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The rapidly growing emergence of drug resistant bacteria has become one of the most important public health concerns.However, the development of new drugs is of more difficulties.Extended infusion or prolonged infusion of antibiotics is a significant way of antimicrobial stewardship programs, which has been proven beneficial to better pharmacokinetic/pharmacodynamic targets attainment and improved clinical outcomes.This review discussed the rationality of prolonging the infusion time of commonly used antibiotics in PICU.
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Objective To compare the efficacy and safety of β - lactams alone and the combination of β - lactams with macrolides in the treatment of community-acquired pneumonia(CAP) in children. Methods PubMed, CNKI and VIP databases were searched by computer. RCT on children with CAP treated by β-lactams and macrolides were collected. The retrieval time was from the establishment of the database to July 2020. Literatures were selected and data was extracted according to inclusion and exclusion criteria. The risk of bias was evaluated, RevMan 5.3 software was used for Meta-analysis. Results Thirteen articles with 1788 patients were included in the study. The results showed that the clinical efficacy of the combination therapy in the experimental group was better than that in the control group [RR = 1.11, CI = 1.07–1.15, P < 0.000 01]. The time for fever returning to normal was shorter in the experimental group than that in the control group [MD = −1.31, CI =−1.58– −1.05, P < 0.000 01]. The disappearance time of pulmonary rales was shorter in the experimental group than that in the control group [MD = −1.75, CI = −2.13– −1.37, P < 0.000 01], There was no statistically significant difference in adverse reactions between the two groups (P > 0.05). Conclusion The combination therapy of β - lactams and macrolides is better than β-lactams alone in children with CAP with no significant difference in adverse reactions. Limited by the quantity and quality of the included studies, the conclusions from this study need to be further verified by large samples of high-quality RCT.
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As d-amino acids play important roles in the physiological metabolism of bacteria, combination of d-amino acids with antibiotics may provide synergistic antibacterial activity. The aim of the study was to evaluate and activity of d-serine alone and in combination with -lactams against methicillin-resistant (MRSA) strains, and to explore the possible sensitization mechanisms. The activity of d-serine, -lactams alone and in combinations was evaluated both by standard MICs, time-kill curves and checkerboard assays, and by murine systemic infection model as well as neutropenic thigh infection model. An synergistic effect was demonstrated with the combination of d-serine and -lactams against MRSA standard and clinical strains. Importantly, the combinations enhanced the therapeutic efficacy in the animal models as compared to -lactam alone groups. Initial mechanism study suggested possible revision of d-alanine-d-alanine residue to d-alanine-d-serine in peptidoglycan by adding of d-alanine in the medium, which may cause decreased affinity to PBPs during transpeptidation. In conclusion, d-serine had synergistic activity in combination with -lactams against MRSA strains both and . Considering the relatively good safety of d-serine alone or in combination with -lactams, d-serine is worth following up as new anti-MRSA infection strategies.
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Bacteremia is a life-threating syndrome often caused by methicillin-resistant (MRSA). Thus, there is an urgent need to develop novel approaches to successfully treat this infection. Staphylococcal accessory regulator A (SarA), a global virulence regulator, plays a critical role in pathogenesis and -lactam antibiotic resistance in . Hypericin is believed to act as an antibiotic, antidepressant, antiviral and non-specific kinase inhibitor. In the current study, we investigated the impact of hypericin on -lactam antibiotics susceptibility and mechanism(s) of its activity. We demonstrated that hypericin significantly decreased the minimum inhibitory concentrations of -lactam antibiotics (.., oxacillin, cefazolin and nafcillin), biofilm formation and fibronectin binding in MRSA strain JE2. In addition, hypericin significantly reduced expression, and subsequently decreased and virulence-related regulators (.., ) and genes (.., and ) expression in the studied MRSA strain. Importantly, the synergistic effect of hypericin with -lactam antibiotic (.., oxacillin) translated into therapeutic outcome in a murine MRSA bacteremia model. These findings suggest that hypericin plays an important role in abrogation of -lactam resistance against MRSA through inhibition, and may allow us to repurpose the use of -lactam antibiotics, which are normally ineffective in the treatment of MRSA infections (.., oxacillin).
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BACKGROUND: The primary objective of this meta-analysis is aimed at determining whether β-lactams prolonged infusion in patients with nosocomial pneumonia (NP) results in higher cure rate and improved mortality compared to intermittent infusion. MATERIALS AND METHODS: Relevant studies were identified from searches of MEDLINE, EMBASE, and CENTRAL from inception to September 1st, 2015. All published articles which evaluated the outcome of extended/continuous infusion of antimicrobial therapy versus intermittent infusion therapy in the treatment of NP were reviewed. RESULTS: A total of ten studies were included in the analysis involving 1,051 cases of NP. Prolonged infusion of β-lactams was associated with higher clinical cure rate (OR 2.45, 95% CI, 1.12, 5.37) compared to intermittent infusion. However, there was no significant difference in mortality (OR 0.85, 95% CI 0.63-1.15) between the two groups. Subgroup analysis for β-lactam subclasses and for severity of illness showed comparable outcomes. CONCLUSION: The limited data available suggest that reduced clinical failure rates when using prolonged infusions of β-lactam antibiotics in critically ill patients with NP. More detailed studies are needed to determine the impact of such strategy on mortality in this patient population.
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Humans , Anti-Bacterial Agents , Critical Illness , Mortality , PneumoniaABSTRACT
Objective To investigate prevalence of resistance genes for β-lactams in clinically isolated multidrug-resistant Acinetobacter baumannii (MDRAB)in a hospital.Methods 22 clinically isolated MDRAB strains were performed antimicrobial susceptibility testing,resistance genes forβ-lactams (TEM,SHV,CTX-M,PER,DHA, IMP ,VIM ,SIM,OXA-23,OXA-24,and OXA-58)in these strains were detected with polymerase chain reaction. Results The resistant rates of 22 isolates of MDRAB to ceftazidime,cefotaxime,cefepime,gentamycin,amikacin, ciprofloxacin,and compound sulfamethoxazole were all 100.00%;to imipenem,meropenem,and cefoperazone/sul-bactam were 50.00%,40.91 %,and 31 .82% respectively,intermediated rates were 31 .82%,36.36%,and 31 .82% respectively.The carriage rates of OXA-23,TEM,IMP ,and PER were 100.00% (n =22),72.73 %(n=16),54.55% (n = 12),and 18.18% (n =4)respectively.Detection results of SHV,CTX-M,DHA,VIM , SIM,OXA-24,and OXA-58 were all negative.Conclusion Carriage of IMP ,TEM,PER,and OXA-23 resistance genes are the major resistance mechanisms of MDRAB to β-lactamase antimicrobial agents in this hospital.
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Objective To construct a prokaryotic expression system for expressing the phosphatase-encoding gene phpP in StkP/PhpP signaling couple in Streptococcus pneumonia ( S.pneumoniae) strains, and to further understand the phosphatase activity of the recombinant protein rPhpP.Methods The entire phpP gene of S.pneumoniae strain ATCC6306 was amplified by PCR.The PCR products were sequenced.A prokaryotic ex-pression system for expressing the phpP gene was constructed by the genetic engineering technique.The ex-pressed protein rPhpP and the solubility of rPhpP were assessed by SDS-PAGE and gel image analyzer.Ni-NTA affinity chromatography was performed to purify rPhpP.The changes of phpP gene transcription after the treat-ment with sublethal dosages of penicillin and cefotaxime were determined by real-time fluorescent quantitative RT-PCR.The functional domain in the sequence of the phpP gene and its type was analyzed by bioinformatic softwares.The activity of rPhpP in hydrolyzing the substrate of PP2C phosphotase was measured with Serine/Threonine Phosphotase Assay Kit.The enzyme kinetic parameters of rPhpP were calculated.Results The se-quence of the cloned phpP gene was identical with that reported in GenBank.The rPhpP in soluble form was ex-pressed in the constructed prokaryotic expression system.An increased expression of phpP gene at mRNA level was induced by sublethal dosage of penicillin or cefotaxime.The domain of PP2Cc type phosphatase was detec-ted in the sequence of phpP gene.The purified rPhpP protein could hydrolyze phosphopeptides [ RRA ( pT) VA], a substrate of PP2C type phosphatase, in a dose-dependent manner with Km and Kcat values of 277.35μmol/L and 0.71 S-1 ,respectively.Conclusion The protein encoded by phpP gene of S.pneumoniae was a PP2C type phosphatase.The expression of phpP gene could be enhanced by sublethal dosage of penicillin or ce-fotaxime.
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Objective To analyze molecular evolution of carbapenemase KPC-12 and its binding free energies with β-lactams.Methods Class A beta-lactamases were divided into 2 clusters:those with carbapenemase activities and those without.Minimum Evolution method in MEGA4.1 software was used to analyze molecular evolution of class A beta-lactamases with carbapenemase activity,including KPC-2 to KPC-13,SFC-1,SME-1,IMI-1,NMC-A,and class A beta-lactamases without carbapenemase activity,including TEM-1,SHV-1.Then,tertiary structure of KPC-12 was predicted by homology modeling as reported in SWISS-MODEL database depending on tertiary structure of KPC-2.Moreover,DOCK module in ArgusLab 4.1 software was used to perform molecular docking of KPC-12 to 10 kinds of beta-lactams substrates,and the binding free energies (△ G) were calculated.Results Molecular evolution between KPC-12 and KPC-2 was the closest.The top three decline in binding free energies of β-lactams were penicillin G sodium salt (△G =-8.45149 kcal/mol),ertapenem (△G =-8.36383 kcal/mol) and ampicillin (△G =-8.19326 kcal/mol),while the last two decline in binding free energies of β-lactams were aztreonam (△G =-6.50614 kca]/mol) and clavulanic acid (△G =-6.88533 kcal/mol).Conclusion Carbapenemase KPC-12 has high catalytic activities to penicillin G sodium salt,ertapenem and ampicillin,while has low catalytic activities to aztreonam and clavulanic acid.
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Objective To investigate resistant mechanisms of a pandrug-resistant Acinetobacter baumannii (js01) to β-1actams.Methods Strain js01 isolated from sputum sample of an inpatient from Ningbo First Municipal Hospital in December 2011 was confirmed by PCR amplifying and sequencing of gyrA and parC,and aligning with BLASTn.Thirty-three kinds of β-lactamase genes ( 13 kinds of class A,10kinds of class B,2 kinds of class C,8 kinds of class D),linkage detection of insertion sequences and β-lactamase genes,as well as outer membrane porin gene carO were analyzed by PCR.Genes encoding PBPI A were divided into three fragments,PCR amplified and bidirectional sequenced,and ligated to the full-length gene.Results Four kinds of β-lactamase genes were positive in js01:TEM-I,ADC-30, OXA-23 and OXA-66.Linkage detection of insertion sequences and β-lactamase genes showed that ISabal-ADC-30 and ISabal-OXA-23 were positive. When compared with sensitive strain (SDF) of Acinetobacter baumannii,sense mutations were found in carO gene of js01,and identity of amino acid sequence of carO gene between js01 and SDF was 76.0％ (189/249),and differences owed to loss of 3 amino acids.Sense mutations were also found in genes encoding PBP1A of js01,and identity of amino acid sequence of genes encoding PBP1A between js01 and SDF was 99.6％ ( 848/851 ),and differences owed to variations of 3amino acids.However,compared with three-dimensional structure of PBP1 A of SDF,PBP1 A of js01 lost 2helixes.Conclusion In strain js01,mutations of housekeeping genes ( genes encoding PBP1A and CarO),and genes producing β-lactamase mediated by mobile genetic elements,may play a key role in resistance to β-lactams.
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Objective To investigate the change of renal tubular function in elderly patients after use of β lactam antibiotic. Methods The elderly patients with pulmonary infection were treated with β lactam antibiotic,the dosage was 50%-70% of normal use. The renal tubular function indicated by urine α1-MG, β2-MG, pro/Cre, NAG/Cre and glomerulus function marked by eGFR, serum creatinine (Cre)), cystatin C were detected during drugs treatment and 7 days after stopping medications. Results The infection was controlled well in 3-7 days after treatment. Urine α1-MG, β2-MG, pro/Cre and NAG/Cre were abnormal before treatment, were elevated in 3, 14 days after using antibiotic, and came down to the level before treatment on 7 days after stopping treatment. The level of Cre and eGFR was (89.0±25.97) μmol/L and (26.39±8.17) ml/min before treatment, then elevated and decreased in 14 days after treatment, respectively, and down to the level before treatment on 7 days after stopping of antibiotic. Cystatin c was abnormal before treatment and did not change significantly after treatment and after stopping antibiotic. Conclusions It is important to protect renal tubular function and to adjust antibiotic dosage according to eGFR during using antibiotic in elderly patients to control infection.