cilastatin--imipenem-drug-combination and panipenem-betamipron

In this review, we summarize the current "state of the art" of carbapenem antibiotics and their role in our antimicrobial armamentarium. Among the β-lactams currently available, carbapenems are unique because they are relatively resistant to hydrolysis by most β-lactamases, in some cases act as "slow substrates" or inhibitors of β-lactamases, and still target penicillin binding proteins. This "value-added feature" of inhibiting β-lactamases serves as a major rationale for expansion of this class of β-lactams. We describe the initial discovery and development of the carbapenem family of β-lactams. Of the early carbapenems evaluated, thienamycin demonstrated the greatest antimicrobial activity and became the parent compound for all subsequent carbapenems. To date, more than 80 compounds with mostly improved antimicrobial properties, compared to those of thienamycin, are described in the literature. We also highlight important features of the carbapenems that are presently in clinical use: imipenem-cilastatin, meropenem, ertapenem, doripenem, panipenem-betamipron, and biapenem. In closing, we emphasize some major challenges and urge the medicinal chemist to continue development of these versatile and potent compounds, as they have served us well for more than 3 decades.

Topics: Anti-Bacterial Agents; beta-Alanine; beta-Lactams; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Doripenem; Drug Combinations; Ertapenem; Humans; Imipenem; Thienamycins

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.

Topics: Adult; Aged; beta-Alanine; Body Temperature; C-Reactive Protein; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Administration Schedule; Drug Combinations; Female; Humans; Imipenem; Leukocyte Count; Meropenem; Middle Aged; Parametritis; Thienamycins

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.

Topics: Anti-Bacterial Agents; beta-Alanine; Cilastatin; Cilastatin, Imipenem Drug Combination; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Combinations; Drug Therapy, Combination; Fasciitis, Necrotizing; Humans; Imipenem; Male; Middle Aged; Minocycline; Thienamycins; Thoracic Wall; Tomography, X-Ray Computed

Topics: Bacteria; Bacterial Infections; beta-Alanine; Carbapenems; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Administration Schedule; Drug Combinations; Drug Resistance, Bacterial; Humans; Imipenem; Meropenem; Thienamycins; Treatment Failure

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.

Topics: Adult; Aged; Anemia, Hemolytic, Autoimmune; Anti-Bacterial Agents; beta-Alanine; Brain Abscess; Cefotaxime; Cilastatin; Cilastatin, Imipenem Drug Combination; Drainage; Drug Combinations; Drug Therapy, Combination; Female; Humans; Imipenem; Immunocompromised Host; Lupus Erythematosus, Systemic; Male; Middle Aged; Minocycline; Nocardia Infections; Postoperative Care; Thienamycins; Trimethoprim, Sulfamethoxazole Drug Combination

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.

Topics: Bacteria; Bacterial Infections; beta-Alanine; Carbapenems; Ceftazidime; Cilastatin; Cilastatin, Imipenem Drug Combination; Drug Combinations; Drug Resistance, Bacterial; Humans; Imipenem; Meropenem; Thienamycins

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.

Topics: Administration, Oral; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Anti-Inflammatory Agents, Non-Steroidal; beta-Alanine; Biphenyl Compounds; Cefazolin; Cilastatin; Cilastatin, Imipenem Drug Combination; Ciprofloxacin; Convulsants; Drug Combinations; Drug Interactions; Enoxacin; Fleroxacin; Fluoroquinolones; Imipenem; Injections, Intravenous; Injections, Intraventricular; Male; Mice; Mice, Inbred ICR; Norfloxacin; Oxazines; Penicillin G; Quinolones; Seizures; Thienamycins

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.

Topics: 4-Quinolones; Ampicillin; Animals; Anti-Bacterial Agents; Anti-Infective Agents; beta-Alanine; Ceftazidime; Ceftriaxone; Cilastatin; Cilastatin, Imipenem Drug Combination; DNA Topoisomerase IV; Dose-Response Relationship, Drug; Drug Combinations; Female; Fluoroquinolones; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Imipenem; Infusions, Intravenous; Male; Meropenem; Methicillin Resistance; Mice; Microbial Sensitivity Tests; Oxazines; Rats; Thienamycins; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors

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.

Topics: Ampicillin; Animals; beta-Alanine; Cefozopran; Ceftriaxone; Cephalosporins; Cilastatin; Cilastatin, Imipenem Drug Combination; Disease Models, Animal; Drug Combinations; Drug Resistance; Imipenem; Male; Meropenem; Mice; Mice, Inbred Strains; Penicillin Resistance; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Thienamycins; Vancomycin