Beta-lactamase Inhibitor Combinations Research Articles

Risk Factors of Nosocomial Infection with Extended-Spectrum Beta-Lactamase-Producing Bacteria in a Neonatal Intensive Care Unit in China

To study risk factors of neonatal nosocomial infection caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria in a neonatal intensive care unit (NICU). A retrospective cohort study was conducted in a university hospital NICU in south China. Medical records of neonatal nosocomial infection caused by Escherichia coli or Klebsiella pneumoniae were reviewed. Twenty-two neonates infected with ESBL-producing bacteria (case patients) were compared with 17 patients infected with non-ESBL producing strains (controls). Univariable and multivariable logistic regression were performed to analyze risk factors for infection with ESBL-producing strains. The spectrum of antimicrobial resistance of ESBL-positive E. coli or K. pneumoniae was also examined. Both univariable and multivariable logistic regression analysis revealed that preterm low birth weight, prolonged mechanical ventilation (> or = 7 days) and prior use of third-generation cephalosporins were risks factors for ESBL-producing E. coli or K. pneumoniae infection (p < 0.05), with an odd ratio of 6.43 (95% CI: 1.51-27.44; p = 0.017), 7.50 (95% CI: 1.38-40.88; p = 0.017) and 9.00 (95% CI: 1.65-49.14; p = 0.008) respectively. However, the length of hospital stay before isolation of pathogens, endotracheal intubation, presence of a central venous catheter, days on third-generation cephalosporins and prior use of beta-lactamase inhibitors were not statistically significant (p > 0.05). Resistance of ESBL-positive strains to piperacillin, tobramycin, aztreonam and cephalosporins was significantly higher than that of ESBL-negative ones (p < 0.05). ESBL-producing strains appeared susceptible to carbapenem, fluoroquinolones, and beta-lactamase inhibitor combination piperacillin-tazobactam. Preterm low birth weight, prolonged mechanical ventilation and prior use of third-generation cephalosporins are risks factors for nosocomial infection with ESBL-producing bacteria in NICU.

Control of extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae in a children's hospital by changing antimicrobial agent usage policy

This ambidirectional intervention study was performed to examine the impact of a change in antibiotic policy on extended-spectrum beta-lactamase (ESBL) prevalence in a children's hospital with a high prevalence of ESBL production among Escherichia coli and Klebsiella pneumoniae. The use of extended-spectrum cephalosporins was restricted and use of beta-lactam/ beta-lactamase inhibitor combinations was encouraged from 2002. All strains of E. coli and K. pneumoniae isolated from sterile body fluids from 1999 to 2005 were analysed for beta-lactamase production and the prevalences of ESBL production were compared at three periods; pre-intervention (1999-2001), transitional period (2002-03) and post-intervention (2004-05). Comparing the pre- and post-intervention periods, overall piperacillin/tazobactam use increased from 2.2 to 108.0 days on antibiotics/1000 patient admission days/year (AD) (P for trend < 0.001), whereas extended-spectrum cephalosporin use decreased from 175.0 to 96.9 AD (P for trend < 0.001). Among 252 strains of E. coli (n = 128) and K. pneumoniae (n = 124), the overall prevalence of ESBL producers decreased from 39.8% (41/103) to 22.8% (18/79) (P for trend = 0.018). This decreasing trend of ESBL production was more evident for K. pneumoniae (64.1% to 25.6%; P for trend < 0.001) than E. coli (25.0% to 19.4%; P for trend = 0.514). The mortality rates of invasive disease caused by E. coli or K. pneumoniae remained unchanged. The substitution of piperacillin/tazobactam for extended-spectrum cephalosporins successfully decreased the prevalence of ESBL production of K. pneumoniae and E. coli in an institute for children where ESBLs were endemic. The impact of change in antibiotic policy was more evident in K. pneumoniae than E. coli.

Tazobactam is a potent inactivator of selected inhibitor-resistant class A beta-lactamases.

The beta-lactam beta-lactamase inhibitor combinations (ampicillin/clavulanate, ampicillin/sulbactam, ticarcillin/clavulanate and piperacillin/tazobactam) were tested against selected inhibitor-resistant class A beta-lactamases of the TEM and OHIO-1 varieties. Minimum inhibitor concentrations (MIC) revealed that the Escherichia coli DH5 alpha transconjugate strains that possessed the OHIO-1 beta-lactamase, Met69Ile mutant of the OHIO-1 beta-lactamase, TEM-30 (Arg244Ser) and TEM-31 (Arg244Cys) beta-lactamase were most susceptible to piperacillin and piperacillin/tazobactam. Kinetic experiments with each beta-lactamase demonstrated that tazobactam was 10-25-fold more potent than clavulanate or sulbactam against TEM-30 and TEM-31 beta-lactamase. Tazobactam was also as effective as clavulanate against the Met69Ile mutant of the OHIO-1 beta-lactamase. Among the clinically available beta-lactams and beta-lactamase inhibitors, piperacillin/tazobactam appears to be the most potent combination against selected inhibitor-resistant strains of TEM and OHIO-1 beta-lactamase.

Risk factors associated with extended-spectrum β-lactamase-producing organisms at a tertiary care hospital

In 1995, beta-lactam inhibitor combinations replaced third-generation cephalosporins as empirical therapy in an effort to manage extended-spectrum beta-lactamase (ESBL) resistance. This study investigated the relationship between antibiotic usage and ESBL organisms from 1994 through 2002 using epidemiological and molecular analysis. A case-control study of 119 patients with ESBL organisms and 132 patients with non-ESBL organisms was conducted. Demographics, co-morbidities, device utilization and antibiotic use were analysed for all patients and infected patients only (cases = 75, controls = 83). Both exposure and degree of exposure (in grams) to antibiotics were included. A dot blot hybridization technique was used to identify genes in plasmid extracts from the ESBL organisms. Ventilator days OR 1.1 (1.06, 1.15) P < 0.001, adult respiratory distress syndrome (ARDS) OR 3.1 (1.0, 9.7) P = 0.05, prior aminoglycoside use OR 2.7 (1.2, 6.1) P = 0.02, prior third-generation cephalosporin use OR 7.2 (2.6, 20) P < 0.001, and prior trimethoprim/sulfamethoxazole use OR 8.8 (3.1, 26) P < 0.001 were significantly associated with ESBL organisms by multivariate analysis. All models were concordant with a significant association of ventilator days, third-generation cephalosporins and trimethoprim/sulfamethoxazole with ESBL organisms. beta-Lactamase inhibitor combinations were not associated with ESBL organisms. Hybridization of plasmid extracts demonstrated that 95% of the ESBL organisms carried intI1, a mobile DNA element with a sulphonamide-resistance (R) gene and a frequent carrier of other R factors. Genes for specific types of trimethoprim-R and aminoglycoside-R were present in 26% and 40% of the extracts, respectively. These data indicate that, besides patient risk factors and third-generation cephalosporins, other antibiotics may provide selective pressures in maintaining ESBL organisms due to multiple resistance genes on plasmids. beta-Lactamase inhibitor combinations appear to be an acceptable substitute to third-generation cephalosporins in strategies to control ESBL organisms.

An epidemiological study of the susceptibility and frequency of multiple-drug-resistant strains of Pseudomonas aeruginosa isolated at medical institutes nationwide in Japan

The susceptibility of 3233 strains of Pseudomonas aeruginosa, isolated primarily in 2001, as agents of infection at 37 medical institutes with various specialties in seven regions of Japan (ranging from Hokkaido to Kyushu/Okinawa), to 18 antipseudomonal agents known to be active against P. aeruginosa was evaluated, in accordance with the National Committee for Clinical Laboratory Standards (NCCLS) guidelines. Of the 18 antipseudomonal agents, including some combinations of beta-lactamase inhibitors and antibacterial agents, ciprofloxacin had the lowest minimum inhibitory concentration (MIC)(50) (0.25 microg/ml) against P. aeruginosa, followed by meropenem, with an MIC(50) of 0.5 microg/ml. The MIC(50) of 7 of the examined antibacterial agents (ceftazidime, cefozopran, imipenem, biapenem, gentamicin, tobramycin, and levofloxacin) was between 1 and 2 microg/ml. Among the antipseudomonal agents tested, tobramycin showed the lowest MIC(90) (2 microg/ml), which was not significantly different from its MIC(50) (1 microg/ml). The MIC(90) of the other antibacterial agents examined ranged from 8 to 64 microg/ml and more. The susceptibility of the 3233 strains to the 12 antibacterial agents covered by the NCCLS guidelines was determined according to the standard method of the NCCLS guidelines. The frequency of strains resistant to meropenem, gentamicin, or tobramycin was relatively low (7.5%-8.3%). The frequency of strains showing intermediate to severe resistance to tobramycin was particularly low (8.0%). The frequency of strains resistant to aztreonam, imipenem, or levofloxacin was 16.7%-19.0%, about twice as high as the frequency of strains resistant to tobramycin. The susceptibility pattern of the 3233 strains (isolated from seven regions of Japan) to five antibacterial agents (ceftazidime, piperacillin, imipenem, gentamicin, and ciprofloxacin) was evaluated in relation to the regions from which they were isolated. The MIC(50) values of these antibacterial agents did not differ significantly among the regions. However, the MIC(90) values of ceftazidime and gentamicin were higher for strains isolated from the Kansai region than for strains isolated from other regions. The MIC(90) of ciprofloxacin was higher for strains isolated from the Tohoku, Kansai, and Kyushu/Okinawa regions than for strains isolated from other regions. Of the 3233 strains, 89 were classified as multiple-drug-resistant (imipenem, gentamicin, and ciprofloxacin) strains. Of these 89 strains, 42 were isolated from urine, 17 from sputum or pharyngeal mucus, 13 from pus, 8 from blood, 1 from cerebrospinal fluid, and 8 from other specimens. The frequency of multiple-drug-resistant strains was higher among strains isolated from the Tohoku and Kansai regions than in strains isolated from other regions.

Antibiotic Resistance in two Water Reclamation Systems for Space Applications

The purpose of this research was to evaluate the antibiotic resistance in two water reclamation systems developed from space missions. The first system is a small-scale water reclamation system operated at Johnson Space Center designed to reclaim wastewater during long-term space missions. The second system was a scaled-down version of the Johnson Space Center system operated at Texas Tech University. Antibiotic resistance patterns to 10 antibiotics were investigated before and after controlled doses of amoxicillin were added to the water reclamation systems. The results of this study indicate that bacteria in all systems were resistant to many antibiotics including beta-lactam antibiotics and a beta-lactam, beta-lactamase inhibitor combination, amoxicillin with clavulanic acid.

Tazobactam Inactivation of SHV-1 and the Inhibitor-resistant Ser130 → Gly SHV-1 β-Lactamase: INSIGHTS INTO THE MECHANISM OF INHIBITION

The increasing number of bacteria resistant to combinations of beta-lactam and beta-lactamase inhibitors is creating great difficulties in the treatment of serious hospital-acquired infections. Understanding the mechanisms and structural basis for the inactivation of these inhibitor-resistant beta-lactamases provides a rationale for the design of novel compounds. In the present work, SHV-1 and the Ser(130) --> Gly inhibitor-resistant variant of SHV-1 beta-lactamase were inactivated with tazobactam, a potent class A beta-lactamase inhibitor. Apoenzymes and inhibited beta-lactamases were analyzed by liquid chromatography-electrospray ionization mass spectrometry (LC-ESI/MS), digested with trypsin, and the products resolved using LC-ESI/MS and matrix-assisted laser desorption ionization-time of flight mass spectrometry. The mass increases observed for SHV-1 and Ser(130) --> Gly (+ Delta 88 Da and + Delta 70 Da, respectively) suggest that fragmentation of tazobactam readily occurs in the inhibitor-resistant variant to yield an inactive beta-lactamase. These two mass increments are consistent with the formation of an aldehyde (+ Delta 70 Da) and a hydrated aldehyde (+ Delta 88 Da) as stable products of inhibition. Our results reveal that the Ser --> Gly substitution at amino acid position 130 is not essential for enzyme inactivation. By examining the inhibitor-resistant Ser(130) --> Gly beta-lactamase, our data are the first to show that tazobactam undergoes fragmentation while still attached to the active site Ser(70) in this enzyme. After acylation of tazobactam by Ser(130) --> Gly, inactivation proceeds independent of any additional covalent interactions.

Febrile neutropenia and Fusobacterium bacteremia: clinical experience with 13 cases.

To assess the disease spectrum of Fusobacterium bacteremia in our neutropenic patients and review the literature. This was a 6.5-year retrospective study in which all the records of neutropenic patients with Fusobacterium bacteremia were analyzed. Fusobacterium bacteremia was found in 13 neutropenic patients, 10 with hematological malignancies and 3 with solid tumors. The standard clinical presentation was that of primary bacteremia with benign evolution under antibiotics with anaerobic coverage. Most patients presented with oral mucositis as the probable portal of entry. Coinfection with other germs was documented in four patients. No patient had a localized infection documented. Most patients were receiving ciprofloxacin chemoprophylaxis. None of the patients had catheter-related infection. All tested strains were susceptible to all standard anaerobic agents. Fusobacterium spp. were responsible for 5% of bacteremias in neutropenic patients in our hospital during the last 6.5 years. Fusobacterium bacteremia is a possible cause of febrile neutropenia, especially in the setting of quinolone prophylaxis and oral mucositis after intense chemotherapeutic regimens. We think that its benign outcome if there is no localized infection detected does not justify the use of antianaerobic prophylaxis. Combination of beta-lactams and beta-lactamase inhibitors is a safe and reasonable treatment.

Antibiotics in otorhinolaryngology practice

This study investigated utilization of antibacterial agents at the Ear, Nose and Throat Department of the Outpatient Service of the Health Center Novi Sad-Liman and at the Ear, Nose and Throat Clinic of the Clinical Center Novi Sad, in the period February-March 2001. All antibacterial agents were classified as group J, regarding Anatomic-Therapeutic-Chemical Classification. Data on drug utilization were presented in Defined Daily Doses (DDD). Patients who were under observation were all treated with antibiotics. In regard to prescribed treatment in the Ear, Nose and Throat Department of the Outpatient Service of the Health Center Novi Sad-Liman, most outpatients were treated with macrolide antibiotics--in 26.21%; combination of penicillin and beta-lactamase inhibitors in 20.83% and pyranosides in 16.12%. At the Ear, Nose and Throat Clinic of the Clinical Center Novi Sad, macrolides and lincosamines were most frequently used--in 20.46%; cephalosporins in 19.87% and penicillins susceptible to beta-lactamase in 18.85%. It is extremely positive and in agreement with current pharmacotherapeutic principles that in both institutions peroral ampicillins have not been prescribed. Aminoglycosides have been prescribed in less than 1% of patients of the Ear, Nose and Throat Department of the Outpatient Service of the Health Center Novi Sad-Liman, whereas they were much more frequently prescribed at the Ear, Nose and Throat Clinic of the Clinical Center Novi Sad--in 11.25%. Although there is a positive postantibiotic effect in regard to these antibiotics and it is recommended to use them once a day, in both examined institutions aminoglycosides were given twice a day. In regard to bacterial identification it was done in 80.76% of patients of the Ear, Nose and Throat Department of the Outpatient Service of the Health Center Novi Sad-Liman, while in the Ear, Nose and Throat Clinic of the Clinical Center Novi Sad it was done only in 32.42%. Although treatment performed on empirical basis and clinical findings is usually correct, a greater percentage of antibiotic prescriptions should be confirmed by antibiograms providing optimal therapy and decreased degree of resistance.

Antimicrobial resistance with Streptococcus pneumoniae: much ado about nothing?

During the past decade in the United States, Streptococcus pneumoniae has changed dramatically in the context of antimicrobial resistance. Resistance to multiple different antibiotic classes including beta-lactams (penicillins, cephalosporins, and beta-lactamase inhibitor combinations), macrolides, clindamycin, the tetracyclines, chloramphenicol, and trimethoprim-sulfamethoxazole (TMP/SMX) has emerged at high rates with this important respiratory tract pathogen. There is no question that the in vitro activity of these antimicrobial agents is substantially lower for many strains of S. pneumoniae than it was even a few years ago. The larger question is, however, what does this decrease in activity mean from a clinical perspective? Stated another way, does resistance defined according to current standards in the laboratory, translate into diminished effectiveness when these agents are used to treat patients with pneumococcal infections? It is this question that serves as the principal basis for this review.

Beta-lactamase-inhibitor combinations in the 21st century: current agents and new developments.

Combinations of beta-lactams and beta-lactamase inhibitors have become one of the most successful antibacterial strategies in our global battle against bacterial infections. The success of these agents is particularly emphasized by the continued efficacy of Augmenting (amoxicillin and clavulanate) after nearly 20 years of clinical use. The clinical situation now dictates that second-generation beta-lactamase inhibitors capable of encompassing both class A and class C beta-lactamases would combat emerging resistance and provide a vital addition to our armory of hospital antibiotics. This realization has generated a renewed interest in beta-lactamase inhibitors and improved the prospects for the delivery of such agents in the future.

Amoxicillin-sulbactam: A clinical and therapeutic review.

Combinations of beta-lactamase inhibitors with penicillins, especially aminopenicillins, have broad-spectrum antibacterial activity against most of the common pathogens of the respiratory and urinary tracts. This means that they are an ideal treatment for infections such as otitis media, sinusitis, special cases of pharyngeal tonsillitis (recurring forms, indirect pathogenic action, or after the failure of amoxicillin monotherapy), acute exacerbations of chronic bronchitis, cystitis, urethritis, etc. The amoxicillin-sulbactam combination is active against both beta-lactamase producer and nonproducer strains, and is effective against Gram-positive cocci (Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus of nonhospital origin), Gram-negative cocci (Neisseria gonorrhoeae, Moraxella catarrhalis and others), Gram-negative bacilli (nonhospital strains of Haemophilus influenzae, Escherichia coli and Klebsiella pneumoniae and others) and anaerobes. Its antimicrobial activity means that it is indicated in the treatment of respiratory, ear, nose and throat, urinary, dermatological and gynecological infections caused by susceptible germs, as well as in a variety of surgical situations (both as a treatment and as prophylaxis). It is absorbed very well orally, and its pharmacokinetic profile is very favorable, with very good tissue penetration. It is reasonably well tolerated: in a variable percentage of cases it may cause modification of intestinal transit and/or fecal consistency, which usually abates spontaneously. The new formulation for administration at intervals of 12 h is easier to use, is better tolerated and favors completion of therapy. In summary, the amoxicillin-sulbactam combination is effective and well tolerated in most infections of nonhospital origin in adults and children. (c) 2001 Prous Science. All rights reserved.

Treatment options for extended-spectrum beta-lactamase-producers.

A review of antibiotic options for the treatment of infections caused by extended-spectrum beta-lactamase-producing isolates is presented. The use of the third-generation cephalosporin, cefotaxime, for infections caused by isolates producing ceftazidimase-type extended-spectrum beta-lactamases is controversial, despite in vitro susceptibility to the antibiotic in many instances. The fourth-generation cephalosporin, cefipime, although active against most extended-spectrum beta-lactamases, is reported to show a marked inoculum effect. The cephamycins, such as cefoxitin. are generally effective against Enterobacteriaceae producing TEM- and SHV-derived extended-spectrum beta-lactamases, but Klebsella pneumoniae strains are prone to cephamycin resistance as a result of porin loss. The use of beta-lactamase inhibitor combinations is variable. Sulbactam is less effective than clavulanate for the inhibition of SHV-derived extended-spectrum beta-lactamases and a marked inoculum effect has been noted, while the efficacy of tazobactam against SHV-derived extended-spectrum beta-lactamase producers is controversial. Furthermore, extended-spectrum beta-lactamases are often encoded by multi-resistant plasmids carrying genes conferring resistance to aminoglycosides, chloramphenicol, sulfonamides, trimethoprim and other antimicrobials, severely limiting even alternative therapies. Extensive susceptibility testing before the institution of antibiotic therapy is thus vital.

In vivo efficacies of combinations of beta-lactams, beta-lactamase inhibitors, and rifampin against Acinetobacter baumannii in a mouse pneumonia model.

The effects of various regimens containing combinations of beta-lactams, beta-lactam inhibitor(s), and rifampin were assessed in a recently described mouse model of Acinetobacter baumannii pneumonia (M. L. Joly-Guillou, M. Wolff, J. J. Pocidalo, F. Walker, and C. Carbon, Antimicrob. Agents Chemother. 41:345-351, 1997). Two aspects of the therapeutic response were studied: the kinetics of the bactericidal effect (treatment was initiated 3 h after intratracheal inoculation, and bacterial counts were determined over a 24-h period) and survival (treatment was initiated 8 h after inoculation, and the cumulative mortality rate was assessed on day 5). Two clinical strains were used: a cephalosporinase-producing strain (SAN-94040) and a multiresistant strain (RCH-69). For SAN-94040 and RCH-69, MICs and MBCs (milligrams per liter) were as follows: ticarcillin, 32, 64, 256, and >256, respectively; ticarcillin-clavulanate, 32, 64, and 512, and >512, respectively; imipenem, 0.5, 0.5, 8, and 32, respectively; sulbactam, 0.5, 0.5, 8, and 8, respectively; and rifampin, 8, 8, 4, and 4, respectively. Against SAN-94040, four regimens, i.e., imipenem, sulbactam, imipenem-rifampin, and ticarcillin-clavulanate (at a 25/1 ratio)-sulbactam produced a true bactericidal effect (>/=3-log10 reduction of CFU/g of lung). The best survival rate (i.e., 93%) was obtained with the combination of ticarcillin-clavulanate-sulbactam, and regimens containing rifampin provided a survival rate of >/=65%. Against RCH-69, only regimens containing rifampin and the combination of imipenem-sulbactam had a true bactericidal effect. The best survival rates (>/=80%) were obtained with regimens containing rifampin and sulbactam. These results suggest that nonclassical combinations of beta-lactams, beta-lactamase inhibitors, and rifampin should be considered for the treatment of nosocomial pneumonia due to A. baumannii.

Antibiotic policy: a tool for controlling resistance of hospital pathogens.

Multiresistant Gram-negative bacilli, including strains of Klebsiella pneumoniae, Enterobacter spp, Acinetobacter baumannii and Pseudomonas aeruginosa, resistant to broad spectrum beta-lactams, aminoglycosides and fluoroquinolones, are recovered at increasing frequency from patients suffering from nosocomial infections, particularly from those receiving intensive care. The emergence and spread of resistant pathogens to endemic and epidemic levels has frequently been related in time and place to the intensive use of antibiotics to which these microorganisms have developed resistance, notably third generation cephalosporins and fluoroquinolones. Recent investigations have indicated that the prevalence of resistance can be reduced by scheduled changes of empiric treatment regimens, involving discontinuation of intensively prescribed drugs and substitution with newly introduced antibiotics of another class to which the prevalent resistant strains remain susceptible. Among these drugs, penicillins---beta-lactamase inhibitor combinations, 'fourth generation' cephalosporins and, where little used previously, fluoroquinolones, have been introduced successfully in high risk units where ceftazidime-resistant strains of K.pneumoniae, Enterobacter and Citrobacter spp or glycopeptide-resistant enterococci had become highly prevalent. However, these studies do not demonstrate a direct causal relationship between changes in prescribing practices and ecological improvements, because their observational design cannot be controlled. In most studies, several important factors influencing the dynamics of resistance were not monitored and the relative contribution of decreased emergence versus control of cross-transmission to the improved susceptibility rates is not clear. We propose that additional long-term studies are required to better track the ecological impact and to determine the optimal modalities of programmed changes of antibiotic prescribing as an antibiotic resistance prevention or control strategy.

Haemophilus influenzae and Moraxella catarrhalis from patients with community-acquired respiratory tract infections: antimicrobial susceptibility patterns from the SENTRY antimicrobial Surveillance Program (United States and Canada, 1997).

Between February and June of 1997, a large number of community-acquired respiratory tract isolates of Haemophilus influenzae (n = 1,077) and Moraxella catarrhalis (n = 503) from 27 U.S. and 7 Canadian medical centers were characterized as part of the SENTRY Antimicrobial Surveillance Program. Overall prevalences of beta-lactamase production were 33.5% in H. influenzae and 92.2% in M. catarrhalis with no differences noted between isolates recovered in the United States and those from Canada. Among a total of 21 different antimicrobial agents tested, including six cephalosporins, a beta-lactamase inhibitor combination, three macrolides, tetracycline, trimethoprim-sulfamethoxazole (TMP-SMX), rifampin, chloramphenicol, five fluoroquinolones, and quinupristin-dalfopristin, resistance rates of > 5% with H. influenzae were observed only with cefaclor (12.8%) and TMP-SMX (16.2%).

Moraxella catarrhalis: clinical significance, antimicrobial susceptibility and BRO beta-lactamases.

Moraxella catarrhalis is an important pathogen of humans. It is a common cause of respiratory infections, particularly otitis media in children and lower respiratory tract infections in the elderly. Colonisation of the upper respiratory tract appears to be associated with infection in many cases, although this association is not well understood. Nosocomial transmission is being increasingly documented and the emergence of this organism as a cause of bacteremia is of concern. The widespread production of a beta-lactamase enzyme renders Moraxella catarrhalis resistant to the penicillins. Cephalosporins and beta-lactamase inhibitor combinations are effective for treatment of beta-lactamase producers, and the organism remains nearly universally susceptible to the macrolides, fluoroquinolones, tetracyclines and the combination of trimethoprim and sulfamethoxazole. Two major beta-lactamase forms, BRO-1 and BRO-2, have been described on the basis of their isoelectric focusing patterns. The BRO-1 enzyme is found in the majority of beta-lactamase-producing isolates and confers a higher level of resistance to strains than BRO-2. The BRO enzymes are membrane associated and their production appears to be mediated by chromosomal determinants which are transmissible by an unknown mechanism. The origin of these novel proteins is unknown.

Scope and limitations of antimicrobial therapy of sepsis in surgery.

The goal of antibiotic therapy for surgical sepsis is to kill bacteria that intermittently or continuously reach the bloodstream from the residue of an operatively treated focus. While sepsis and conditions leading to sepsis compromise the immune system, antibiotics may become a fundamental determinant of the host's defense. No data from sound prospective randomized clinical antibiotic trials dealing with sepsis are available. Therefore we tested the hypothesis that treatment recommendations can be based on pharmacodynamics comparing in vitro activity of commonly used antimicrobials with concentrations sustained in vivo to provide for full coverage for bacteria of concern. The application of strict criteria for antibiotic choice to avoid selection of primary resistant strains reveals that most commonly used antibiotics render insufficient activity to eliminate pathogens that commonly cause surgical sepsis. Antibiotics that sustain in vivo concentration exceeding fourfold the MIC100 (highest minimal inhibitory concentration for all (100%) species tested) of Escherichia coli, for example, are 400 mg ciprofloxacin IV (MIC100 of 1224 strains=0.06 mg/dl, in vivo concentration=1 mg/dl for 12 h), and 1000 mg imipenem/cilastatin (MIC100 of 3142 strains=0.14 mg/dl, in vivo concentration=2 mg/dl for 6 h). The third choice is one of the fourth- or, less convincingly, third-generation cephalosporins. Similar data for most pathogens causing sepsis are provided. First- and second-generation cephalosporins and penicillin beta-lactamase inhibitor combinations generally do not achieve sufficient concentrations to cover the most important pathogens of sepsis. Sepsis is defined as a whole body's inflammatory response that is characterized by systemic signs and symptoms secondary to a focal infection. While many antibiotic trials have dealt with a focal infection, no prospective randomized antibiotic trial has dealt with sepsis per se. Antibiotic trials on focal infections generally exclude patients when their focal infection has progressed to sepsis. To circumvent the lack of controlled clinical trials we show that pharmacodynamics may provide sound foundation for antibiotic choice for sepsis.

Antimicrobial resistance patterns of Bacteroides fragilis group organisms in Korea.

Antimicrobial resistance patterns of 913 clinical isolates of Bacteroides fragilis group organisms were monitored during an 8-year period in Korea. In general the resistance rates of the non-fragilis B. fragilis group species were higher than those of B. fragilis for all the drugs tested. The rate of resistance to clindamycin remarkably increased and those to some beta-lactam drugs such as piperacillin and cefotaxime also increased. No isolates were found to be resistant to imipenem, metronidazole, or chloramphenicol. beta-lactam and beta-lactamase inhibitor combinations and cefoxitin were more active than the other beta-lactams. Therefore, these agents may be considered when empirical selection of antimicrobial agents is required to treat severe anaerobic infections.

Non-inducible, mainly cell-associated beta-lactamase from Nocardia asteroides strain 108.

The beta-lactamase of the soil-borne strain 108 (parental strain) of Nocardia asteroides is a non-inducible enzyme mainly associated with the cells; it can be efficiently extracted by ultrasonication and SDS treatment. Crude enzyme preparations showed penicillinase and cephalosporinase activity. The kinetics of beta-lactamase production and in-vitro susceptibility to combinations of beta-lactam antibiotics plus beta-lactamase inhibitors have been studied in two stable overproducer mutants (A14 and B1) obtained by mutagenization of the parental strain with nitrosoguanidine. The cell-associated enzyme increased with bacterial growth in parental and mutant strains and was particularly abundant in stationary phase cells. The beta-lactamase inhibitors sulbactam and clavulanic acid decreased MIC values of penicillins more efficiently in the parental strain than in mutants, thus indicating some involvement of the enzyme in the resistance of N. asteroides strain 108 to beta-lactam antibiotics.