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At least 19 recordsLinked to original sources
PubMed2002

Beta-lactam versus beta-lactam-aminoglycoside combination therapy in cancer patients with neutropaenia.

BACKGROUND: Chemotherapy treated cancer patients are prone to neutropaenia and life-threatening infections. Early, empirical antibiotic treatment is therefore administered routinely to febrile neutropaenic patients. Currently, either beta-lactam-aminoglycoside combination treatment or beta-lactam monotherapy are recommended. OBJECTIVES: We compared beta-lactam monotherapy versus beta-lactam-aminoglycoside combination therapy for cancer patients with fever and neutroepaenia. SEARCH STRATEGY: Cochrane Library (Issue 4,2001), the Cochrane Cancer Network Register of trials (July 2000), EMBASE (January 1980-2000), MEDLINE (1966-8/2001), and ICAAC conference proceedings (1995 onwards). We scanned references of all included studies, pertinent reviews, and contacted the first author of each included trial and the pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials comparing any beta-lactam antibiotic monotherapy to any combination of a beta-lactam and an aminoglycoside antibiotic, for the initial, empirical treatment of febrile neutropaenic cancer patients. DATA COLLECTION AND ANALYSIS: Data concerning mortality, treatment failure (including treatment modifications), superinfections, adverse effects and study quality measures were extracted independently by two reviewers. Relative risks with their 95% confidence intervals (CI) were estimated. Outcomes were extracted by intention-to-treat analysis whenever possible. MAIN RESULTS: Forty-six trials and 7642 patients were included. All cause mortality was the primary outcome assessed. For all mortality comparisons, no significant difference between monotherapy and combination therapy was seen, relative risk 0.85 (95% CI 0.72-1.02) for all studies combined. Treatment failure was the outcome reported in all included trials. No significant difference between study groups was shown for studies comparing the same beta-lactam, relative risk 1.12 (95% CI 0.96-1.29). A significant advantage to monotherapy was observed for studies comparing different beta-lactams, relative risk 0.86 (95% CI 0.80-0.93). Bacterial and fungal superinfections developed with similar frequencies in the monotherapy and combination treatment groups. Adverse events were significantly more common in the combination treatment group, relative risk 0.83, (95% CI 0.72-0.97). These included events associated with significant morbidity, primarily renal toxicity. Results were consistent for subgroup and sensitivity analyses. REVIEWER'S CONCLUSIONS: We have shown an advantage to broad-spectrum beta-lactam monotherapy over beta-lactam-aminoglycoside combination therapy for febrile neutropaenia. This advantage comprises of 1) a similar, if not better, survival, 2) a significantly lower treatment failure rate, 3) comparable probability for secondary infections and, 4) most importantly, a lower rate of adverse events associated with significant morbidity. Monotherapy can be regarded, therefore, as the standard of care for febrile neutropaenic patients.

Aminoglycosides↗
PubMed1984

Intestinal absorption of several beta-lactam antibiotics. V. Effect of amino beta-lactam analogues and dipeptides on the absorption of amino beta-lactam antibiotics.

The absorption mechanism of amino beta-lactam antibiotics was investigated by using the whole small intestine of a rat. Mutual inhibition among amino beta-lactam analogues and the effects of dipeptides were studied. The influences of glycylglycine on the absorption of cephradine at the four different parts of intestine were also studied. Similarly to the case of cephalexin and cephradine, the absorption of amoxicillin was significantly inhibited by cyclacillin, cephradine, and cephalexin, but the absorption of ampicillin was not reduced by all tested antibiotics. In the experiments using dipeptides (6.0 mM), the absorption of cyclacillin was reduced significantly by glycylglycine, not by L-carnosine. And cephalexin absorption was influenced by L-carnosine (6.0, 10 mM), not by glycylglycine (6 mM). On the contrary, the absorption of cephradine was not reduced at all by these dipeptides. And from the experiment using the four different parts of intestine, it was shown that the transport interaction of glycylglycine with cephradine was observed in only one segment (the upper part of jejunum). These result suggest that the carrier-mediated transport system correlated to dipeptides participates only to a small degree in the common absorption mechanisms of these amino beta-lactam antibiotics.

Amoxicillin↗
PubMed2006

Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis.

BACKGROUND: Optimal antibiotic treatment for sepsis is imperative. Combining a beta-lactam antibiotic with an aminoglycoside antibiotic may have certain advantages over beta-lactam monotherapy. OBJECTIVES: We compared clinical outcomes for beta lactam-aminoglycoside combination therapy versus beta lactam monotherapy for sepsis. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library, Issue 3, 2004); MEDLINE (1966 to July 2004); EMBASE (1980 to March 2003); LILACS (1982 to July 2004); and conference proceedings of the Interscience Conference of Antimicrobial Agents and Chemotherapy (1995 to 2003). We scanned citations of all identified studies and contacted all corresponding authors. SELECTION CRITERIA: We included randomized and quasi-randomized trials comparing any beta-lactam monotherapy to any combination of one beta-lactam and one aminoglycoside for sepsis. DATA COLLECTION AND ANALYSIS: The primary outcome was all-cause fatality. Secondary outcomes included treatment failure, superinfections, colonization, and adverse events. Two authors independently collected data. We pooled relative risks (RR) with their 95% confidence intervals (CI) using the fixed effect model. We extracted outcomes by intention-to-treat analysis whenever possible. MAIN RESULTS: We included 64 trials, randomizing 7586 patients. Twenty trials compared the same beta-lactam in both study arms, while the remaining compared different beta-lactams using a broader spectrum beta-lactam in the monotherapy arm. In studies comparing the same beta-lactam, we observed no difference between study groups with regard to all-cause fatality, RR 1.01 (95% CI 0.75-1.35) and clinical failure, RR 1.11 (95% CI 0.95-1.29). In studies comparing different beta-lactams, we observed an advantage to monotherapy: all cause fatality RR 0.85 (95% CI 0.71-1.01), clinical failure RR 0.77 (95% CI 0.69-0.86). No significant disparities emerged from subgroup and sensitivity analyses, including the assessment of patients with Gram-negative and Pseudomonas aeruginosa infections. We detected no differences in the rate of resistance development. Adverse events rates did not differ significantly between the study groups overall, although nephrotoxicity was significantly more frequent with combination therapy, RR 0.30 (95% CI 0.23-0.39). We found no heterogeneity for all comparisons. We included a small subset of studies addressing patients with Gram-positive infections, mainly endocarditis. We identified no difference between monotherapy and combination therapy in these studies. AUTHORS' CONCLUSIONS: The addition of an aminoglycoside to beta-lactams for sepsis should be discouraged. All-cause fatality rates are unchanged. Combination treatment carries a significant risk of nephrotoxicity.

Aminoglycosides↗
PubMed2005

Lower mortality among patients with community-acquired pneumonia treated with a macrolide plus a beta-lactam agent versus a beta-lactam agent alone.

A cohort of 1,391 patients with community-acquired pneumonia of unknown etiology, atypical pneumonia, Legionella pneumophila pneumonia, viral pneumonia, or pneumococcal pneumonia was studied according to a standard protocol to analyse whether the addition of a macrolide to beta-lactam empirical treatment decreases mortality rates. Patients admitted to the intensive care unit were excluded. Severity was assessed using the PORT score. An etiological diagnosis was achieved in 498 (35.8%) patients (292 infections due to Streptococcus pneumoniae). Treatment was chosen by the attending physician according to his/her own criteria: beta-lactam agent in 270 and beta-lactam agent plus a macrolide in 918 cases. The mortality rate was 13.3% in the group treated with a beta-lactam agent alone and 6.9% in the group treated with a beta-lactam agent plus a macrolide (p=0.001). The percentage of PORT-group V patients was 32.6% in the group treated with a beta-lactam agent alone compared to 25.7% in the group who received a beta-lactam agent plus a macrolide (p=0.02). After controlling for PORT score, the odds of fatal outcome was two times higher in patients treated with a beta-lactam agent alone than in those treated with a beta-lactam agent plus a macrolide (adjusted OR = 2, 95%CI 1.24-3.23). The results suggest that the addition of a macrolide to an initial beta-lactam-based antibiotic regimen is associated with lower mortality in patients with community-acquired pneumonia, independent of severity of infection, thus supporting the recommendation of a beta-lactam-agent plus a macrolide as empirical therapy.

Amoxicillin-Potassium Clavulanate Combination↗
PubMed1986

Comparative review of combination therapy: two beta-lactams versus beta-lactam plus aminoglycoside.

Febrile neutropenic patients are usually treated with a combination of a beta-lactam and an aminoglycoside. Since Pseudomonas aeruginosa is an important pathogen in these patients, the empiric use of possibly synergistic combinations against that organism has been traditionally recommended. The recent appearance of beta-lactams more active against P. aeruginosa and the well-known nephrotoxicity of aminoglycosides have led some to advocate the use of beta-lactam combinations for empiric treatment of fever in neutropenic cancer patients. This article reviews the available literature on the controlled use of combinations of beta-lactams in the treatment of febrile neutropenic patients as compared with that of combinations of beta-lactams and aminoglycosides. The review includes comparison of overall response, response in patients with septicemia or other infections, response associated with different pathogens, the effect of profound neutropenia, and an evaluation of the toxicities encountered. Overall, these results show that response rates with a combination of two beta-lactams are similar to those obtained with the combinations of a beta-lactam and an aminoglycoside for infections in patients with serious underlying disease and compromised mechanisms of defense. They also suggest that the steady emergence of resistance of pathogens to beta-lactams has often been overcome by the use of newer drugs in regard to infections caused by the Enterobacteriaceae but much less effectively in regard to P. aeruginosa. There are still important theoretic reasons for preferring an aminoglycoside-containing combination as empiric therapy in febrile neutropenic patients, and our overall conclusion is that it would be appropriate to conduct a large-scale trial comparing beta-lactam combinations with the traditional beta-lactam plus aminoglycoside regimens in that setting.

Aminoglycosides↗
PubMed2005

Effect of aminoglycoside and beta-lactam combination therapy versus beta-lactam monotherapy on the emergence of antimicrobial resistance: a meta-analysis of randomized, controlled trials.

BACKGROUND: The addition of an aminoglycoside to a beta -lactam therapy regimen has been suggested to have a beneficial effect in delaying or preventing the development of antimicrobial resistance. We studied the effect of aminoglycoside/ beta -lactam combination therapy versus beta-lactam monotherapy on the emergence of resistance. METHODS: We performed a meta-analysis of randomized, controlled trials (RCTs) that compared aminoglycoside/ beta-lactam combination therapy with beta-lactam monotherapy and that reported data regarding the emergence of resistance (primary outcome) and/or development of superinfection, treatment failure, treatment failure attributable to emergence of resistance, treatment failure attributable to superinfection, all-cause mortality during treatment, and mortality due to infection. Data for this meta-analysis were identified from the PubMed database, Current Contents database, Cochrane central register of controlled trials, and references in relevant articles. RESULTS: A total of 8 RCTs were included in the analysis. Beta -lactam monotherapy was not associated with a greater emergence of resistance than was the aminoglycoside/ beta-lactam combination (odds ratio [OR], 0.90; 95% confidence interval [CI], 0.56-1.47). Actually, beta -lactam monotherapy was associated with fewer superinfections (OR, 0.62; 95% CI, 0.42-0.93) and fewer treatment failures (OR, 0.62; 95% CI, 0.38-1.01). Rates of treatment failure attributable to emergence of resistance (OR, 3.09; 95% CI, 0.75-12.82), treatment failure attributable to superinfection (OR, 0.60; 95% CI, 0.33-1.10), all-cause mortality during treatment (OR, 0.70; 95% CI, 0.40-1.25), and mortality due to infection (OR, 0.74; 95% CI, 0.46-1.21) did not differ significantly between the 2 regimens. CONCLUSIONS: Compared with beta-lactam monotherapy, the aminoglycoside/ beta-lactam combination was not associated with a beneficial effect on the development of antimicrobial resistance among initially antimicrobial-susceptible isolates.

Aminoglycosides↗
PubMed2000

Costs of beta-lactam allergies: selection and costs of antibiotics for patients with a reported beta-lactam allergy.

OBJECTIVE: To evaluate antibiotic selection and the cost effect of reported beta-lactam allergies. DESIGN: Retrospective medical records review comparing antimicrobial selection and costs in patients with a reported beta-lactam allergy with a group in which no such allergy had been documented. SETTING: University-based family medicine clinic. PATIENTS: Patients who were prescribed at least 1 antibiotic for an upper respiratory tract infection, otitis media, sinusitis, and/or a urinary tract infection were eligible. One thousand two hundred one patients were identified via ICD-9-CM (International Classification of Diseases, Ninth Revision, Clinical Modification) codes. Four hundred sixty-five patients were initially identified and an additional 195 family members were eligible for inclusion. MAIN OUTCOME MEASURES: Comparison of antimicrobial selection and costs (by average wholesale price) between patients with and without a reported beta-lactam allergy. RESULTS: Of the 660 patients eligible for inclusion, 99 (15%) had a documented beta-lactam allergy. Of the patients with a documented allergy, only 33% had a description of their purported reaction. The mean antibiotic cost for patients with a beta-lactam allergy was significantly higher compared with those without a beta-lactam allergy ($26.81 vs $16.28, respectively; P =.004). Patients with a beta-lactam allergy were more likely to have received a cephalosporin, macrolide, or a miscellaneous agent (eg, quinolone, tetracycline, or nitrofurantoin) (P =.001). CONCLUSIONS: Patients with a beta-lactam allergy had higher antibiotic costs and were more likely to receive a broader-spectrum antibiotic. Most patients with a reported allergy did not have a description of their reaction. Skin testing may be of use in detecting true beta-lactam allergies; however, further study is needed to determine its cost-effectiveness.

Adolescent↗
PubMed2003

Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for fever with neutropenia: systematic review and meta-analysis.

OBJECTIVE: To compare the effectiveness of beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy in the treatment of patients with fever and neutropenia. DATA SOURCES: Medline, Embase, Lilacs, the Cochrane Library, and conference proceedings to 2002. References of included studies and contact with authors. No restrictions on language, year of publication, or publication status. STUDY SELECTION: All randomised trials of beta lactam monotherapy compared with beta lactam-minoglycoside combination therapy as empirical treatment for patients with fever and neutropenia. DATA SELECTION: Two reviewers independently applied selection criteria, performed quality assessment, and extracted data. An intention to treat approach was used. Relative risks were pooled with the random effect model. MAIN OUTCOME MEASURE: All cause fatality. RESULTS: Forty seven trials with 7807 patients met inclusion criteria. Nine trials compared the same beta lactam. There was no significant difference in all cause fatality (relative risk 0.85, 95% confidence interval 0.72 to 1.02). For success of treatment there was a significant advantage with monotherapy (0.92, 0.85 to 0.99), though there was considerable heterogeneity among trials. There was no significant difference between monotherapy and combination treatment in trials that compared the same beta lactam, whereas there was major advantage with monotherapy in trials that compared different beta lactams (0.87, 0.80 to 0.93). Rates of superinfection were similar. Adverse events, including those associated with severe morbidity, were significantly more common in the combination treatment group. Detected flaws in methods did not affect results. CONCLUSIONS: For patients with fever and neutropenia there is no clinical advantage in treatment with beta lactam-aminoglycoside combination therapy. Broad spectrum beta lactams as monotherapy should be regarded as the standard of care for such patients.

Aminoglycosides↗
PubMed1993

Efficacy of prophylaxis with beta-lactams and beta-lactam-beta-lactamase inhibitor combinations against wound infection by methicillin-resistant and borderline-susceptible Staphylococcus aureus in a guinea pig model.

Although some beta-lactams and beta-lactam-beta-lactamase inhibitor combinations exhibit activity against methicillin-resistant Staphylococcus aureus, there remains the concern that therapeutic failures may result from the selection of resistant subpopulations. The prophylactic use of these antibiotics in clean surgery, however, may prove adequate since wound infections arise from the inoculation of small numbers of bacteria. In this clinical setting, heterogeneity in the phenotypic expression of beta-lactam resistance may facilitate antibiotic efficacy. Similarly, beta-lactamase-mediated resistance in S. aureus is dependent on inoculum size, and it may be possible to prevent infection from small inocula with relatively labile beta-lactams. To test this hypothesis, antibiotics were administered to guinea pigs as prophylaxis against infection by two methicillin-resistant strains and one borderline-susceptible strain. Following prophylaxis with sulbactam or placebo, inoculation of only a dozen or fewer bacteria had a 50% probability of creating an abscess (50% infective dose [ID50]). The efficacy of ampicillin was similar to that of cefazolin, exhibiting moderate activity against the borderline-susceptible strain (ID50s, greater than 300 bacteria) and minimal activity against the methicillin-resistant strains (ID50s, fewer than 100 bacteria). Coadministration of sulbactam with ampicillin or cefazolin yielded better results than the beta-lactam alone for five of six strain-beta-lactam combinations, including an 80-fold increase in the efficacy of ampicillin-sulbactam compared with that of ampicillin for one methicillin-resistant strain (ID50s, 2,017 and 25 bacteria, respectively). Prophylaxis with beta-lactams, especially beta-lactam-beta-lactamase inhibitor combinations, reduces the risk of wound infection by beta-lactam-resistant S. aureus.

Ampicillin↗
PubMed2000

Synthesis and structure of 6-amino-2,3,6-trideoxy-D-erythro-hexono-1,6-lactam and 6-amino-3,6-dideoxy-D-xylo-hexono-1,6-lactam.

Solid-state conformations of 6-amino-2,3,6-trideoxy-D-erythro-hexono-1,6-lactam (3a) and 6-amino-3,6-dideoxy-D-xylo-hexono-1,6-lactam (7a) were determined using X-ray diffraction. Conformations of the compounds 3a, 7a, and their per-O-acetyl derivatives 4,5-di-O-acetyl-6-amino-2,3,6-trideoxy-D-erythro-hexono-1,6-lactam (3b) and 2,4,5-tri-O-acetyl-6-amino-3,6-dideoxy-D-xylo-hexono-1,6-lactam (7b) in solutions were deduced from the analysis of NMR spectra using a modified Karplus equation and compared with the results of circular dichroism measurement of lactams 3a and 7a. Conformation 4C(1,N) was revealed for solid lactams 3a and 7a and for lactams 7a and 7b in solution, while lactams 3a and 3b in solution exist in the approximately 1:1 equilibrium of the conformers 4C(1,N) and (1,N)C4.

Carbohydrate Conformation↗
PubMed2004

Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: systematic review and meta-analysis of randomised trials.

OBJECTIVE: To compare beta lactam monotherapy with beta lactam-aminoglycoside combination therapy for severe infections. DATA SOURCES: Medline, Embase, Lilacs, Cochrane Library, and conference proceedings, to 2003; references of included studies; contact with all authors. No restrictions, such as language, year of publication, or publication status. STUDY SELECTION: All randomised trials of beta lactam monotherapy compared with beta lactam-aminoglycoside combination therapy for patients without neutropenia who fulfilled criteria for sepsis. DATA SELECTION: Two reviewers independently applied selection criteria, performed quality assessment, and extracted the data. The primary outcome assessed was all cause fatality by intention to treat. Relative risks were pooled with the random effect model (relative risk < 1 favours monotherapy). RESULTS: 64 trials with 7586 patients were included. There was no difference in all cause fatality (relative risk 0.90, 95% confidence interval 0.77 to 1.06). 12 studies compared the same beta lactam (1.02, 0.76 to 1.38), and 31 studies compared different beta lactams (0.85, 0.69 to 1.05). Clinical failure was more common with combination treatment overall (0.87, 0.78 to 0.97) and among studies comparing different beta lactams (0.76, 0.68 to 0.86). There was no advantage to combination therapy among patients with Gram negative infections (1835 patients) or Pseudomonas aeruginosa infections (426 patients). There was no difference in the rate of development of resistance. Nephrotoxicity was significantly more common with combination therapy (0.36, 0.28 to 0.47). Heterogeneity was not significant for these comparisons. CONCLUSIONS: In the treatment of sepsis the addition of an aminoglycoside to beta lactams should be discouraged. Fatality remains unchanged, while the risk for adverse events is increased.

Aminoglycosides↗
PubMed1987

[A comparative review of combination therapy: 2 beta-lactams versus beta-lactam plus aminoglycoside].

We have reviewed the available literature on the controlled use of combinations of beta-lactams in the treatment of fever in neutropenic patients, as compared to that of combinations of beta-lactams and aminoglycosides. We compared overall responses, responses in septicemia and various other infections, according to different pathogens and degree of neutropenia, and we evaluated toxicity. Overall, these results showed that response rates with combinations of two beta-lactams are similar to those obtained with combinations of a beta-lactam and an aminoglycoside for infections in immunocompromised patients with serious underlying diseases. They also suggest that the emergence of resistance of pathogens to beta-lactams has often been coped by the use of newer drugs in infections caused by Enterobacteriaceae, but much less effectively in the case of Pseudomonas aeruginosa infections. There are still other important theoretical reasons for preferring an aminoglycoside-containing combination for empiric therapy in febrile neutropenic patients, and our overall conclusion is that a large-scale study comparing beta-lactam combinations to the traditional beta-lactam plus aminoglycoside regimens is mandatory.

Aminoglycosides↗
PubMed2000

Hydrolytic stability versus ring size in lactams: implications for the development of lactam antibiotics and other serine protease inhibitors.

beta-Lactam antibiotics act by acylating a serine hydroxyl group in the catalytic center of bacterial proteases. This requires, among other things, suitable reactivity of the lactam moiety. To evaluate the possible suitability of other lactam systems, kinetic studies were performed using the model reaction of lactams with hydroxide. Following the pace of the reaction by NMR, we found gamma-butyrolactam to be hydrolyzed considerably slower than beta-propiolactam. Surprisingly, delta-valerolactam and beta-propiolactam had the same reactivity. beta-Lactam antibiotics were more reactive than both by approximately a factor of 10(3). Medium-sized lactams were least susceptible to hydrolysis. The study highlights the as yet overlooked six-membered lactam ring as a promising vantage point for the development of new classes of antiinfectives and other serine protease inhibitors.

Anti-Bacterial Agents↗
PubMed2002

Preparation of alpha-phosphono lactams via electrophilic phosphorus reagents: an application in the synthesis of lactam-based farnesyl transferase Inhibitors.

Conversion of N-alkyl lactams to the corresponding alpha-phosphono lactams has been investigated through procedures that involve formation of the lactam enolate and reaction with a phosphorus electrophile. With N-octylpyrrolidinone, the enolate could be trapped efficiently on oxygen by reaction with diethyl phosphorochloridate, and the resulting vinyl phosphate rearranges smoothly to the desired phosphonate upon treatment with additional LDA. Attempts to apply the same protocol to N-farnesyl lactams met with limited success. Studies with an isolated alpha-phosphono N-farnesyl lactam have shown that the farnesyl group is not stable to the excess of strong base required for rearrangement of a vinyl phosphate. However, a series of N-farnesyl lactams and imides was converted to the desired phosphonates through formation of the lactam enolate, reaction with diethyl phosphorochloridite, and subsequent oxidation of the phosphorus intermediate to the P(V) state.

Alkyl and Aryl Transferases↗
PubMed1990

Estimation of the molecular volumes of the reaction products between beta-lactam antibiotics and aminoglycoside antibiotics, and those of the degradation products of beta-lactam antibiotics by isotachophoresis.

The correlative equations between the molecular volume and the qualitative indication (hR) for beta-lactam antibiotics, the reaction products between beta-lactam antibiotics and kanamycin, and the degradation products of beta-lactam antibiotics were hR = 0.32 + 0.080 VA2/3//Z/(N = 15, r = 0.972 for penicillins) and hR = 0.04 + 0.072 VA2/3//Z/(N = 12, r = 0.987 for cephems). Where VA is van der Waals volume (A3/molecule), hR is the relative step height in the isotachopherogram, and Z is the electric change, respectively. According to these equations, the molecular volumes of the reaction products between beta-lactam antibiotics and the other aminoglycoside antibiotics, and those of the degradation products of beta-lactam antibiotics can be estimated from the value of hR. Also according to the step height in the isotachopherogram, the reaction products or the degradation products may be estimated directly when the electric charge is known. It was confirmed that a molecule of aminoglycoside antibiotics reacted with a molecule of beta-lactam antibiotics. Therefore, the inactivation of aminoglycoside antibiotics is much greater than for beta-lactam antibiotics when the clinical doses of these antibiotic combinations are used.

Aminoglycosides↗
PubMedDate not supplied

Solid-phase synthesis of extended lactam ring systems: preparation of amino acid alpha-fluorenylmethyl esters for the synthesis of reverse-extended lactams.

Conventional side-chain to side-chain cyclization between Lys/Orn and Asp/Glu side chains has the inherent shortcoming of limited variability in the ring sizes; limited by the amino acids involved in the lactamization. A novel approach to modulate the ring size has been introduced by using "spacers" (e.g., Gly, beta-Ala, gamma-Aba). General solid-phase procedures were developed that enabled the insertion of these spacers for the preparation of extended and reverse-extended lactam ring systems. Extended lactam ring systems were prepared using the Boc/Bzl strategy with Fmoc protection on the side chain of the basic residue, Lys/Orn. The spacer was introduced as the Fmoc amino acid, and chain elongation proceeded by the Boc/Bzl strategy. The acidic residue, Asp/Glu, involved in the lactam bridge was introduced with side-chain -OFm protection. Selective deprotection of the Fmoc and -OFm functions was followed by BOP cyclization, further chain elongation and HF cleavage. Reverse-extended lactam ring systems were prepared analogously using the Boc/Bzl strategy with the initial introduction of -OFm protection on the side chain of the acidic residue. In this case, amino acid alpha-fluorenylmethyl esters were used as the spacers. Amino acid alpha-fluorenylmethyl ester hydrochlorides were prepared in two steps from N-t-butyloxycarbonyl amino acids in excellent yield. These intermediates have general utility in peptide synthesis, including their specific application as "spacers" for the solid-phase synthesis of extended cyclic peptides (lactams). Using these intermediates, we prepared a model dicyclo-peptide that contains both an extended and reverse-extended lactam ring system.

Amino Acid Sequence↗
PubMed2000

Design and synthesis of pyrrolidine-5,5-trans-lactams (5-oxo-hexahydro-pyrrolo[3,2-b]pyrroles) as novel mechanism-based inhibitors of human cytomegalovirus protease. 1. The alpha-methyl-trans-lactam template.

Mechanism-based inhibitors of human cytomegalovirus (HCMV) protease have been designed based on the pyrrolidine-5,5-trans-lactam ring system. New routes to the beta-methyl-, desmethyl-, and alpha-methyl-pyrrolidine-5,5-trans-lactam templates have been developed from 2,4-diaminobutyric acid. ESI/MS studies have shown that these inhibitors can bind covalently and reversibly to the viral enzyme in a time-dependent manner by a mechanism which is consistent with acylation of HCMV deltaAla protease at the active site nucleophile Ser 132. SAR in this series of pyrrolidine-5, 5-trans-lactams has defined the relative stereochemisty of the methyl substituent adjacent to the lactam carbonyl, the functionality on the lactam nitrogen, and the mechanism of action of this novel series of serine protease inhibitors against the HCMV deltaAla protease. Activity decreases on moving from the alpha-methyl to the desmethyl to the beta-methyl series. This selectivity is the opposite of that observed for these templates against the elastase and thrombin enzymes. The activity against HCMV deltaAla protease is the greatest with inhibitors based on the Cbz-protected alpha-methyl-5,5-trans-lactam template which have low micromolar activity against the viral enzyme.

Cytomegalovirus↗
PubMed1991

State of penicillin-binding proteins and requirements for their bactericidal interaction with beta-lactam antibiotics in Serratia marcescens highly resistant to extended-spectrum beta-lactams.

The quantities of penicillin-binding proteins (PBPs), and sensitivity to extended-spectrum beta-lactams, were measured in isogenic strains of Serratia marcescens with high (HR) and low (LR) resistance to extended-spectrum beta-lactam antibiotics and with constitutively overproduced chromosomal beta-lactamase in the periplasm. The binding of structurally different beta-lactams to PBPs in growing resistant bacteria was determined quantitatively. In S. marcescens HR, the amounts of PBPs 3 and 6 were, respectively, 1.5 and 2 times those in strain LR and in sensitive reference strains. Sensitivities of the essential PBPs in S. marcescens LR and HR to the tested beta-lactams were identical. Only a single target, PBP 3, was highly sensitive to cefotaxime, ceftazidime and aztreonam. In contrast, three PBPs (2, 1A and 3) were highly sensitive to imipenem. In growing S. marcescens HR and LR, all antibiotics, even at fractions of their minimal growth inhibitory concentrations (MICs), bound extensively to those PBPs which were highly sensitive to them. Thus, overproduced beta-lactamase did not prevent PBP-beta-lactam interaction. Only at or above their (high) MICs did cefotaxime, ceftazidime and aztreonam bind to multiple targets. Growth inhibition of the otherwise highly resistant S. marcescens HR at the lower MIC of imipenem was correlated with the binding of this antibiotic to multiple, highly sensitive targets in the bacteria. Killing of the bacteria by inactivation of multiple targets was suggested. This assumption was supported by the synergistic killing of HR bacteria by combinations of the PBP-2-specific mecillinam with PBP-3-specific beta-lactams.

Anti-Bacterial Agents↗