Presence Of Beta-lactamase Research Articles

Resistance genomics and molecular epidemiology of high-risk clones of ESBL-producing Pseudomonas aeruginosa in young children.

The emergence of multidrug-resistant Pseudomonas aeruginosa poses a global threat, but the distribution and resistance profiling are unclear, especially in young children. Infections due to P. aeruginosa are common, associated with high mortality, and increasingly β-lactam drug resistant. We studied the molecular epidemiology and antibiotic resistance mechanisms in 294 clinicalisolates of P. aeruginosa from a pediatric hospital in China. Non-duplicate isolates were recovered from clinical cases and were identified using an API-20 kit followed by antimicrobial susceptibility testing using the VITEK®2 compact system (BioMerieux, France) and also by broth dilution method. In addition, a double-disc synergy test for the ESBL/E-test for MBL was performed. The presence of beta-lactamases, plasmid types, and sequence types was determined by PCR and sequencing. Fifty-six percent (n = 164) of the isolates were resistant to piperacillin-tazobactam, followed by cefepime (40%; n = 117), ceftazidime (39%; n = 115), imipenem (36%; n = 106), meropenem (33%; n = 97), and ciprofloxacin (32%; n = 94). Forty-two percent (n = 126) of the isolates were positive for ESBL according to the double-disc synergy test. The blaCTX-M-15 cephalosporinase was observed in 32% (n = 40/126), while 26% (n = 33/126) werepositive for blaNDM-1 carbapenemase. Aminoglycoside resistance gene aac(3)IIIawas observed in 16% (n = 20/126), and glycylcyclines resistance gene tet(A) was observed in 12% (n = 15/126) of the isolates. A total of 23 sequence types were detected, including ST1963 (12%; n = 16), followed by ST381 (11%; n = 14), ST234 (10%; n = 13), ST145 (58%; n = 10), ST304 (57%; n = 9), ST663 (5%; n = 7), and a novel strain. In ESBL-producing P. aeruginosa, 12 different Incompatibility groups (Inc) were observed, the most common being IncFI, IncFIS, and IncA/C. The MOBP was the most common plasmid type, followed by MOBH, MOBF, and MOBQ. Our data suggest that the spread of antibiotic resistance is likely due toclonal spread and dissemination of different clinical strains of P. aeruginosa harbouring different plasmids. This is a growing threat in hospitals particularly in young children which needs robust prevention strategies.

Characterization of Genus Proteus Isolated from Various Clinical Specimens and Detection of Extended-Spectrum β-Lactamase Production

Background: Among Gram-negative bacteria, the presence of beta-lactamases is a defined modality of resistance to antibiotics of the beta-lactam group. Proteus species also has been showing various degrees of resistance to these groups of antibiotics and thereby appearing multidrug resistant. The aim of our study was to know the occurrence of Proteus species from different clinical samples their antibiotic susceptibility, extended-spectrum β-lactamase (ESBL) production, and the associated patient risk factors. Materials and Methods: This observational descriptive study was done from December 2020 to December 2021. All Proteus isolates obtained from various clinical samples, were biochemically identified, antibiogram, and screening for ESBL production was done using a combination of cefotaxime and cefotaxime clavulanic acid antibiotic discs. Results: Seventy-nine Proteus isolates were obtained from hospitalized patients. In that, Proteus mirabilis was the most common isolate followed by Proteus vulgaris. Proteus infections were common in the age groups of 41–60 years and males were affected more than females. Out of the 79 Proteus isolates 12 were ESBL producers. Among these, 25% of ESBL producers were P. mirabilis and 75% of them were P. vulgaris. Conclusion: The most common isolate was P. mirabilis among hospitalized patients and P. vulgaris was the main ESBL producers when compared to P. mirabilis. These pathogens mainly caused wound and urinary tract infections. The patient age groups ranged mainly from 49–60 years. Diabetes mellitus was the most significant risk factor in these Proteus infections.

Allergic Reactions and Cross-Reactivity Potential with Beta-Lactamase Inhibitors.

Although beta-lactam allergies are an emerging focus of stewardship programs and interventions, less is publicly released regarding allergies to beta-lactamase inhibitors. This review presents and evaluates the data regarding allergic reactions with beta-lactamase inhibitors. Clavulanate, sulbactam, and tazobactam are beta-lactam-based beta-lactamase inhibitors that are combined with several penicillins or cephalosporins in order to preserve antimicrobial activity in the presence of beta-lactamases. Avibactam, relebactam, and vaborbactam are non-beta-lactam beta-lactamase inhibitors that are combined with cephalosporins or carbapenems in order to expand the antimicrobial activity against broader-spectrum beta-lactamases. Case reports document hypersensitivity reactions to clavulanate, sulbactam, and tazobactam, but not to avibactam, relebactam, or vaborbactam. Based on these reports and considering the chemical structures, cross-allergenicity with beta-lactams is likely with sulbactam and tazobactam. Considering the slightly altered beta-lactam structure, cross-allergenicity is less likely with clavulanate, but still possible. It appears that cross-allergenicity between beta-lactam antimicrobials and the newer, non-beta-lactam beta-lactamase inhibitors is unlikely. It is important for clinicians to perform allergy testing to both the beta-lactam and the beta-lactamase inhibitor in order to confirm the specific allergy and reaction type.

Naturally Evolving Extended Spectrum Cephalosporin Resistance in Soil Borne Isolates of Enterobacteriaceae

Soil is the richest natural source of antibiotic producing bacteria as well as for the development of resistance against the produced antibiotics or their residues. The present study was performed to assess the presence of beta lactamase among environmental isolates obtained from soil from regions with history of selective pressure due to human activity as well as from regions with no anthropogenic activity. A total of 64 isolates of family Enterobacteriaceae were obtained from the soil samples from different sites of Shillong, Meghalaya. Antimicrobial susceptibility was performed by Kirby-Bauer disc diffusion method. All the isolates were subjected to phenotypic detection of AmpC beta-lactamases and extended spectrum beta lactamases (ESBLs). Multiplex PCR targeting ESBL genes (blaTEM, blaCTX-M, blaSHV, blaOXA-2, blaOXA-10 and blaGES) and AmpC genes (blaMOX, blaCIT, blaDHA, blaACC, blaEBC and blaFOX) was performed for detection of the genes responsible for the extended spectrum cephalosporin resistance. Phenotypically ESBL production was obtained in 5/64 (7.8 %) and AmpC beta-lactamase was detected in 9/64 (14.0 %) isolates. In three isolates (Escherichia coli and Citrobacter koseri) variant of blaCTX-M gene were found to be responsible for the resistance to extended spectrum cephalosporins. Two CTX-M harboring isolates also displayed resistance to amikacin. All the five ESBL producing isolates were obtained from soil of forest region which remains undisturbed by the human activities. Thus the study provides the evidence for the presence of extended spectrum cephalosporin resistance in the soil irrespective of its exposure to anthropogenic activities. It reveals the natural phenomena of resistance development in soil microbiota.

Phenotypic and molecular characterization of clinical isolates of Acinetobacter baumannii isolated from Delhi, India.

BackgroundAcinetobacter has gained importance as a multi-drug resistant and hence a difficult to treat pathogen. This study was done to characterize our isolates with respect to drug resistance and presence of beta-lactamases which is a major mechanism of resistance and to type using RAPD and MLST so that comparison of our clones can be made with the existing international clones.Methods100 isolates recovered from clinical samples from two hospitals in Delhi were tested for their susceptibility against major groups of antimicrobials. The resistant isolates were screened and confirmed phenotypically for presence of ESBL, MBL and AmpC and MBLs also by PCR. The isolates were typed by RAPD and MLST.ResultsOut of the 100 isolates, 91, 78 and 2 % were MDR, XDR and PDR respectively. 97, 100 and 85 were screen positive for ESBL, AmpC and MBL respectively. Of these, 38.1 % were confirmed phenotypically to produce ESBL, 99 % produced AmpC and 29.4 % produced MBL comprising of GIM, VIM, SIM and IMP. MLST showed known STs 110, 188, 146, 69, 103, 108 and 194. Eight new STs were encountered. The RAPD showed a high degree of genetic variability among the isolates.ConclusionMajority of our isolates were MDR, producing one or more types of beta-lactamases. We encountered drug resistant international clones by MLST which are found in other continents there by confirming their spread to Indian sub continent. No data on ST types of other Indian isolates is available in the MLST database and hence comparison is not possible.

Ongoing spread of colistin-resistant Klebsiella pneumoniae in different wards of an acute general hospital, Italy, June to December 2011

We describe polyclonal spread of colistin-resistant Klebsiella pneumoniae in an acute general hospital in Italy. Between June and December 2011, 58 colistin-resistant K. pneumoniae isolates were recovered from 28 patients admitted to different wards, but mainly in the intensive care units. All isolates were tested for drug susceptibility and the presence of beta-lactamase (bla) genes. Clonality was investigated by repetitive extragenic palindromic (rep)-PCR and multilocus sequence typing (MLST). Fifty-two isolates had minimum inhibitory concentrations (MICs) for colistin of 6-128 mg/L, carried bla(KPC3) and were attributed to sequence type ST258. The remaining six isolates were susceptible to carbapenems, exhibited MICs for colistin of 3-32 mg/L, and belonged to two different types, ST15 and ST273. Rep-PCR included all isolates in three clusters, one containing all ST258 KPC-3-producing isolates and two containing ST15 and ST273 isolates.Cross-transmission containment measures and intensification of staff and environmental hygiene could not stop the outbreak. Selective pressure and horizontal transmission probably contributed to emergence and spread of three different strains of colistin-resistant K. pneumoniae in the hospital. Strict implementation of the above measures and a wider awareness of the antimicrobial resistance threat are crucial to preserve the last therapeutic options of the multidrug-resistant Gram-negative infections.

Susceptibilidad antimicrobiana y bases genéticas de la resistencia de cepas de Enterococcus causantes de infecciones en Cuba

To identify infection-causing Enterococcus species in Cuban hospitals and determine their susceptibility to antimicrobial drugs, as well as their resistance mechanisms. A total of 687 Enterococcus isolates from 30 Cuban hospitals in nine provinces of the country were studied over the period 2000-2009. The species were identified using both the conventional method and the automatic API(®) system. The minimum inhibitory concentration was determined for 13 antimicrobial drugs following the standards recommended by the Clinical Laboratory and Standards Institute. The polymerase chain reaction technique was used to characterize the genes that were resistant to aminoglycosides, erythromycin, tetracycline, and glucopeptides. The presence of beta-lactamase was determined by the chromogenic cephalosporin test. The most prevalent species were Enterococcus faecalis (82.9%) and E. faecium (12.2%). Resistance to glucopeptides (1.0%) was mediated by the vanA and vanB genes. The strains resistant to ampicillin (6%) did not produce beta-lactamases. A high percentage of resistance to aminoglycosides was observed. Gentamicin (31.0%) and streptomycin and amikacin (29.1%) were mediated by the aac(6')Ie-aph(2")Ia, aph(3')-IIIa, ant(6)Ia, and ant(3")(9) genes. A correlation was found between resistance to tetracycline (56.0%) and presence of the tet(M) (75.1%) and tet(L) genes (7.0%), while resistance to erythromycin (34.1%) was due to the erm(B) gene (70.9%). Resistance to vancomycin is infrequent in Cuba, as opposed to a high level of resistance to aminoglycosides, which may be indicative of treatment failures. The microbiology laboratory is a cornerstone of Enterococcus infection surveillance, along with ongoing monitoring of the susceptibility of these infections to antimicrobial drugs at a time when resistance of this microorganism is on the rise.

Staphylococcus lugdunensis: um olhar diferenciado no laboratório clínico

Os estafilococos coagulase negativos (ECNs) sao cocos Gram-positivos usualmente considerados contaminantes em laboratorios de microbiologia clinica. Apesar de pertencer a este grupo, Staphylococcus lugdunensis pode causar infeccoes complicadas, como endocardites, infeccoes de pele e tecidos moles, osteomielites, entre outras. Alem da formacao de biofilmes, apresenta patogenicidade similar ao Staphylococcus aureus. E um dos principais agentes causadores de endocardites, com taxa de mortalidade de ate 70%. Pode ser confundido com S. aureus quando se utilizam testes rapidos para sua identificacao, como a pesquisa de clumping factor, no caso de teste de coagulase em lâmina, ou em testes de aglutinacao direta em latex. Pode ser facilmente identificado por meio de provas bioquimicas acessiveis, como a presenca de atividade da ornitina descarboxilase e pirrolidonil arilamidase (PYR). Apresenta sensibilidade a maioria dos agentes antimicrobianos, devendo ser pesquisada rotineiramente a presenca de betalactamases e do gene mecA por meio de testes com cefalosporina cromogenica e suscetibilidade a cefoxitina, respectivamente. Convem salientar que os criterios interpretativos utilizados para avaliar a sensibilidade a cefoxitina sao os mesmos preconizados para S. aureus e diferentes dos utilizados para os outros ECNs. Apesar de incomum, o S. lugdunensis e um patogeno com acentuada virulencia que deve ser corretamente identificado, pois raramente podera ser considerado contaminante quando isolado de sitios estereis.

Activity of mecillinam against Escherichia coli resistant to third-generation cephalosporins

To assess the activity of mecillinam against two groups of Escherichia coli: (i) a selection of international isolates with mechanisms of resistance caused by the presence of defined beta-lactamases; and (ii) isolates resistant to third-generation cephalosporins referred from across Wales. Antibiotic susceptibility testing with mecillinam, meropenem, amoxicillin, co-amoxiclav, cefotaxime, piperacillin/tazobactam, ciprofloxacin, nitrofurantoin, trimethoprim and gentamicin was performed using the BSAC agar dilution method against 30 international strains of E. coli with known beta-lactamase presence. Antibiotic susceptibility testing with mecillinam using the same method was performed against 325 regional isolates of E. coli resistant to third-generation cephalosporins. The susceptibility results showed that the only antibiotics to which the 30 international isolates were consistently susceptible were mecillinam (100%) and meropenem (100%), irrespective of the presence of beta-lactamases. Of the local isolates, 93.5% (304/325) were susceptible to mecillinam, having MICs < 8 mg/L. Our results show that mecillinam has excellent in vitro activity against a range of E. coli exhibiting beta-lactamase activity, some with the production of multiple beta-lactamases. It is time to further evaluate the clinical utility of mecillinam in the treatment of infections caused by such organisms.

Prevalence and type distribution of human papillomavirus infection in women from Datong, China

This survey of 931 cervical specimens in women from Datong, China indicates that the overall human papillomavirus (HPV) prevalence was 18.6%, and the most prevalent high-risk HPV types were 16, 58, 18, 52 and 33. This study demonstrates the epidemiology of HPV infection in Datong and the potential impact of vaccination in this region.

Evaluation of Multidrug Resistant (MDR) Isolates Against Tigecycline: A Canadian Perspective

 Tigecycline's MIC 90 of 1 mcg/mL was comparable to imipenem and 2 to 64 fold better than the beta-lactams, betalactam/beta-lactamase inhibitor combinations and levofloxacin against all Enterobacteriaceae tested.  Tigecycline demonstrated potent in vitro activity against both ESBL and non-ESBL producing E. coli, K. oxytoca and K. pneumoniae.  Tigecycline showed potent activity against A. baumannii with low MIC 50/90 values of 0.25 and 1 mcg/mL, respectively.  Tigecycline's limited activity against P. aeruginosa is similar to other tetracyclines and their analog derivatives.  Tigecycline showed potent inhibitory activity against S. aureus regardless of methicillin-resistant phenotype.  At 0.12 mcg/mL tigecycline had the lowest MIC 90 value of all comparative agents against both vancomycinsensitive and -resistant strains of E. faecium and E. faecalis.  Tigecycline presented a MIC 90 value of 0.5 mcg/mL against H. influenzae and was unaffected by the presence of beta-lactamase.  The in vitro activity of tigecycline in this study suggests that tigecycline is a promising compound in the treatment of serious infections caused by the most commonly encountered nosocomial and community acquired pathogens. BACKGROUND

Emergence of ArmA and RmtB aminoglycoside resistance 16S rRNA methylases in Belgium

16S rRNA methylase-mediated high-level resistance to aminoglycosides has been reported recently in clinical isolates of Gram-negative bacilli only from a limited number of countries. This study was conducted to investigate the occurrence of this type of resistance in clinical isolates of Enterobacteriaceae from two Belgian hospitals and the characteristics of the strains. We screened for high-level gentamicin, tobramycin and amikacin resistance in clinical isolates of Enterobacteriaceae consecutively collected between 2000 and 2005 at two laboratories by PCR for the armA, rmtA and rmtB 16S rRNA methylase genes. The beta-lactamase presence in the strains was also determined by phenotypic and genotypic methods. Overall armA genes were detected in 18 Klebsiella pneumoniae, Escherichia coli, Enterobacter aerogenes, Enterobacter cloacae and Citrobacter amalonaticus whereas rmtB was detected in a single E. coli isolate. The rmtA gene was not found. All 16S rRNA methylase-bearing strains produced extended-spectrum beta-lactamases (ESBLs), predominantly type CTX-M-3, as well as various types of beta-lactamases. In the majority of the strains, the armA gene was carried by conjugative plasmids of the IncL/M incompatibility group whereas rmtB was borne by an IncFI plasmid. This is the first report of the emergence of 16S rRNA methylases in Enterobacteriaceae in Belgium. The rapid spread of multidrug-resistant isolates producing both ESBLs and 16S rRNA methylases raises clinical concern and may become a major therapeutic threat in the future.

DISSEMINATION OF SALMONELLA ENTERICA SEROTYPE AGONA AND MULTIDRUG-RESISTANT SALMONELLA ENTERICA SEROTYPE TYPHIMURIUM IN CUBA

The molecular epidemiology, antimicrobial susceptibility, and mechanisms of resistance of 34 Salmonella spp. strains causing acute gastroenteritis, isolated from different provinces in Cuba, were determined. Sixty-four percent of the strains showed multiresistance. Salmonella typhimurium was the most frequent with 15 strains (44%), 13 of which belonged to phagotype 104 and presented similar genetic profiles of pulsed field gel electrophoresis. High levels of resistance to tetracycline (53%), spectinomycin (50%), ampicillin (44%), and chloramphenicol (41%) were found. Resistance to tetracycline was associated with the tet G and tet A genes. Resistance to ampicillin was caused by the presence of beta-lactamases, mainly the CARB type. The floR gene was the main mechanism of resistance to chloramphenicol. Our results showed an antimicrobial susceptible clone of Salmonella enterica serotype Agona in two separate regions. This is the first report of the widespread dissemination of a multiresistant clone of S. enterica serotype Typhimurium definitive phage type 104 in Cuba.

Detection and assay of beta-lactamases in clinical and non-clinical strains of Yersinia enterocolitica biovar 1A.

To detect beta-lactamases (A & B) and extended-spectrum beta-lactamases (ESBLs) in clinical and non-clinical isolates of Yersinia enterocolitica biovar 1A, and to determine their activity in the presence of specific lactamase inhibitors. The presence of beta-lactamases and ESBLs was detected by disc diffusion in 219 (36 clinical, 183 non-clinical) isolates. beta-Lactamase activity was assayed spectrophotometrically in all 36 clinical and 10 representative non-clinical isolates using nitrocefin as the substrate. Inhibition of beta-lactamases was studied by clavulanic acid, aztreonam and cloxacillin. Of the 219 isolates, all except two non-clinical isolates indicated the presence of beta-lactamase A (Bla-A) based on the smaller (2-8 mm) radius of the inhibition zone around the ticarcillin disc. Synergy between ticarcillin and co-amoxiclav discs was, however, observed in only 34% of isolates of non-clinical origin. beta-Lactamase B (Bla-B) was found to be consistently positive among all the clinical and non-clinical isolates, as indicated by its characteristic appearance of flattening of the zone of inhibition around the cefotaxime disc adjacent to an imipenem disc. Bla-B was induced more strongly in clinical than in non-clinical isolates. Inhibition of enzyme A by clavulanic acid, aztreonam and cloxacillin was found to be similar, whereas enzyme B was inhibited more strongly by aztreonam and cloxacillin. None of the isolates showed the unequivocal presence of ESBL. This is the first report on beta-lactamases of Yersinia enterocolitica biovar 1A from Asia. Y. enterocolitica biovar 1A expressed both Bla-A and Bla-B. Heterogeneity was, however, discerned in the expression of Bla-A and by induction of Bla-B among clinical and non-clinical isolates of Y. enterocolitica biovar 1A.

Resistencia a quinolonas y betalactámicos en Salmonella enterica, y su relación con mutaciones en las topoisomerasas, alteraciones en la permeabilidad celular y expresión de un mecanismo de expulsión activa

The mechanisms of resistance to fluoroquinolones and beta-lactams were studied in isolates of Salmonella enterica resistant to both antimicrobial groups, isolated over time from two patients treated with fluoroquinolones. The clonal relationships among the various strains was established by serotyping and pulsed-field gel electrophoresis. MICs for beta-lactams, quinolones, chloramphenicol and tetracycline were determined. Presence of beta-lactamases was ruled out by a colorimetric assay. Quinolone resistance-determining regions of the gyrA, gyrB, parC, and parE genes were sequenced, and the relevance of the mutations in these regions was evaluated by complementation assays. Outer membrane protein profiles, the effect of phenylalanyl-arginyl-naphthylamide (PAN, 20 mg/l) on the MICs of several quinolones, and norfloxacin accumulation in the absence and in the presence of a metabolic inhibitor were also determined. The following mutations were found: gyrA (Asp87 --> Gly; Ser83 --> Phe; Asp87 --> Lys), gyrB (Ser463 --> Phe) and parC (Glu84 --> Gly). Altered outer membrane protein profiles, including decreased expression of a porin equivalent to OmpF from Escherichia coli was observed. Active efflux of norfloxacin was proved in both a clinical isolate and a mutant obtained in vitro. In the presence of PAN, nalidixic acid MICs decreased 4-32 times (except in one strain), pefloxacin MICs decreased 4-16 times for 5 out of 9 evaluated strains, and MICs of both norfloxacin and ciprofloxacin did not change or changed within a single dilution step. Quinolone-resistance is the consequence of a combination of mutations in topoisomerase-encoding genes, altered permeability and active efflux. Altered permeability and active efflux would also contribute to decreased susceptibility to beta-lactams.

Efficacy of cefpodoxime in the prophylaxis of recurrent pharyngotonsillitis

Background: Recurrent acute pharyngotonsillitis remains a common illness in children and young adults and can lead to serious complications if not treated. cefpodoxime proxetil is a second-generation oral cephalosporin, which shows potent antibacterial activity against both Gram-positive and Gram-negative bacteria and high stability in the presence of beta-lactamases. Objective: We aimed to evaluate the efficacy of second-generation cephalosporins in the prophylaxis of recurrent pharyngotonsillitis in children. Methods: A total of 180 children aged between 4 and 14 years with recurrent pharyngotonsillitis were randomized to receive either cefpodoxime proxetil (100 mg twice a day, 6 days a month for 6 months) or placebo (at the same dosage). Results and conclusions: Our results show that treatment with cefpodoxime proxetil may be effective in reducing symptoms of recurrent pharyngotonsillitis and preventing recurrences without causing side effects or developing bacterial resistance.

Efficacy of cefpodoxime in the prophylaxis of recurrent pharyngotonsillitis

Background: Recurrent acute pharyngotonsillitis remains a common illness in children and young adults and can lead to serious complications if not treated. Cefpodoxime proxetil is a second-generation oral cephalosporin, which shows potent antibacterial activity against both Gram- and Gram-negative bacteria and high stability in the presence of beta-lactamases. Objective: We aimed to evaluate the efficacy of second-generation cephalosporins in the prophylaxis of recurrent pharyngotonsillitis in children. Methods: A total of 180 children aged between 4 and 14 years with recurrent pharyngotonsillitis were randomized to receive either cefpodoxime proxetil (100 mg twice a day, 6 days a month for 6 months) or placebo (at the same dosage). Results and conclusions: Our results show that treatment with Cefpodoxime proxetil may be effective in reducing symptoms of recurrent pharyngotonsillitis and preventing recurrences without causing side effects or developing bacterial resistance.

Conditionally cleavable radioimmunoconjugates: a novel approach for the release of radioisotopes from radioimmunoconjugates.

One of the limitations of therapy with radiolabeled monoclonal antibodies (mAbs) is that significant toxicities can arise from circulating non-tumor-bound radiolabeled conjugate. Here, we describe a new method to reduce systemic radiation exposure from radiolabeled mAbs involving the attachment of the radioisotope through a linker that can be cleaved by an administered enzyme. To demonstrate the feasibility of this approach, we prepared a conditionally cleavable radioimmunoconjugate (RIC) composed of (131)I-labeled cephalosporin conjugated to Tositumomab, a mAb against the CD20 antigen. The cleavable RIC bound antigen identically to directly iodinated antibody, and in the presence of beta-lactamase, about 80-85% of the radioisotope was released. In vivo studies in mice revealed that the cleavable RIC and the directly iodinated anti-CD20 antibody had similar biodistribution patterns. Systemically administered beta-lactamase induced a 2-3-fold decrease in the percent injected dose (ID) of the cleavable RIC/g of blood, marrow, spleen, lung, and liver 1 h after enzyme treatment, and a 4-6-fold decrease 20 h after enzyme treatment. This was accompanied by a 20-fold increase in % ID/g in urine 1 h after enzyme treatment, indicating that the released radiolabel was rapidly excreted through the kidneys. In mice with human tumor xenografts, there was no decrease in the %ID/g in tumor 1 h after enzyme treatment, but by 4 h after enzyme injection, decreases in tumor radioactive content began to diminish the targeting advantage. These studies demonstrate that the cleavable RIC substrate is able to bind to tumor antigens and localize within human tumor xenografts and that accelerated systemic clearance can be induced with beta-lactamase.

In vitro and In vivo activities of LB 10827, a new oral cephalosporin, against respiratory pathogens.

The in vitro antibacterial activities of LB 10827, a new oral cephalosporin, against common respiratory tract pathogens were compared with those of six beta-lactams (cefdinir, cefuroxime, cefprozil, penicillin G, amoxicillin-clavulanate, and ampicillin), two quinolones (trovafloxacin and ciprofloxacin), and one macrolide (clarithromycin). The MIC of LB 10827 at which 90% of the penicillin-resistant strains of Streptococcus pneumoniae tested were inhibited was 0.5 microg/ml, and the drug was 4- to 32-fold more active than the compared beta-lactams. The potent activity of LB 10827 against Haemophilus influenzae and Moraxella catarrhalis was retained, and the presence of beta-lactamase in both strains had little effect on the in vitro activity of the compound. Time-kill studies revealed that LB 10827 had bactericidal activity against these respiratory pathogens. This agent reduced original counts of all pathogens tested by >/=3 log(10) CFU/ml at the MIC, and the regrowth was completely prevented for 12 h. The potent in vitro antibacterial activity of LB 10827 against respiratory pathogens has been proved in both mouse pneumonia and neutropenic rat models. These results strongly suggest that this agent has potential for the treatment of respiratory tract infections.

Antimicrobial resistance with focus on oral beta-lactamases.

Over the last 10-15 yr antibiotic resistance has increased in the oral microflora. The beta-lactam antibiotics, i.e., penicillins and cephalosporins, are the most frequently used antimicrobial agents. Unfortunately, the efficiency of these drugs is increasingly being challenged by the emergence of resistant bacteria, which is mainly due to their production of beta-lactamases. In this paper, mechanisms of antibiotic resistance are reviewed, with emphasis on beta-lactamases. This review also discusses how the presence of beta-lactamases in oral microorganisms may affect the treatment of oral diseases. Dentists can influence the emerging global crisis of antibiotic resistance by carefully evaluating the indications for antibiotic treatment. General guidelines for when and how to use antibiotics in dentistry are reviewed.