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PubMed1985

Emergence of resistance to beta-lactam antibiotics in Pseudomonas aeruginosa during treatment with new beta-lactams.

In 12 patients treated with cefsulodin for Pseudomonas aeruginosa infections, resistance to cefsulodin developed in the infecting strains of two patients who failed to improve clinically. In both cases, cross-resistance also appeared for a broad spectrum of new antipseudomonal beta-lactams, except imipenem. The resistant isolate from one patient had a new constitutive beta-lactamase for cephalothin which also had modest activity for cefsulodin, ceftazidime, and carbenicillin. Furthermore, all of the non-hydrolyzed beta-lactams appeared to be bound by a beta-lactamase in this isolate. The origin and role in beta-lactam resistance of the observed beta-lactamase activity are obscure. The resistant isolate from the other patient had no demonstrable beta-lactamase activity that could account for the beta-lactam resistance. In five patients treated with imipenem for P. aeruginosa infections, resistance to imipenem developed in the strains of two patients who failed to improve clinically. The strain from one patient was already resistant to all other antipseudomonal beta-lactams before imipenem therapy. The initial strain from the other patient was broadly susceptible, and it developed resistance only to imipenem. Prior to imipenem therapy, another patient, who had P. aeruginosa endocarditis, had isolates from blood with three different susceptibility patterns: susceptible to all antipseudomonal beta-lactams, resistant to all but imipenem, and resistant to imipenem alone. There was no demonstrable beta-lactamase activity to account for imipenem resistance in any of the isolates in these patients. None of the resistant P. aeruginosa isolates had a change in penicillin-binding proteins from those of their susceptible counterparts that might explain the development of resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

Intestinal uptake of dipeptides and beta-lactam antibiotics. I. The intestinal uptake system for dipeptides and beta-lactam antibiotics is not part of a brush border membrane peptidase.

The uptake of beta-lactam antibiotics into small intestinal enterocytes occurs by the transport system for small peptides. The role of membrane-bound peptidases in the brush border membrane of enterocytes from rabbit and pig small intestine for the uptake of small peptides and beta-lactam antibiotics was investigated using brush border membrane vesicles. The enzymatic activity of aminopeptidase N was inhibited by beta-lactam antibiotics in a non-competitive manner whereas dipeptidylpeptidase IV was not affected. The peptidase inhibitor bestatin led to a strong competitive inhibition of aminopeptidase N whereas the uptake of cephalexin into brush border membrane vesicles was only slightly inhibited at high bestatin concentrations (greater than 1 mM). Modification of brush border membrane vesicles with the histidine-modifying reagent diethyl pyrocarbonate led to a strong irreversible inhibition of cephalexin uptake whereas the activity of aminopeptidase N remained unchanged. A modification of serine residues with diisopropyl fluorophosphate completely inactivated dipeptidylpeptidase IV whereas the transport activity for cephalexin and the enzymatic activity of aminopeptidase N were not influenced. With polyclonal antibodies raised against aminopeptidase N from pig renal microsomes the aminopeptidase N from solubilized brush border membranes from pig small intestine could be completely precipitated; the binding protein for beta-lactam antibiotics and oligopeptides of apparent Mr 127,000 identified by direct photoaffinity labeling with [3H]benzylpenicillin showed no crossreactivity with the aminopeptidase N anti serum and was not precipitated by the anti serum. These results clearly demonstrate that peptidases of the brush border membrane like aminopeptidase N and dipeptidylpeptidase IV are not directly involved in the intestinal uptake process for small peptides and beta-lactam antibiotics and are not a constituent of this transport system. This suggests that a membrane protein of Mr 127,000 is (a part of) the uptake system for beta-lactam antibiotics and small peptides in the brush border membrane of small intestinal enterocytes.

Affinity Labels↗

PubMed1990

Intestinal absorption of dipeptides and beta-lactam antibiotics. II. Purification of the binding protein for dipeptides and beta-lactam antibiotics from rabbit small intestinal brush border membranes.

By photoaffinity labeling of brush border membrane vesicles from rabbit small intestine with photoreactive derivatives of beta-lactam antibiotics and dipeptides, a binding protein for dipeptides and beta-lactam antibiotics with an apparent molecular weight of 127,000 was labeled. The labeled 127 kDa polypeptide could be solubilized with the non-ionic detergents Triton X-100, n-octyl glucoside or CHAPS. If the vesicles were solubilized prior to photoaffinity labeling, no clear incorporation of radioactivity into the 127 kDa polypeptide occurred indicating a loss of binding ability upon solubilization. By affinity chromatography of solubilized brush border membrane proteins on an agarose wheat germ lectin column, the binding protein for dipeptides and beta-lactam antibiotics of Mr 127,000 was retained on the column. With N-acetyl-D-glucosamine the photolabeled binding protein for beta-lactam antibiotics and dipeptides was eluted together with the brush border membrane-bound enzyme aminopeptidase N. Separation from aminopeptidase N and final purification was achieved by anion-exchange chromatography on DEAE-sephacel. Polyclonal antibodies against the purified binding protein were raised in guinea pigs. The photolabeled 127 kDa protein could be precipitated from solubilized brush border membranes with these antibodies. Incubation of brush border membrane vesicles with antiserum prior to photoaffinity labeling significantly reduced the extent of labeling of the 127 kDa protein. Treatment of brush border membrane vesicles with antiserum significantly inhibited the efflux of the alpha-aminocephalosporin cephalexin from the brush border membrane vesicles compared to vesicles treated with preimmune serum. These studies indicate that the binding protein for dipeptides and beta-lactam antibiotics of apparent molecular weight 127,000 in the brush border membrane of rabbit small intestinal enterocytes is directly involved in the uptake process of small peptides and orally active beta-lactam antibiotics across the enterocyte brush border membrane.

Affinity Labels↗

PubMed1989

Lactivicin, a naturally occurring non-beta-lactam antibiotic having beta-lactam-like action: biological activities and mode of action.

Lactivicin is moderately active against a wide range of Gram-negative bacteria and highly active against Gram-positive bacteria. It shows various biological activities commonly observed with beta-lactam antibiotics, such as higher activity against beta-lactam hypersensitive mutants than against their parents, sensitivity to beta-lactamases, inhibitory activity against beta-lactamases and ability to induce beta-lactamase activity. The primary lethal target of lactivicin in Escherichia coli is highly likely to be penicillin-binding protein (PBP) 1; lactivicin strongly lysed E. coli cells with induction of spheroplasts at its MIC, and showed high affinity for PBPs 1A and 1B. At concentrations above x 5 MIC, however, lactivicin dominantly exhibited secondary antibacterial action possibly owing to inhibition of crucial SH proteins engaged in the fundamental membrane functions. In contrast, against Bacillus subtilis, lactivicin showed the typical beta-lactam action under a wide range of concentrations. It showed high affinity for PBPs 1, 2 and 4, the possible lethal targets of beta-lactam antibiotics in this organism. In conclusion, lactivicin is the first non-beta-lactam antibiotic showing beta-lactam action through binding to PBPs.

Anti-Bacterial Agents↗

PubMed2001

Kinetics of beta-lactam interactions with penicillin-susceptible and -resistant penicillin-binding protein 2x proteins from Streptococcus pneumoniae. Involvement of acylation and deacylation in beta-lactam resistance.

Kinetic interactions of beta-lactam antibiotics such as penicillin-G and cefotaxime with normal, penicillin-susceptible PBP2x from Streptococcus pneumoniae and a penicillin-resistant PBP2x (PBP2x(R)) from a resistant clinical isolate (CS109) of the bacterium have been extensively characterized using electrospray mass spectrometry coupled with a fast reaction (quench flow) technique. Kinetic evidence for a two-step acylation of PBP2x by penicillin-G has been demonstrated, and the dissociation constant, K(d) of 0.9 mm, and the acylation rate constant, k(2) of 180 s(-1), have been determined for the first time. The millimolar range K(d) implies that the beta-lactam fits to the active site pocket of the penicillin-sensitive PBP rather poorly, whereas the extremely fast k(2) value indicates that this step contributes most of the binding affinity of the beta-lactam. The values of K(d) (4 mm) and k(2) (0.56 s(-1)) were also determined for PBP2x(R). The combined value of k(2)/K(d), known as overall binding efficiency, for PBP2x(R) (137 m(-1) s(-1)) was over 1000-fold slower than that for PBP2x (200,000 m(-1) s(-1)), indicating that a major part is played by the acylation steps in penicillin resistance. Most of the decreased binding efficiency of PBP2x(R) comes from the decreased ( approximately 300-fold) k(2). Kinetic studies of cefotaxime acylation of the two PBP2x proteins confirmed all of the above findings. Deacylation rate constants (k(3)) for the third step of the interactions were determined to be 8 x 10(-6) s(-1) for penicilloyl-PBP2x and 5.7 x 10(-4) s(-1) for penicilloyl-PBP2x(R), corresponding to over 70-fold increase of the deacylation rate for the resistant PBP2x(R). Similarly, over 80-fold enhancement of the deacylation rate was found for cefotaxime-PBP2x(R) complex (k(3) = 3 x 10(-4) s(-1)) as compared with that of cefotaxime-PBP2x complex (3.5 x 10(-6) s(-1)). This is the first time that such a significant increase of k(3) values was found for a beta-lactam-resistant penicillin-binding protein. These data indicate that the deacylation step also plays a role, which is much more important than previously thought, in PBP2x(R) resistance to beta-lactams.

Acylation↗

PubMed2006

[Combined effect of vancomycin or teicoplanin plus a beta-lactam antibiotic in mouse infection models caused by beta-lactam antibiotec-induced vancomycin resistant MRSA (BIVR)].

The concomitant use of low concentration beta-lactam antibiotics antagonizes the activity of vancomycin against some strains of MRSA. These strains, called beta-lactam antibiotic-induced vancomycin resistant MRSA (BIVR), have been increasing for a number of years. We previously reported that the combination of VCM and ceftizoxime displayed this antagonism not only in vitro, but also in vivo, in a systemic infection caused by BIVR in mice. In the present study, we validated the antagonism in combinations of VCM with other beta-lactams, i.e., flomoxef (FMOX), ampicillin (AMPC), azthreonam (AZT) and imipenem/cilastatin (IPM/CS), in systemic infections and pneumoniain in mice. The survival rate of the mice with systemic infections caused by BIVR treated with combinations of FMOX, AMPC, AZT, and IPM/CS with VCM were significantly lower than with VCM monotherapy, and the number of residual viable cells in the kidneys of mice treated with combinations of FMOX and IPM/CS with VCM were significantly higher than with VCM monotherapy The number of residual viable cells in the lungs of mice with pneumonia caused by BIVR treated with the combination of IPM/CS and VCM was significantly higher than with VCM monotherapy. On the other hand, the survival rate with combination therapy consistings IPM/CS plus teicoplanin (T EIC) was significantly higher, and the number of residual viable cells in the kidney was significantly lower, than with TEIC monotherapy alone. In the mice with pneumonia, the number of residual viable cells in the lung after combination therapy with IPM/CS and TEIC was significantly lower than with TEIC monotherapy. Combination therapy with beta-lactams plus VCM showed antagonistic in models of systemic infection and pulmonary infection caused by BIVR, whereas combination therapy consisting of a beta-lactam plus TEIC had a synergistic effect in the same models, even though VCM and TEIC are member of the same glycopeptide antibiotic class.

Animals↗

PubMed1985

Role of beta-lactam hydrolysis in the mechanism of resistance of a beta-lactamase-constitutive Enterobacter cloacae strain to expanded-spectrum beta-lactams.

Enterobacter cloacae strains producing chromosomally mediated beta-lactamase constitutively show high degrees of resistance to most of the third-generation beta-lactams. It has been proposed that this resistance is due to the nonhydrolytic binding or trapping of beta-lactams by the enzyme. We found that the outer membrane of E. cloacae strain 55M indeed had permeability to cefazolin about 14-fold lower than that of Escherichia coli, and that the number of beta-lactamase molecules produced by this constitutive mutant was exceptionally large (2 X 10(5) per cell). These conditions are expected to produce a low degree of resistance, but could not explain the high resistance level of the mutant. We showed that the beta-lactamase of this strain hydrolyzed third-generation beta-lactams at measurable rates. Although the V max for these compounds was less than 0.01% of that for cefazolin, the enzyme could hydrolyze them at rates comparable to the rate for cefazolin when the substrate concentration was near 0.1 microM, a concentration thought to be physiologically relevant for the inhibition of cell growth, because of the exceptionally high affinity of the enzyme to many third-generation compounds. Calculations based on kinetic parameters of the enzyme, outer membrane permeability, and affinity toward penicillin-binding proteins succeeded in predicting the MICs for several third-generation beta-lactams. The data suggest that hydrolysis may be more important than nonhydrolytic binding for the expression of the resistant phenotype, and that studies on the susceptibility of beta-lactams to beta-lactamases should be carried out at physiologically relevant, very low concentrations of the drug, rather than the customary very high concentrations, such as 100 microM.

Anti-Bacterial Agents↗

PubMed2005

Prevalence of the genes encoding extended-spectrum beta-lactamases, in Escherichia coli resistant to beta-lactam and non-beta-lactam antibiotics.

The prevalences of extended-spectrum beta-lactamases (ESBL) and their encoding bla genes, TEM, SHV and CTX_M, were investigated in isolates of Escherichia coli that were resistant to beta-lactam and/or non-beta-lactam antibiotics. Of the 250 E. coli isolates investigated, all of which came from patients in a major hospital in southern Lebanon, 61 (13.3%) were found to have ESBL, their production of beta-lactamase being confirmed by the ceftazidime and ceftazidime/clavulanic-acid disc methods. All 61 ESBL isolates were resistant to beta-lactams and sensitive to imipenem, piperacillin/tazobactam and cefoxitime. Only 40% were resistant to fluoroquinolones, 33% were resistant to aminoglycosides, and 18% were considered to have multi-drug resistance. The results of the PCR-based amplification of the bla gene in DNA samples from the 61 ESBL isolates indicated that 11 (18%) of the isolates carried both the TEM and SHV genes, 37 (61%) carried the TEM gene but not the SHV, and 13 (21%) had the SHV gene but not the TEM. None of the isolates carried the CTX_M gene. Of the 37 TEM-positive/SHV-negative isolates, 43% were resistant to fluoroquinolones and 37% to aminoglycosides. Increased resistance to non-beta-lactam antibiotics was observed in the isolates harbouring both the TEM and SHV genes, of which 54% were resistant to all of the tested antibiotics except imipenem, 36% were only resistant to fluoroquinolones, and 9.1% only resistant to aminoglycosides. The possibility that the concomitant presence of TEM- and SHV-type beta-lactamases is associated with resistance to non-beta-lactam antibiotics requires further research. The prevalences of ESBL and their encoding genes in Gram-negative bacteria collected from various regions in Lebanon will now be investigated.

DNA, Bacterial↗

PubMed2000

Baicalin synergy with beta-lactam antibiotics against methicillin-resistant Staphylococcus aureus and other beta-lactam-resistant strains of S. aureus.

Bacterial resistance to antibiotics is a serious global problem and includes strains of beta-lactam-resistant Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Novel antimicrobials and/or new approaches to combat the problem are urgently needed. The Chinese herb Xi-nan Huangqin (Scutellaria amoena C.H. Wright) has been used in traditional Chinese medicine to treat a wide range of infectious diseases. In this study we have examined the antibacterial action of baicalin, a flavone isolated from the herb. When combined with 16 microg mL(-1) baicalin, minimum inhibitory concentrations (MICs) of benzylpenicillin against MRSA and penicillin-resistant S. aureus were reduced from 125 and 250 microg mL(-1) to 4 and 16 microg mL(-1), respectively. This activity of baicalin was dose-dependent. Viable counts showed that the killing of MRSA and beta-lactam-resistant S. aureus cells by 10 to 50 microg mL(-1) ampicillin, amoxycillin, benzylpenicillin, methicillin and cefotaxime was potentiated by 25 microg mL(-1) baicalin. From the study it was concluded that baicalin has the potential to restore the effectiveness of beta-lactam antibiotics against MRSA and other strains of beta-lactam-resistant S. aureus. In view of its limited toxicity baicalin offers potential for the development of a valuable adjunct to beta-lactam treatments against otherwise resistant strains of microorganisms.

Ampicillin↗

PubMed1992

[Studies on the pathogenic mechanism of beta-lactam hypersensitivity by the detection of leucocyte migration activating factor and leucocyte migration inhibitory factor--structural correlations with allergic symptoms due to beta-lactam antibiotics].

Structural correlations between allergic symptoms and beta-lactam antibiotics were investigated by the use of leucocyte migration inhibition tests on 147 patients in whom allergy to the drugs was detected from among 193 patients suspected of having beta-lactam hypersensitivity. No significant difference was found in the allergic symptoms between the mother nucleus structure of beta-lactam antibiotics or the C-3 side chain structure of cephem antibiotics. But, in both beta-lactam and cephem antibiotics, those with an aminothiazolyl group in the acylamido in their side chain structure induced fever or hepatopathy significantly more often than skin eruption. In contrast, drugs with a benzyl group induced skin eruptions significantly more often than hepatopathy. Leucocyte migration activating factor (LMAF) was found significantly more often than leucocyte inhibitory factor in patients with fever or hepatopathy, and cephem antibiotics with an aminothiazolyl group in the 7-acylamido side chain produced LMAF at a very high rate (80%). Our findings indicate that the specificity of the chemical structure of beta-lactam antibiotics and allergic symptoms is dependent on the acylamido side chain structure, and an aminothiazolyl group structure has a high capability of inducing fever or hepatopathy. Moreover, the high LMAF-inducing ability of the aminothiazolyl group structure is involved in this pathogenic mechanism.

Anti-Bacterial Agents↗

PubMed1995

Mechanism of inhibition of human leucocyte elastase by beta-lactams. 2. Stability, reactivation kinetics, and products of beta-lactam-derived E-I complexes.

The monocyclic beta-lactams reported by Knight et al. [Knight, W. B., et al. (1992) Biochemistry 31, 8160; Chabin, R., et al. (1993) Biochemistry 32, 8970] as inhibitors of human leucocyte elastase (HLE) produce stable HLE-inhibitor complexes that slowly reactivate with half-lives ranging from less than 1 to 15 h at 37 degrees C. The complexes produced between PPE and two C-3 dimethyl-substituted beta-lactams are less stable than those produced between HLE and analogous C-3 diethyl-substituted lactams. The stability of the HLE-I complexes is governed primarily by the structure of the substituted urea portion of the inhibitors and not by the identity or presence of a leaving group at C-4 of the lactam ring. In some cases substitutions on the urea portion of the inhibitors yielded complexes that displayed biphasic reactivation kinetics. This suggests the presence of at least two different complexes. The stereochemistry of the leaving group at C-4 has a small effect on the stability of the final complex (1.3-2-fold); therefore, the identity of the final complex is dependent upon the initial stereochemistry at that position. The stability of the complexes was relatively insensitive to hydroxylamine, which suggests that the acyl-enzymes are protected from nucleophilic "rescue". The rate of reactivation of the complex derived from L-680,833,[S-R*,S*)]-4-[(1-(((1-(4- methylphenyl)butyl)amino)carbonyl)-3,3-diethyl-2-oxo-4-azetidinyl)ben zeneacetic acid, was pH independent, while the L-684,481, (R)-(1-(((1-(4-methylphenyl)butyl)amino)carbonyl)-3,3-diethyl-2-azeti din one generated complex displayed a pH-dependent reactivation rate. In the latter case, the increase in reactivation rate with pH displayed a pKa of 7.2. This is consistent with the requirement for base catalysis by the active site histidine to regenerate enzymatic activity. Reactivation of the L-680,833-derived complex produced different products as a function of pH, suggesting two different pH-dependent routes of reactivation. At low pH a route that produced primarily the substituted urea is favored, while at higher pH production of two six-membered ring diastereomers competes with urea generation. Thus, the apparent pH independence of the return of activity is the result of two offsetting pathways. Other compounds such as L-670,258, (S)-4-[((((2-naphthylmethyl)amino)carbonyl)-3,3-diethyl-4-oxo-2- azetidinyl)oxy]benzoic acid, reactivate by these two routes as well as by aminolysis by the other urea nitrogen to produce an additional regioisomer. The temperature dependence of the reactivation of the complexes derived from L-684,481 and L-680,833 suggests different mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)

Chromatography, High Pressure Liquid↗

PubMed2006

In vitro antibacterial activity of beta-lactams and non-beta-lactams against Streptococcus pneumoniae isolates from Sydney, Australia.

AIMS: This study was undertaken to determine the antimicrobial resistance patterns of strains of Streptococcus pneumoniae from Sydney, Australia, comparing penicillin-susceptible, -intermediate and -resistant isolates. METHODS: Non-duplicate cultures of S. pneumoniae were collected from 1 January to 31 December 2002 in the three penicillin-susceptibility categories. Minimum inhibitory concentrations (MICs) of 19 antibacterial agents were determined by agar dilution based on the National Committee for Clinical Laboratory Standards (NCCLS) methodology. Overall for 2002, 687 non-duplicate isolates were obtained, of which 190 (28%) were intermediate or resistant to penicillin. From this set, 183 isolates were selected for study: 88 (48%) in the penicillin-susceptible group (MIC or= 2.0 mg/L). RESULTS: Resistance to non-beta-lactams was more common in penicillin-intermediate or -resistant strains. Multidrug resistance (resistance to >or= 2 non-beta-lactams) was found in 3% of penicillin-susceptible, 52% of penicillin-intermediate and 87% of penicillin-resistant isolates. Erythromycin resistance was seen in 22% of the penicillin-susceptible strains but increased significantly to 60% and 89% in the penicillin-intermediate and resistant strains, respectively. Clindamycin, tetracycline and trimethoprim/sulfamethoxazole showed similar diminished activity in penicillin-intermediate and -resistant strains; 64, 84 and 91% of the penicillin-resistant isolates were resistant to clindamycin, tetracycline and to trimethoprim/sulfamethoxazole, respectively. Chloramphenicol resistance was comparatively low level except 19% of the penicillin-resistant strains were resistant. Ciprofloxacin MICs for 14 strains were raised (MICs 4-16 mg/L); three of these were penicillin-susceptible, one penicillin-intermediate and 10 penicillin-resistant. Only one isolate was resistant to moxifloxacin and to gatifloxacin. Resistance to rifampicin, vancomycin, oritavancin, or linezolid was not detected. Twenty-three isolates were intermediate and one resistant to quinupristin/dalfopristin - 22 of these were penicillin resistant. CONCLUSIONS: Streptococcus pneumoniae isolates from Sydney are commonly resistant to beta-lactams and available non-beta-lactam agents, especially if they are penicillin non-susceptible. Resistance to moxifloxacin and gatifloxacin is still rare, but some isolates were non-susceptible to quinupristin/dalfopristin. It is important to continue to survey resistance patterns to recognise emerging resistances which affect the selection of empirical antimicrobials to treat infections with S. pneumoniae.

Anti-Bacterial Agents↗

PubMed1998

Evolution of the clusters of genes for beta-lactam antibiotics: a model for evolutive combinatorial assembly of new beta-lactams.

beta-Lactam antibiotics are produced by prokaryotic and eukaryotic organisms. The genes for beta-lactam biosynthesis are organized in clusters but the location of the different genes is not identical. Biosynthesis genes are clustered with genes for resistance (bla, pbp) and for the efflux of the antibiotic (cmcT) in prokaryotes. Comparison of proteins reveals much larger differences for primary metabolism enzymes than for beta-lactam biosynthesis enzymes in producing organisms. This suggests a horizontal transfer of the beta-lactam antibiotic biosynthesis genes.

Actinomycetales↗

PubMed1999

Comparison of a beta-lactam alone versus beta-lactam and an aminoglycoside for pulmonary exacerbation in cystic fibrosis.

UNLABELLED: We determined whether a beta-lactam and an aminoglycoside have efficacy greater than a beta-lactam alone in the management of a pulmonary exacerbation in patients with cystic fibrosis. STUDY DESIGN: Azlocillin and placebo or azlocillin and tobramycin were administered to 76 patients with a pulmonary exacerbation caused by Pseudomonas aeruginosa in a randomized double-blind, third-party monitored protocol. Improvement was assessed by standardized clinical evaluation, pulmonary function testing, sputum bacterial density, sputum DNA content, and time to the next pulmonary exacerbation requiring hospitalization. RESULTS: No significant difference was seen between the 2 treatment groups in clinical evaluation, sputum DNA concentration, forced vital capacity, forced expiratory volume in second 1, or peak expiratory flow rate at the end of treatment (33 receiving azlocillin alone and 43 both antibiotics); adverse reactions were equivalent in each group. Sputum P. aeruginosa density decreased more with combination therapy (P =.034). On follow-up evaluation, an average of 26 days after the end of treatment, all outcome indicators had worsened in both groups. Time to readmission for a new pulmonary exacerbation was significantly longer in the group receiving azlocillin plus tobramycin (P <.001). Treatment-emergent tobramycin resistance occurred in both groups and was more frequent with combination therapy. CONCLUSION: We conclude that the combination of a beta-lactam and an aminoglycoside produces a longer clinical remission than a beta-lactam alone and slightly better initial improvement.

Adolescent↗

PubMed1986

[Selection of resistant variants by broad spectrum beta-lactam antibiotics: to what extent is there cross resistance between imipenem and other beta-lactam antibiotics?].

Resistant variants can be selected in the presence of most of the recently developed beta-lactam antibiotics thus resulting in cross resistance between penicillin-, cephalosporin- and monocyclic derivatives except for imipenem. Among the Enterobacteriaceae-resistant so-called beta-lactamase-overproducing variants can be selected in some species in the presence of various broad-spectrum beta-lactams except for imipenem. However, imipenem-resistant variants can be selected from clinical Pseudomonas aeruginosa isolates in a frequency comparable to those obtained for other beta-lactams. Imipenem resistance in Pseudomonas aeruginosa is presently understood to be independent of either enzymatic degradation or an alteration of the penicillin-binding proteins; moreover, it has to be attributed to characteristic changes of the outer membrane proteins, thus explaining imipenem resistance due to impaired penetration. Consequently, resistance to imipenem in Pseudomonas aeruginosa has to be considered independent of resistance to other beta-lactams.

Anti-Bacterial Agents↗

PubMed2004

Design and synthesis of bridged gamma-lactams as analogues of beta-lactam antibiotics.

Anti-Bredt bridged bicyclo[3.2.1] gamma-lactams were designed as inhibitors of penicillin binding proteins (PBPs). The compounds were prepared by a carbenoid insertion into a lactam N-H bond. Their weak antibacterial activity could either be explained by a poor chemical stability or by unfavorable steric interactions of the methylene bridge of the gamma-lactam with the targeted enzymes.

Anti-Bacterial Agents↗

PubMed2003

Studies on the endogenous L-selectin ligands: systematic and highly efficient total synthetic routes to lactamized-sialyl 6-O-sulfo Lewis X and other novel gangliosides containing lactamized neuraminic acid.

Systematic syntheses of lactamized neuraminic acid-containing gangliosides GM4, sulfated sialylparagloboside, and sulfated/nonsulfated sialyl Lewis X are described. The highly efficient, one-step lactamization of neuraminic acid was accomplished by treatment of the N-deacetylated sialic acid (neuraminic acid)-containing gangliosides with HBTU and HOBt in DMF at 65 degrees C. Both the lactamized neuraminic acid residue and the sulfate group at O-6 of the GlcNAc residue were found to be involved in the antigenic determinant defined by G159 monoclonal antibody, while the fucose residue may not be critical for the recognition by G159 mAb.

Antibodies, Monoclonal↗

PubMed2005

Activities of various beta-lactams and beta-lactam/beta-lactamase inhibitor combinations against Acinetobacter baumannii and Acinetobacter DNA group 3 strains.

Acinetobacter baumannii and Acinetobacter DNA group 3 are members of the so-called A. calcoaceticus-A. baumannii complex and are important nosocomial pathogens. Multiresistance in these organisms is increasingly frequent, and alternative treatment options are needed. The beta-lactamase inhibitors clavulanate, sulbactam and tazobactam have intrinsic activity against Acinetobacter strains. In the present study, broth microdilution was used to assess the in-vitro activities of currently available beta-lactam/beta-lactamase inhibitor combinations and sulbactam alone against 469 Acinetobacter isolates (A. baumannii, n=395; Acinetobacter DNA group 3, n=74) collected from various laboratories in Germany. Fixed concentrations and fixed ratios of beta-lactamase inhibitors were used. Sulbactam-containing combinations (susceptibility rates of 90.4-92.7% for A. baumannii and 97.3-100% for Acinetobacter DNA group 3) and sulbactam alone were superior to clavulanate- and tazobactam-containing combinations. The activity of sulbactam-containing combinations against members of the A. calcoaceticus-A. baumannii complex was conferred exclusively by the intrinsic activity of the beta-lactamase inhibitor and did not result from enhanced beta-lactam activity. Testing with the inhibitor added at a fixed ratio of inhibitor to beta-lactam appeared to give more reliable results than testing at a fixed concentration of the inhibitor. Resistance to carbapenems (0.3%) remains low in Germany.

Acinetobacter↗