade fever and an association with underlying diseases and gastrointestinal symptoms. Of note, 3 agammaglobulinemic patients presented with bacteremia and extraintestinal infections and had multiple relapses. Based on the findings of our 9 cases and previous reports, the affected patients were divided into two groups according to clinical syndrome and therapeutic intervention. One group consisted of previously healthy children or young adults showing bacteremia. Most of them had enterocolitis complications but had a good prognosis. The other group consisted of patients with underlying diseases or elderly patients who presented with bacteremia alone or bacteremia with extraintestinal infections. The latter group, especially among those with humoral immunodeficiency, should be parentally treated with antimicrobial agents and requires careful monitoring for relapse. This is the largest case series study to examine invasive C. jejuni/coli infections in Japan, and it provides important epidemiological information on this rare infection.

A 78-year-old woman who had been treated for two years with ITCZ for chronic pulmonary aspergillosis associated with prior pulmonary tuberculosis was admitted to our hospital because of general fatigue and hemosputum along with deterioration of her chest radiographic findings. Mycobacterium abscessus had been isolated once from her sputum one year before admission. We performed fiberoptic bronchoscopy (FOB) in order to help establish a final diagnosis. Sputum aspirated from her bronchus on FOB stained positive for acid-fast bacilli and was negative for Tbc and MAC using PCR. From these results, we diagnosed the patient with pulmonary M. abscessus infection. Chemotherapy with AMK, IPM/cs, and CAM was initiated. Because her symptoms rapidly improved, we switched the chemotherapy to long-term oral CAM and LVFX, and she has been in a good condition at 12 months after the initiation of the therapy. Recently, subtypes of M. abscessus complex, such as M. massiliense, have been recognized, which are more sensitive to chemotherapy. Considering the good response to therapy, there is a possibility that is the patient in the current case had a M. massiliense infection.

Tebipenem pivoxil (TBPM-PI), the first oral carbapenem antibiotic both in Japan and abroad, was examined on its convulsive liability. We used ICR male mice and Sprague-Dawley male rats to examine the pro-convulsive effect and anticonvulsive effect of TBPM-PI and its active metabolite, TBPM. (1) When mice were treated with TBPM-PI (30-1000 mg/kg, p.o.) or TBPM (10-300 mg/kg, i.v.), no convulsion was noted at any dose level. When rats were treated with TBPM (300 mg/kg, i.v.), no convulsant effects were noted in electroencephalography or behavioral observation. In intraventricular injection of TBPM in mice, clonic convulsion was observed in 7/10 animals at 100 microg but no effect at 30 microg. On the other hand, the administration of 10/10 microg imipenem/cilastatin (IPM/CS) resulted in clonic convulsion in all animals and tonic convulsion in 3/10 animals, and 4/10 animals died. The administration of 100 microg meropenem did not cause any effects. (2) When mice were co-administered with pentylenetetrazole (45 mg/kg: maximum dose level at which no convulsion is induced) and TBPM-PI (30-300 mg/kg, p.o.) or TBPM (300 mg/kg, i.v.), convulsion enhancing effect was not noted. On the other hand, the co-administration of pentylenetetrazole with IPM/CS (300/300 mg/kg, i.v.) enhanced a convulsive effect of pentylenetetrazole. (3) When mice were treated with TBPM-PI (30-300 mg/kg, p.o.) or TBPM (100 mg/kg, i.v.), inhibitory effect was not noted on convulsions induced by electrostimulation, pentylenetetrazole or strychinine. In conclusion, there were no pro-convulsive effects or anticonvulsive effect in the oral administration of TBPM-PI or intravenous administration of TBPM. Pro-convulsive effect was observed in the intraventricular injection of TBPM as in the case of other carbapenem antibiotics, but such action was weaker than that in IPM/CS administration. Accordingly, the risk of occurrence of convulsion related to TBPM-PI administration was low compared to IPM/CS administration, and TBPM-PI was considered to be less potential to induce convulsions in clinical use.

Cigar-shaped clostridia such as Clostridium clostridioforme and Clostridium symbiosum have been found in serious infections such as bacteremia. In Japan, however, these strains are unrecognized as clinically significant because they are overlooked as unidentified gram-negative rods. We isolated 60 strains of cigar-shaped Clostridium spp. from 48 clinical specimens treated at our laboratory from November 2004 to September 2006. Of these, 19 (39.6%) were primary infections and 29 (60.4%) postsurgical. Primary infections included infected decubitus ulcer (7), peritonitis, intra abdominal abscess, sepsis (2 cases in each group), pyometra, Bartholin's gland abscess, and Fournier's gangrene (1 case in each group). Secondary infections included 28 cases of surgical site infection and 1 case of pyothorax. CRP in 30 cases (62.5%) exeeded 10 mg/dL. In 26 (54.2%), WBC exceeded 12,000/microL. The 60 isolated strains were as follows by 16S rRNA sequencing: Clostridium hathewayi (26.7%), C. clostridioforme (16.7%), Clostridium bolteae (18.3%), Clostridium citroniae (10%), Clostridium aldenense (8.3%), and Clostridium symbiosum (20%). In antimicrobial susceptibility, strains of C. hathe-wayi showed relatively higher MIC for cefotaxime (MIC50; 64 microg/mL, MIC90; 128 microg/mL). Three strains of C. bolteae were beta-lactamase-producing and their MICs for ampicillin exceeded 128 microg/mL.

A 78-year-old man underwent a left lower sleeve lobectomy and lymph node dissection for lung cancer. His postoperative course had been uneventful until postoperative day (POD) 3, but severe dyspnea occurred suddenly and the chest X-p showed infiltration shadow on POD 3. Streptococcus pneumonia antigen in the urine was elevated, suggesting pneumonia caused by Streptococcus pneumonia. The patient was treated with double dose of imipenem/cilastatin sodium and supported with a mechanical ventilator in an intensive care unit. Although the patient recovered from penicillin resistant Streptococcus pneumonia, he was suffered from Klebsiella sepsis and expired on the POD 26.

We evaluated the clinical features of multidrug-resistant Pseudomonas aeruginosa cases determined by sputum culture between April, 2005 and December, 2006. The clinical features of most cases were: (1) pneumonia in the elderly with cerebrovascular diseases, (2) previous administration of carbapenems and antipseudomonal cephems, (3) PIPC, CAZ and ISP sensitve MDRP, (4) MRSA was isolated concurrently, (5) not necessary of therapy against MDRP, (6) good outcome.

A 42-year-old woman presented with persistent cough, bloody sputum and fever. Her chest X-ray film showed an infiltrative shadow with cavitation in the upper lobe of the left lung. Acid-fast-bacilli were shown by sputum smear staining. The anti-tuberculosis drugs isoniazid, refampicin, ethambutol and pyrazinamide were prescribed, but her symptoms and chest X-ray findings did not improve. Findings of MTD and MAC-PCR were negative but Mycobacterium abscessus was confirmed by sputum culture with the DNA hybridization method. Combination therapy with clarithromycin, amikacin and imipenem/cilastatin for one month improved her symptoms and chest X-ray shadow, and clarithromycin monotherapy was carried out for another ten months. Drug susceptibility tests revealed this mycobacterium was sensitive to clarithromycin and amikacin. To determine the environmental factors related to this infection, several samples were examined. Acid-fast-bacilli were present in a smear from the bath room drain. However, to confirm the infectious routes, longer observation is needed. Moreover, serum amyloid protein A and ESR were useful markers to estimate the clinical course.

A 52-year-old man was given a diagnosis of type 2 diabetes mellitus at age 39. At age 46, he stopped taking medication. Two weeks after burning his legs at low temperature, he fell, using his right arm to protect his legs. The next day, he complained of pain and slight swelling from his right shoulder to his anterior chest and came to our hospital. At that time, a plain computed tomography scan suggested gasogenic bacterial infection and we discussed the indications for debridment. Although his widespread inflammation required extensive treatment including thoracostomy, we abandoned surgical treatment and administered several antibiotics in appropriate combination because of his severe condition. After admission, the mass grew rapidly and it was diagnosed as necrotizing fasciitis based on percutaneous needle biopsy and clinical findings. Although both inflammatory reactions and mass size tended to improve, he had repeated recurrence of pain and swelling in his right anterior chest. When he had a second recurrence, he received additional short-term steroid therapy. Afterwards he had no further recurrence. In this case, early clinical diagnosis, using broad-spectrum antibiotics prior to definite diagnosis, and additional short-term steroid therapy at the time of the recurrence were effective.

A 47-year-old woman was hospitalized because of urinary-tract infection. She was treated with antibiotics for 6 days. However, severe watery diarrhea and pyrexia developed 6 days after stopping administration of antibiotics. Stool, throat and blood cultures were positive for methicillin-resistant Staphylococcus aureus (MRSA) and negative for Clostridium difficile DI toxin. In spite of administration of VCM, she died of septic shock. At autopsy, macroscopic observation revealed a pseudomembrane in the ileum. MRSA enterocolitis can occur in patients with antibiotic-related diarrhea, and physicians should be aware of its rapid clinical course and possible lethal outcome.

Nocardial infections in an immunocompromised host have been increasingly reported. Nocardial brain abscess, the most common presentation of nocardiosis in the central nervous system, is associated with a high mortality rate because of its delayed diagnosis and its unresponsiveness to the usual antibiotic therapy. We report four patients who experienced a long-term cure of nocardial brain abscess due to treatment by a combination of surgery and postoperative antibiotic therapy; 1 man and 3 women, ages ranging from 43 to 67 years old. Two patients were associated with systemic lupus erythematosus and two with autoimmune hemolytic anemia. Patients underwent surgical aspiration and drainage of brain abscess. Nocardia was identified from the aspirated specimen and postoperative antibiotic therapy for 5-6 weeks was performed using effective antibiotic agents; sulfamethoxazole/trimethoprim (ST), imipenem/cilastatin and minocycline (MINO) in Case 1, ST and MINO in Case 2, erythromycin in Case 3, and panipenem/betamipron and cefotaxime in Case 4. Case 3 and Case 4 with multilobulated brain abscess underwent total excision of the brain abscess. All patients showed successful cure of nocardial brain abscess with no recurrence for the period of 1-8 years. The combination of surgery and postoperative antibiotic therapy provides a good prognosis for nocardial brain abscess.

Although bacterial translocation (BT) is thought to be a main cause of secondary pancreatic infection, the clinical significance is still unclear. Therefore, we investigated relationship between pancreatic infection and BT, analyzing the results of treatments such as continuous regional arterial infusion of protease inhibitor and antibiotics (CRAI), selective digestive decontamination, and early enteral nutrition (SDD/EN) in 45 severe acute pancreatitis patients. The infection rate of 17 cases without CRAI, SDD/EN was 58.8%, and mortality was 23.5%. Antibiotics-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) was often proven in infected pancreatic tissue. Whereas, in 16 cases who underwent both therapy, only one patient died of multi-organ failure (6.3%). Pseudomonas aeruginosa and K. pneumoniae were proven from his feces before pancreatic infection coincidence, and, in autopsy, these bacteria and MRSA were proved from necrotic pancreatic tissue. BT must be large cause of secondary pancreas infection, because CRAI and SDD/ EN prevent secondary pancreatic infection. But we must consider other infection routes, and development of antibiotics resistant bacteria.

A 58-year-old man was admitted to our hospital because of an abnormal shadow found on chest radiography. Chest radiographs and chest CT on admission showed a bulla with a niveau and infiltration in the right upper lobe. Smear of sputum and bronchial lavage were negative for acid-fast bacilli. Despite treatment with meropenem and clindamycin, the infiltrating shadow worsened. Since bronchial lavage and sputum culture were positive for M. fortuitum, these drugs were replaced with minocycline and imipenem. Thereafter, the shadow on the chest radiograph improved. After discharge, outpatient treatment with clarithromycin and levofloxacin was continued. After 4 months, the residual tumor shadow in the right upper lobe gradually grew. When a CT-guided transcutaneous needle lung biopsy was undertaken, malignant cells were found. Right upper lobectomy was performed. Pathological examination of the lesion demonstrated small-cell lung cancer. If a lesion does not change after nontuberculous mycobacteria treatment, the physician should consider other lesions such as lung cancer.

We report a case of lung infection due to Mycobacterium abscessus (M. abscessus). A 60 year-old woman was admitted to our hospital because of an abnormal shadow found on chest radiography and a bloody sputum. Chest radiography revealed infiltrative and linear shadows in the middle and lower fields of both lungs. The sputum smears were negative for acid-fast bacilli, but sputum culture was positive. Rapidly growing mycobacteria were detected. The patient was treated with clarithromycin. Since M. abscessus was identified from repeated cultures of the sputa, the patient was treated with Imipenem/Cilastatin and Amikacin for four weeks, during which the chest radiography improved. After discharge, the treatment with clarithromycin and minocycline was continued for ten months, and the chest radiography improved further. Our treatment for M. abscessus may be a useful choice for drug treatment of such cases.

We report a case of bulla infection caused by Mycobacterium fortuitum. The patient was a 66 year-old female associated with interstitial pneumonitis. The chest X-ray film showed cavities with thick walls and niveau formation, which initially suggested pulmonary abscesses. The chest CT scan showed infiltrative shadows surrounding multiple bullae. Smears and cultures of the sputum were repeatedly positive for mycobacteria, which was identified to be M. fortuitum. By chemotherapy with imipenem/cilastatin sodium, clarithromycin, levofloxacin, and minocycline on the basis of susceptibility test, sputum converted to negative within 2 months, abnormal shadows on the roentgenogram and laboratory data showed improvement. There are no signs of recurrence after completion of the treatment for 12 months.

Antibacterial activity of biapenem (BIPM) against clinical isolates of 8 species between 2000 and 2002 was compared with those of imipenem/cilastatin (IPM/CS), meropenem (MEPM), panipenem/betamipron (PAPM/BP) and ceftazidime (CAZ). The MICs of biapenem for Gram-positive bacteria were higher than those of IPM/CS and PAPM/BP, equal to those of MEPM and lower than those of CAZ. The MICs of BIPM for Gram-negative bacteria were higher than those of MEPM, equal to those of IPM/CS and PAPM/BP, and lower than those of CAZ. Antibacterial activity of BIPM against Pseudomonas aeruginosa was equal to those of IPM/CS and MEPM and superior to those of PAPM/BP and CAZ. In conclusion, BIPM showed broad antibacterial activity against both Gram-positive and Gram-negative clinical isolates. These results suggest that BIPM is useful for the treatment of various bacterial infections.

Seventy-two women diagnosed as parametritis were enrolled in this study and examined on the effective administration method of carbapenems, imipenem/cilastatin (IPM/CS), panipenem/betamipron (PAPM/BP) and meropenem (MEPM). The total dosage of each carbapenem was 1.5 g/day, and administration frequency was twice a day (0.75 g x 2) or three times a day (0.5 g x 3). We reviewed the highest body temperature, white blood cell count and CRP value, before treatment and the fourth day after the start of treatment. Three times a day method was statistically superior to twice a day method in the highest body temperature, and CRP value. When we use carbapenem antimicrobial agents, the basis of PK/PD of time above MIC would lead to the increasing clinical effects.

We investigated the in vitro and in vivo antibacterial activities of pazufloxacin mesilate (PZFX mesilate), a new injectable quinolone, and obtained the following results. 1) The MIC50 and MIC90 values of PZFX against clinically isolated Gram-positive and -negative bacteria, ranged from 0.0125 to 12.5 micrograms/ml and 0.025 to 100 micrograms/ml, respectively. PZFX showed broad spectrum activity. The antibacterial activities of PZFX against quinolone-susceptible, methicillin-resistant Staphylococcus aureus, beta-lactamase-negative, ampicillin-resistant Haemophilus influenzae, extended spectrum beta-lactamase possessing Klebsiella pneumoniae and imipenem/cilastatine (IPM/CS)-resistant Pseudomonas aeruginosa were superior to those of ceftazidime (CAZ), ceftriaxone, IPM/CS, meropenem and panipenem/betamipron. 2) PZFX showed superior bactericidal activity against S. aureus, Escherichia coli, Proteus mirabilis, Serratia marcescens and P. aeruginosa to those of CAZ and IPM/CS after treatment for 15 minutes at the drug concentration equivalent to that in human serum at clinical dose to be continued for 15 minutes. 3) CAZ and IPM/CS had no bactericidal activity at the 16 times of MIC against P. aeruginosa in human polymorphonuclear leucocytes, while PZFX exhibited potent bactericidal activity in a dose-dependent manner against such bacteria. 4) PZFX inhibited both DNA gyrase and topoisomerase IV from S. aureus at nearly the same level. PZFX showed poor inhibitory activity against topoisomerase II from human placenta and showed high selectivity to bacterial topoisomerase. 5) PZFX mesilate showed superior therapeutic activity to that of CAZ with following infection model caused by S. aureus and P. aeruginosa or each; systemic infection with cyclophosphamide-treated mice, systemic infection in mice with high challenge doses, CMC pouch infection in rat, and calculus infection in rat bladder. 6) Intravenous administration of PZFX with high plasma concentration just after administration, showed more excellent therapeutic effect against the rat intraperitoneal infection, than p.o. and s.c. administration.

Convulsant activity of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, in combination with nonsteroidal anti-inflammatory drug (NSAID) was investigated in mice after intravenous or intracerebroventricular administration. Following results were obtained. 1. In combination with 4-biphenylacetic acid (BPAA) at an oral dose of 100 mg/kg, PZFX mesilate did not induce any convulsions at intravenous doses up to 200 mg/kg. Reference quinolones induced convulsions at the following intravenous doses: Enoxacin (ENX), 3.13 mg/kg or more; norfloxacin (NFLX) and lomefloxacin (LFLX), 6.25 mg/kg or more; ciprofloxacin (CPFX), 50 mg/kg or more; sparfloxacin (SPFX) and temafloxacin (TMFX), 100 mg/kg or more; fleroxacin (FLRX), 200 mg/kg. 2. PZFX mesilate at an intravenous dose of 50 mg/kg did not induce convulsions in mice after oral administration of any of 14 kinds of NSAIDs. It induced convulsions at 200 mg/kg in combination with aspirin at an oral dose of 600 mg/kg, while it did not with the other 13 kinds of NSAIDs. 3. Convulsion-inducing dose of PZFX mesilate after intracerebroventricular administration was 100 mg/body, which was higher than those of reference quinolones (NFLX, CPFX, ENX, LFLX, TMFX, levofloxacin, ofloxacin, FLRX and SPFX) and beta-lactam antibiotics (penicillin G, cefazoline, imipenem/cilastatin and panipenem/betamipron). In addition, concurrent dosing of BPAA (1 microgram/body) did not reduce the convulsion-inducing dose of PZFX mesilate. These results suggest that PZFX mesilate has remarkably weak convulsant activity.

We report a case of Mycobacterium abscessus infection complicated with diabetes mellitus. A 38-year-old man with diabetes mellitus as an underlying disease, was admitted to our hospital because of a productive cough. He had had pulmonary tuberculosis two years before. Chest radiography revealed infiltration in both lung apices and chest CT showed a cavitary lesion in the left upper lobe. Gaffky 2 was found on a sputum smear. However, in the examination of PCR on sputum, not only M. tuberculosis but M. avium complex was negative, and repeated cultures of sputum were positive for M. abscessus. On the basis of the diagnosis of an M. abscessus infection, the patient was initially treated with amikacin, imipenem/cilastatin and levofloxacin during hospitalization while receiving insulin for diabetes mellitus. The smear and culture of sputum became negative for Mycobacterium, and the findings of chest radiography and chest CT improved. After discharge, treatment was continued with clarithromycin and levofloxacin. It is considered that the choice of effective drugs and the additional treatment of an underlying disease are very important for the treatment of a Mycobacterium abscessus infection.

Efficacy of panipenem/betamipron (PAPM/BP) against experimental pneumonia caused by penicillin-resistant Streptococcus pneumoniae (PRSP: MIC of benzylpenicillin, > or = 1.56 micrograms/ml) in mice was compared with those of imipenem/cilastatin (IPM/CS), meropenem (MEPM), cefozopran (CZOP), ceftriaxone (CTRX), ampicillin (ABPC), and vancomycin (VCM). The infection was induced by inoculating a PRSP clinical isolate, 9601 (serotype 6) or 10,693 (serotype 19), into ddY male mice intranasally. Drugs were administered subcutaneously at doses of 0.4, 2, and 10 mg/kg, 18, 26, 42, and 50 hours post-infection. Viable cell counts in the lungs were determined 66 hours post-infection. PAPM/BP showed the greatest efficacy against the infections among tested drugs. MICs of PAPM against PRSP 9601 and 10,693 were both 0.125 microgram/ml, which were superior to those of IPM (0.25 and 0.5 microgram/ml, respectively), MEPM (0.5 and 1 microgram/ml, respectively), CZOP (2 and 1 microgram/ml, respectively), CTRX (both 1 microgram/ml), ABPC (both 4 micrograms/ml), and VCM (0.5 and 0.25 microgram/ml, respectively). These results suggest that the potent in vivo activity of PAPM/BP reflects the potent in vitro activity of PAPM. MICs of PAPM, IPM, MEPM, and CZOP against clinical isolates, penicillin-susceptible S. pneumoniae (PSSP: MIC of benzylpenicillin, < or = 0.05 microgram/ml), penicillin-intermediate S. pneumoniae (PISP: MIC of benzylpenicillin, 0.1-0.78 microgram/ml), and PRSP, were tested by an agar dilution method. MIC90s of the drugs against the PSSP, PISP, and PRSP were as follows: PAPM, 0.012, 0.05, and 0.39 microgram/ml; IPM, < or = 0.006, 0.1, and 0.78 microgram/ml; MEPM, 0.05, 0.39, and 1.56 micrograms/ml; and CZOP, 0.2, 0.78, and 6.25 micrograms/ml, respectively. Thus, PAPM showed the most potent activity among tested drugs against clinical isolates of PISP and PRSP.

Although septic shock has a high mortality rate of 43%, recently the endotoxin adsorption column was established and its efficacy is interesting. We report a very effective case of endotoxin adsorption the rapy for septic shock due to acute pyelonephritis. A 59-year-old man with chief complaints of pyrexia and right backache was referred to our hospital with a small right ureteral stone (4 mm) associated with a low degree of right hydronephrosis. Since it was diagnosed as right acute pyelonephritis, antibiotics were administered; and then septic shock occurred on the day of hospitalization. Endotoxin adsorption therapy was performed for two days and hemodynamic stability was achieved. The concentration of blood endotoxin was reduced remarkably and the efficacy of endotoxin adsorption therapy was suggested.

The in vitro interactions of piperacillin (PIPC) and imipenem/cilastatin (IPM/CS) combined with 5 kinds of aminoglycosides (gentamicin, tobramycin, amikacin (AMK), isepamicin and netilmicin) were investigated against IPM/CS-susceptible (MIC of IPM/CS was < or = 3.13 micrograms/ml) and IPM/CS-resistant (MIC of IPM/CS was > or = 12.5 micrograms/ml) Pseudomonas aeruginosa. The following results were obtained. 1. In the checkerboard dilution studies, the combinations of PIPC with aminoglycosides showed synergistic effect for more than 50% of the each 54 strains of IPM/CS-susceptible and IPM/CS-resistant P. aeruginosa. The synergistic/additive effects of PIPC with aminoglycosides were demonstrated for all tested strains. 2. In the checkerboard dilution studies, the combinations of IPM/CS with aminoglycosides showed no antagonism against any strains. The synergistic effects of IPM/CS with aminoglycosides were demonstrated for 0 to 14.8%, and these values were smaller than the combinations of PIPC with aminoglycosides. 3. Corresponding to the results of checkerboard dilution studies, the combination of PIPC with AMK was more effective than the combination of IPM/CS with AMK on the killing curve for IPM-resistant P. aeruginosa. In conclusion, PIPC showed the synergistic effects in combinations with aminoglycosides against IPM/CS-resistant P. aeruginosa. These results suggest that the combination therapies of PIPC with aminoglycosides are useful for the clinical treatment of serious infections due to P. aeruginosa.

Therapeutic efficacy and the treatment days for cure of imipenem/cilastatin sodium (IPM/CS) in treatment of pulmonary infections were prospectively determined in comparison with those of beta-lactams other than carbapenems mainly ceftazidime (CAZ) or sulbactam/cefoperazone (SBT/CPZ). The overall response rate was 84.9% (62/73) in the IPM/CS group and 74.7% (56/75) in the beta-lactam group, the difference not being significant. In the subjects having underlying respiratory diseases, the response rate was 91.1% (41/45) and 73.9% (34/46) in the IPM/CS and beta-lactam groups, respectively. In patients with infections secondary to chronic respiratory disease, the rate was 91.2% (31/34) in the former group and 66.7% (24/36) in the latter group, respectively. The differences were significant for both stratified analyses. The treatment days for cure judged by the attending physician were 12.9 +/- 0.6 days in the IPM/CS group, and 14.5 +/- 0.7 days in the beta-lactam group. The difference was not, however, significant. In patients with mild to moderate infections, the treatment days for cure was 12.0 +/- 0.6 days (n = 64) in the IPM/CS group and 14.3 +/- 0.7 days (n = 70) in the beta-lactam group. In patients with underlying respiratory disease, the treatment days for cure were 11.8 +/- 0.7 days (n = 45) and 14.7 +/- 0.9 days (n = 46) in the IPM/CS and beta-lactam groups, respectively. In patients with infections secondary to chronic respiratory disease, the days were 11.1 +/- 0.7 days (n = 34) and 14.7 +/- 1.1 days (n = 36), respectively. Thus, IPM/CS therapy significantly reduced the number of treatment days until cure. There was, however, no significant difference between the two therapy groups in treatment of the patients with severe infections, those without underlying respiratory disease, or those with pneumonia and/or lung abscess. The treatment days for cure were also assessed by the members of review committee taking into consideration of body temperature, leukocyte count, and C-reactive protein. As the result, it was 6.9 +/- 0.5 days in the IPM/ CS and 10.3 +/- 0.7 days in the beta-lactam groups; respectively, and the difference was significant. Time (days) until cure was also compared between the two groups using survival time analysis, confirming a more rapid response in the IPM/CS group. Although IPM/CS therapy was associated with a shorter response time as assessed by both the attending physicians and the review committee, there were considerable differences between the results of these judgements. Thus, the duration of treatment with injectable antibiotics requires reevaluation in the future. No significant differences were observed between the groups with respect to parameters indicating side effects and laboratory abnormalities. There were no severe symptoms or laboratory findings, and symptoms and changes in laboratory values, if any resolved during the course of therapy or after the withdrawal of treatment. In conclusion, IPM/CS seems to be very useful as first-line therapy for respiratory tract infections and for shortening the duration of treatment.

An 84-year-old male presented to the emergency room with the chief complaint of painful, swollen penis following the use of a constriction ring to maintain penile erection. A high fever, chills and hypotension were recognized. Septic shock was presumed, and administration of antibiotics was started. Microbiologic cultures revealed Escherichia coli in blood. We herein report a rare but serious complication accompanying incarceration of the penis.

An intramuscular preparation of imipenem/cilastatin (IPM/CS, 500 mg/500 mg) was administered to 59 patients with complicated urinary tract infections (UTI; cystitis and pyelonephritis) to evaluate its efficacy and safety. The obtained results are summarized as follows: In patients with cystitis, evaluations based on daily frequencies of administration were also performed. 1) According to the treating doctors, the drug showed an overall efficacy rate of 80% (45/56 patients). The efficacy rate was 89% in patients with cystitis treated by a u.i.d. regimen. Among patients treated by a b.i.d. regimen, the efficacy rate was 67% for cystitis cases and 84% for pyelonephritis cases. 2) When clinical efficacy was assessed according to the criteria for UTI drug efficacy evaluation, the drug was 'markedly effective' in 14 patients, 'effective' in 23, and ineffective in 11 patients, for an efficacy rate of 77% (37/48 patients). 3) The microbiological eradication rate was 88% (59/67 strains). The rate was 95% (20/21 strains) for Gram-positive bacteria and 85% (39/46 strains) for Gram-negative bacteria. The efficacy for Enterobacter faecalis and Pseudomonas aeruginosa was 100% and 73%, respectively. 4) As side effects, pain at the injection site was reported by one patient and abnormal laboratory test values were observed in 2 patients. All of these reactions were mild and resolved shortly after the completion of treatment. Based on these findings, it is concluded that this intramuscular preparation of IPM/CS is effective for treating complicated urinary tract infections.

We evaluated the clinical efficacy of imipenem/cilastatin sodium (IPM/CS--a carbapenem antibiotic) against orthopedic infections, and the drug levels of the bone tissues were determined. The clinical efficacies for 6 patients in the infection group were good in 3 cases, and fair in the other 3; giving an efficacy rate of 50%. Bacteriologically, 8 strains were isolated from patients with the infection and an eradication rate of 87.5% was obtained upon the treatment. In 39 patients that were given the drug prophylactically, no postoperative infections occurred. Mean IPM levels in the bone and the bone marrow at 1 hour after administration in 5 patients of the prophylactic group were 17.3 micrograms/ml and 5.9 micrograms/g, respectively. The ratio of concentrations the bone to those in the bone marrow was 34.6%. The results of this study suggest that IMP/CS reaches to the bone tissue providing sufficient concentrations and that the drug is efficacious for the prophylaxis and the treatment of orthopedic infections.

Therapeutic efficacy of the combined regimen, imipenem/cilastatin (IPM/CS) plus vancomycin (VCM), was examined in a total of 13 patients infected with MRSA (10 patients with pneumonia, 2 with sepsis and 1 with urinary tract infection). Based on the results of determination of FIC indices, in vitro combined effects were synergistic in 4 strains and additive in 3 strains. There was, however, no apparent correlation between the in vitro combined effect in terms of FIC index and clinical outcome. No side effects or abnormal laboratory findings were observed. The average daily doses of IPM/CS and VCM were 1.2 g and 1.25 g and the average administration periods were 17.5 and 14.9 days, respectively. The present results suggested that simultaneous use of IPM/CS and VCM at the standard doses could yield an enhancement of both bacteriological and clinical efficacies in treatment of the patients with MRSA infection.

Imipenem/cilastatin sodium (IPM/CS) was administered to 102 patients with respiratory tract infections and lung cancer. Patients with other serious diseases were excluded and a total of 73 patients were enrolled. They were divided into 12 patients who underwent surgery (operated group) and 61 who did not (non-operated group); the latter group included 28 patients treated with anticancer agents or radiation therapy (treated group) and 33 untreated patients (untreated group). IPM/CS was effective in 75% of the patients, both with and without surgery. The drug was effective in 81% of the treated group, although many of the patients had Stage III or more advanced cancer, as well as bronchial occlusion. IPM/CS was also effective in 69% of the untreated group, although many of the patients have serious infections and a PS (Performance Status) of 3 or greater. Thus, IPM/CS treatment achieved good results. Bacteriological studies showed that 3 out of 4 strains in the operated group and 16 out of 18 in the non-operated group were eliminated. Safety was evaluated in all patients. Two patients (2%) experienced side effects and two others (2%) showed abnormal clinical findings, but the symptoms were mild and resolved after discontinuation or completion of therapy. In conclusion, IPM/CS was very effective for treating respiratory infections in patients with lung cancer.

One hundred and nine patients with infections concurrent with hematopoietic disorders were treated with imipenem/cilastatin sodium (IPM/CS) either alone (IPM/CS monotherapy) or in combination with other antimicrobial drugs (IPM/CS combination therapy). The following results were obtained. 1. One hundred and nine patients were allocated at random to two groups: 53 patients to IPM/CS monotherapy and 56 patients to IPM/CS combination therapy. Fourteen patients (6 and 8 in the 2 groups, respectively) were excluded from the clinical evaluation. There were not significant differences between the two groups with respect to the background. 2. The efficacy rates of the 2 treatments against bacterial infections were as follows: in the IPM/CS monotherapy group, 62.5% in 8 patients with sepsis, 75.0% in 23 patients with fever of undetermined origin (FUO), 50.0% in 10 patients with pneumonia, and 68.3% in the 47 patients, and in the IPM/CS combination group, 85.7% in 7 patients with sepsis, 63.6% in 24 patients with FUO, 50.5% in 8 patients with pneumonia, and 67.4% in the 48 patients. The differences between the two groups were not significant. 3. Among the drugs used in combination with IPM/CS, antibiotics other than penicillins, cephalosporins, and aminoglycosides were used in 12 patients and a high efficacy rate of 91.7% was obtained. 4. Bacteriologically, 19 and 17 strains were isolated from the IPM/CS monotherapy and combination therapy groups respectively, and the eradication rates were 100% and 88.9% respectively. 5. Side effects were noted in 2 patients in the IPM/CS monotherapy group and 7 in the combination therapy group, but all of these resolved after discontinuation or completion of the treatment. The efficacies against severe bacterial infections in the presence of hematopoietic disorders were not different between IPM/CS alone and IPM/CS in combination with other antibiotics. Adverse reactions were uncommon with the monotherapy.

Vancomycin hydrochloride (VCM) has an antibacterial action against Gram positive bacteria, e.g., Methicillin-resistant Staphylococcus aureus (MRSA). In the clinical situation, there are patients with serious infections, being infected with not only MRSA, but also with Gram negative bacteria like Pseudomonas aeruginosa. Because VCM has the adverse reaction of nephrotoxicity, we are apprehensive about using VCM with other antibiotics, which might increase this problem. Therefore, the nephrotoxic effects and pharmacokinetics of VCM were examined in rabbits and compared with those in rabbits administered with VCM and other antibiotics. Responses indicating nephrotoxicity such as increases of serum creatinine concentration and BUN and morphological changes of the kidney were induced by the single injection of VCM at 300 mg/kg, i.v. In contrast, no abnormality of clinical data and morphological alteration were observed in the groups injected with VCM and imipenem (IPM)-cilastatin sodium (CS), flomoxef sodium (FMOX) or fosfomycin sodium (FOM). This was not true for groups injected with VCM and ceftazidime, cefpimizole sodium (CPIZ) or cefoperazone sodium. Clearance of VCM increased obviously in the groups injected with VCM and IPM-CS, FMOX or FOM, but decreased in those given VCM and CPIZ. Since the renal concentrations of VCM in the groups that were administered VCM with IPM-CS, FMOX or FOM were lower than that in the control group, IPM-CS, FMOX and FOM may decrease the nephrotoxicity of VCM by inhibiting its uptake into the kidney.

The clinical effectiveness of a combination treatment using imipenem/cilastatin sodium (IPM/CS) with G-CSF was studied in neutropenic patients (< 500/mm3) with hematological malignancies and secondary infections. Thirty seven patients were entered in the trial, and 30 patients were eligible. This combination was effective in 20 patients, thus the overall efficacy rate was 66.7 percent. The combination was effective in all 6 cases with septicemia, in 10 case out of 15 cases with fever after chemotherapy (efficacy rate; 66.7%), in 3 out of 8 cases with respiratory infections including 7 cases with pneumonia (efficacy rate; 37.5%), and a case with laryngopharyngitis. According to the order of the administration, the efficacy rates were 60.0% in 5 cases in whom G-CSF treatment was started before IPM/CS, 66.7% in 21 cases given both G-CSF and IPM/CS simultaneously, and 75.0% in 4 cases in whom IPM/CS was started before G-CSF. The difference was statistically not significant on the efficacy rates in the three groups. The efficacy in 18 cases treated with monotherapy on antibiotic was 72.2% and that in 12 cases treated with IPM/CS in combination with other antibiotics was 58.3%, and the difference in the efficacy rates in these two groups was not statistically significant. According to the neutrophil counts before and after the treatment, high response rate (60.0%) was obtained in cases of severe neutropenia (less than 100/mm3). Bacteriological examinations showed that all of bacteria detected as pathogens (10 strains of Gram-positive bacteria and 6 strains of Gram-negative bacteria) were eradicated, though 3 strains were replaced by other pathogens.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of imipenem/cilastatin (IPM/CS) therapy, flomoxef (FMOX) therapy and combined ceftazidime + aspoxicillin (CAZ/ASPC) therapy as initial therapies for chorioamnionitis were assessed clinically. 1. The subjects were 49 women with threatened abortion and 29 with premature rupture of membranes (PROM), complicated in all cases by chorioamnionitis. The inflammation was treated with IPM/CS in 19 patients, FMOX in 39, CAZ in 11, and CAZ/ASPC in 9. 2. The response rate to therapy for chorioamnionitis was 95.9% (47/49) in the threatened abortion group. Of the 49 patients in this group, 16 (32.7%) underwent premature labor. Of the therapies administered, IPM/CS tended to prevent premature labor more frequently than did any other therapy. The latent period (from rupture of membranes to delivery) was equal to or longer than 7 days in the PROM group. The percent prolongation of the latent period in these patients (55.5%) was significantly greater than that previously obtained with penicillin therapy. 3. The bacterial elimination rate was 50.9% (29/57). Of the 36 bacterial isolates, 66.7% were Gram-positive bacteria. The bacteriological efficacy rate was 89.7% (26/29). These results suggest that antibacterial agents effective against Gram-positive bacteria should be selected for treatment of chorioamnionitis, and that IPM/CS therapy is particularly useful considering the drug's good transfer into amniotic fluid and its antibacterial spectrum.

An 80-year-old blind man with lepromatous leprosy suffered from right femoral neck and humeral neck fractures on July 9, 1993. Because of fever (38.6 degrees C), difficult expectoration and diffuse bilateral perihilar infiltrates with consolidation in the left lower lung field on his chest radiograph, severe pneumonia was diagnosed. With intravenous hyperalimentation, imipenem/cilastatin (IPM/CS), ceftazidime, minocycline, gentamicin (GM), and human immunoglobulin were administrated. On July 29, hip screw-plate fixation was done. Citrobacter freundii was isolated from the sputum and its susceptibility was IPM/CS+, GM3+. Multi-drug therapy with GM and other antibiotics improved the patients' condition, but Citrobacter freundii were still detected and 43 days of medication were needed. According to a report by the Ministry of Health and Welfare in 1992, the resistance rate of IPM/CS against Citrobacter freundii is only 0.7%, and IPM/CS is more effective than beta-Lactams. This is a very rare case of severe pneumonia in an elderly patient caused by Citrobacter freundii that was suspected to have low susceptibility to IPM/CS.

Using the envelope method, we allocated 125 patients with infections accompanied by hematopoietic disorders into two groups treated with imipenem/cilastatin sodium (IPM/CS) at a daily dose of 1 g/1 g b.i.d. (group BID) or 0.5 g/0.5 g q.i.d. (group QID), and obtained the following results. 1. In group BID, ANLL was observed in 25 patients; ALL in 6; and NHL in 12. In group QID, ANLL was observed in 27 patients; ALL in 7; and NHL in 13. 2. In group BID, efficacy rates were 54.5% (6/11) in sepsis, 63.0% (17/27) in fever of undetermined origin and 50.0% (4/8) in pneumonia, thus the overall efficacy was 61.8% (34/55). In group QID, efficacy rates were 66.7% (4/6) in sepsis, 76.0% (19/25) in fever of undetermined origin and 35.7% (5/14) in pneumonia, thus the over all was 61.1% (33/54). No significant difference in response rates were observed between the two groups. 3. Bacteriologically, 22 bacterial strains were isolated in group BID and 21 21 strains, in group QID. The eradication rates after treatment with IPM/CS was 100% in group BID and 66.7% in group QID. 4. Side effects were observed in 8 patients in group BID and 3 in group QID. Laboratory examination revealed abnormal values in 9 patients in group BID and 6 in group QID. However, all of the side effects disappeared after the suspension or discontinuation of IPM/CS. The efficacies of IPM/CS therapy for severe infections in patients with hematopoietic disease were similar between 1 g/1 g b.i.d. and 0.5 g/0.5 g q.i.d. groups.

In the present study, we used the envelope method to divide patients with respiratory infections into two groups: a monotherapy group given imipenem/cilastatin sodium (IPM/CS) and a combination therapy group given imipenem/cilastatin sodium plus amikacin sulfate (AMK). We then compared the clinical efficacy and safety between groups. 1. Safety was evaluated in 83 patients in the IPM/CS group and 88 in the IPM/CS + AMK group while clinical efficacy was evaluated in 77 and 80 patients in the respective groups. 2. The overall efficacy rate was 84.4% in the IPM/CS group. Among the main infections, the efficacy rates were 82.7% in 52 cases of pneumonia (including lung abscess), 100% in cases of infected bronchiectasis, 66.7% in six cases of secondary infection of chronic respiratory disease, and 100% in four cases of chronic bronchitis. The overall efficacy rate was 83.8% in the IPM/CS + AMK group. Among the main infections, the efficacy rates were 88.1% in 59 cases of pneumonia (including lung abscess), 83.3% in 12 cases of infected bronchiectasis, and 60.0% in five cases of secondary infection of chronic respiratory disease. No significant differences in efficacies were seen between groups. 3. In the IPM/CS group, the efficacy rates were 92.3% for patients without prior antibiotic therapy in the IPM/CS group and 68.0% for those with prior therapy; in the IPM/CS + AMK group, the respective rates were 83.7% and 83.9%. In the IPM/CS group, there was a significant difference in the responses of patients with and without prior antibiotic therapy (P < 0.05). 4. Side effects were observed in six patients in the IPM/CS group (7.2%) and two patients in the IPM/CS + AMK group (2.3%). Abnormal laboratory test results were noted in 5 patients in the IPM/CS group (6.0%) and in 10 in the IPM/CS + f1p4group (11.4%). There was no significant difference in the incidence of side effects between groups and no severe adverse reactions in either group. These results indicate that IPM/CS alone produces of good response in moderate to severe respiratory infections while IPM/CS combined with AMK is useful in intractable respiratory infections.

We administered imipenem/cilastatin sodium (IPM/CS) to patients with gynecological infections as initial treatment and evaluated changes in blood interleukin 6 (IL-6) as an infection marker. 1. The subjects consisted of 7 patients with chorioamnionitis, 4 with intrauterine infections, and 1 with subcutaneous abscess. IPM/CS (1-2 g/day) was intravenously drip infused. This therapy was markedly effective in 1 patient and effective in 11; the response rate was 100%. 2. IL-6 generally began to decrease earlier than CRP. Before drug administration, correlations were observed between IL-6 and CRP (r = 0.946) between IL-6 and elastase (r = 0.355), and between elastase and CRP (r = 0.579). During the entire course, correlations were observed between IL-6 and CRP (r = 0.581), between IL-6 and elastase (r = 0.303), and between elastase and CRP (r = 0.776). These results suggest that blood IL-6 reflects early the pathologic state and treatment effects, and is a useful infection marker in gynecological infections.

We evaluated the effectiveness and safety of imipenem/cilastatin sodium (IPM/CS) in gynecological infections at gynecological departments at multiple institutions in Yamagata Prefecture. The subjects consisted of 64 patients with gynecological infections, 9 with urinary tract infections, and 21 with other infections. IPM/CS was intravenously drip infused at a dose of 1-2 g/day. The overall response rate was 97.9% (92/94); 96.9% (62/64) for gynecological infections, 100% (9/9) for urinary tract infections, and 100% (21/21) for other infections. Bacteriologically the response rate was 97.3% (36/37), and the eradication rate was 97% (32/33). As for subjective and objective side effects, only diarrhea was observed in 1 patient. Clinical laboratory examinations showed no abnormal values. These results suggest the usefulness of IPM/CS for gynecological infections.

The clinical and bacteriological efficacy of imipenem/cilastatin (IPM/CS) was evaluated in 30 cases of serious infections associated with hematological malignancies. 1. Among 28 evaluable cases, excellent efficacy was obtained in 6 cases and good effectiveness in 10 cases, resulting in a high clinical efficacy rate (57.1%). The clinical effectiveness of IPM/CS was not dependent on neutrophil count in peripheral blood. A 53.8% efficacy rate was observed in 26 cases which had received pretreatment with other antibiotics. 2. Antibacterial activities of IPM/CS have so far been evaluated against organisms isolated in 20 of 28 cases: 2 strains of coagulase-negative Staphylococcus, 2 strains of methicillin-resistant Staphylococcus aureus, 2 strains of Enterococcus faecalis, 9 strains of Enterobacter cloacae, and 8 other strains. 3. Among 3 evaluable cases treated with IPM/CS alone, response was good in 1 case. Among 25 patients receiving IPM/CS in combination with an aminoglycoside or a penicillin, the efficacy rate was 60%. 4. Five patients had IPM/CS-related adverse events; nausea and vomiting in 2 cases, seizures in 1 case, small increases in GOT and GPT in 2 cases, and the appearance of casts in urine sediment in 1 case. These patients, however, tolerated the complete course of therapy with IPM/CS except the 2 cases with nausea and vomiting. These results indicate that chemotherapy with IPM/CS is effective for the treatment of severe infectious diseases accompanied by hematological disorders.

A 40-year-old male with no history of underlying disease was admitted to Hokusho Central Hospital on May 25, 1991, complaining of high fever and headache. Physical examination on admission revealed a temperature of 38.5 degrees C, a pulse rate of 84 beat/min (relative bradycardia) and no abnormal findings for the chest or abdomen. Slight neck stiffness without Kernig's sign was observed at neurological examination. Laboratory data were: ESR 11 mm/lh, WBC 12000/mm3, C-reactive protein positive. Lumbar puncture showed an initial pressure of 230 mmH2O; CSF revealed a cell count of 2633/3 mm3 with mononuclear pleocytosis, total protein of 76 mg/dl and sugar of 54 mg/dl (CSF:blood glucose ratio 0.47). We initially suspected tuberculous or cryptococcal meningitis, but Campylobacter fetus subsp. fetus (C. fetus) was isolated from the CSF and venous blood on the 27th hospital day. IPM/CS 1 g/day, MINO 200 mg/day and FOM 4 g/day were intravenously administered. This antibiotic therapy was very effective: the patient was soon afebrile, and gradually all signs and symptoms were resolved. C. fetus was sensitive to IMP/CS, MINO, KM, GM, EM, OFLX, CP. The patient was discharged with no complication. He has eaten raw beef frequently before admission, but stool culture for C. fetus was negative.

Clinical efficacy of sodium imipenem/cilastatin was studied on 45 patients with complicated urinary tract infections, on whom prior antimicrobial agents were ineffective. A 0.5g dose of IPM/CS was administered by drop infusion twice a day for 5 days. The clinical efficacy was evaluated according to the criteria of the Japanese UTI committee. Of a total of 65 strains, 29 strains of gram positive bacteria and 36 strains of gram negative bacteria, were detected as causative microbials. Bacteriologically, 23 strains of gram positive bacteria (79%) and 34 strains of gram negative bacteria (94%) were eradicated following the treatment. S. aureus, E. faecalis and Flavobacterium sp. were less sensitive to IPM/CS. Overall clinical effectiveness rate of IPM/CS in the present study was 87%. Adverse drug side effects were observed in six patients, namely they were eruption, headache and slight elevation of serum transaminase. These findings suggest that IPM/CS is an effective agent for the treatment of complicated UTI even when the prior medicine was ineffective.

We evaluated the clinical efficacy and safety of intramuscular (as a new route of administration) imipenem/cilastatin sodium (IPM/CS) in patients with intrauterine infections which are typical in the field of obstetrics and gynecology. The obtained results are summarized as follows. 1. Twenty-seven patients were treated with IPM/CS, 250 mg/250 mg b.i.d. (3 patients), 500 mg/500 mg b.i.d. (22) and other dosages (a change in dosing regimen, 2). The duration of treatment ranged from 3 to 11 days and the total dosage during an entire course of treatment varied from 1.5 to 9.0 g. The drug was suspended in a lidocaine solution and administered in the gluteal muscle of the patients. 2. Clinical efficacies were excellent in 7 patients (26%), good in 19 (70%) and poor in 1 (4%) and the overall efficacy rate was 96.3%. All of the 8 patients who had not previously showed improvements with treatment by other antibiotics responded well to this drug. 3. Bacteriologically, the clinical efficacy rate was 95.8% (23/24) and the eradication rate was 76.2% (16/21). 4. No adverse effects due to the drug were observed. As abnormal laboratory test results, transient elevations of GOT and GPT were noted in one patient.

The efficacy and the safety of intramuscular imipenem/cilastatin sodium (IPM/CS) were evaluated in 22 patients with obstetric and gynecologic infections. 0.5 g/0.5 g of IPM/CS was suspended in a lidocaine solution and administered in the gluteal muscle twice a day for 3-7 days. Nineteen patients with intrauterine infections were evaluable for the clinical efficacy and 22 for the safety. 1. Clinical efficacies were excellent in 6 patients, good in 11 and poor in 2, and the efficacy rate was 89.5%. Thirteen out of 14 patients who had not responded to treatments with other previously administered antibiotics showed excellent or good responses to IPM/CS. 2. Causative bacteria were eradicated in 5 patients, decreased in 2, unchanged in 3 and replaced in 3, with an eradication rate of 61.5%. 3. Among 22 patients treated with IPM/CS, an eruption and general itching were observed in 1 patient, but no abnormal laboratory test values were observed.

A multi-center clinical study was carried out at the first Department of Surgery, Okayama University Medical School and its affiliated institutions to evaluate the efficacy and safety profiles of intramuscular imipenem/cilastatin sodium (IPM/CS) in surgical infections, which were mainly biliary tract infections and peritonitis. The following results were obtained: 1. The efficacy rate was 72.0% in a total of 25 evaluable patients and 81.8% in patients with cholecystitis. 2. The efficacy rates in patients with and without underlying diseases were 70.0% and 73.3%, respectively, and they were 71.4% in patients with mild or moderate infections and 75.0% in patients with severe infections. 3. Bacteriologically, the eradication rate was 100% for Gram-positive bacteria and 62.5% for Gram-negative bacteria, with an overall eradication rate of 78.6%. The eradication rate for monomicrobial infections was 71.4% and that for polymicrobial infections was 100%. 4. Out of 25 patients, one developed diarrhea as a drug-related adverse reaction, and laboratory abnormalities attributable to the treatment were observed in 5 patients. None of them was serious, however. 5. The overall usefulness rate was 60.0%, and the usefulness for cholecystitis (72.7%) was superior to that for cholangitis (33.3%).

Imipenem/cilastatin sodium (IPM/CS) was administered to a total of 67 patients with severe infections complicating hematological disorders and solid tumors. Fifty patients are included in the present analysis of efficacy and 64 in that of safety. 1. Out of 31 patients with hematological disorders, responses were excellent in 10 patients, good in 10 patients, and the efficacy rate was 64.5%. Out of 19 patients with solid tumors, responses were excellent in 8 patients, good in 8 patients and the efficacy rate was 84.2%. 2. For patients whose responses to other antibiotics had been poor, the efficacy rate was 59.3% in the group with hematological disorders and 62.5% in the group with solid tumors. 3. The relationship between the neutrophil count and efficacy was studied in the patients with hematological disorders. The efficacy rate for 8 patients whose neutrophil counts were 500/mm3 or less was 75.0%. 4. For the patients with hematological disorders, the efficacy rate for patients from whom causative organisms were isolated was 70.0% and that for patients for whom they were unknown was 61.9%. 5. Adverse reactions were observed in 3 patients and abnormal laboratory test results in 2 patients. However, they were mild and disappeared after discontinuation of this drug. From these results, IPM/CS is considered to be a useful antibiotic for the treatment of severe infections complicating hematological disorders and solid tumors.

Fifty-two patients with moderate or severe infections associated with internal medicine were treated with imipenem/cilastatin sodium (IPM/CS) and the efficacy and the safety of this drug were evaluated. There were 20 patients with pneumonia, 10 with acute exacerbation of chronic respiratory tract infections, 9 with sepsis, 2 with pyothorax, 3 with intraabdominal infection, 2 with urinary tract infection, 1 with pulmonary abscess, 1 with infective endocarditis, 4 with fever of unknown origin. Forty-four patients were evaluable for the efficacy. Clinical efficacies were excellent in 12 patients, good in 26, fair in 3 and poor in 3. The overall clinical efficacy was 86.4%. The efficacy rate was 63.6% in patients previously treated and 93.9% in patients previously untreated with other antibiotics. Bacteriologically, Staphylococcus aureus (8 strains), Streptococcus pneumoniae (5), Streptococcus pyogenes (1), other Gram-positive coccus (1), Klebsiella pneumoniae (8), Haemophilus influenzae (4), Pseudomonas aeruginosa (3), Serratia marcescens (3), Escherichia coli (3), Branhamella catarrhalis (1), Citrobacter freundii (1), Klebsiella oxytoca (1), Enterobacter sp. (1), and Peptostreptococcus sp. (1) were eradicated. P. aeruginosa (3) and Acinetobacter sp. (1) decreased. S. aureus (1), S. epidermidis (1), P. aeruginosa (5), and S. marcescens (1) persisted or appeared. The eradication rate was 83.7%. Six patients showed adverse reactions including general fatigue 1, epigastralgia 1, eruption 1, eosinophilia 1 and elevation of S-GOT 2. But all of the adverse reactions were mild or slight, and transient. These findings indicate that IPM/CS is a useful and safe drug against bacterial infections in internal medicine.

The safety and pharmacokinetics of imipenem/cilastatin sodium (IPM/CS) were evaluated in comparative studies using single intramuscular injection, intravenous infusion or multiple intramuscular administration. The studies were done employing 30 healthy volunteers. Adverse effects were observed in 5 of 18 volunteers in the single intramuscular dose study. One of them complained of mild itching and mild pain at the injection site, and the other 4 volunteers had mild pain at the injection sites. With the other methods of administration, no adverse effects were observed. No other abnormal physical findings nor abnormal laboratory test values were observed in any of the studies. Imipenem (IPM) was absorbed rather slowly through the muscles, resulting in a low maximum plasma concentration (Cmax) and a prolonged half life (T1/2) upon intramuscular injection compared to the results obtained upon intravenous infusion. The total areas under the curves obtained with these 2 methods were similar, however. Cilastatin (CS) was absorbed rapidly after intramuscular injection, and the Cmax obtained was higher than that obtained for IPM. The T1/2 and the AUC of CS obtained with intramuscular injection were similar to those obtained with intravenous infusion. Cumulative urinary recovery rates obtained with these 2 different routes of administration were not different. Detectable urinary levels of IPM were maintained much longer upon intramuscular injection than upon intravenous infusion. In the multiple dose study, neither IPM nor CS showed tendency to accumulate.