Case of sepsis caused by multidrug-resistant neutropenic-phase Pseudomonas aeruginosa treated successfully with antibiotic combination therapy

Multidrug-resistant Pseudomonas aeruginosa (MDRP), defined as Pseudomonas aeruginosa resistant to aminoglycosides, carbapenems, and fluoroquinolones, has emerged as an increasingly problematic cause of hospital-acquired infection. With parenteral colistin unavailable in Japan, effective antimicrobial options are severely limited. We report a case of MDRP bacteremia successfully treated with antibiotic combination therapy screened by a 'Break-point Checkerboard Plate'. A 54-year-old man with malignant lymphoma who became febrile 9 days after a recent course of chemotherapy had a neutrophil count of 176/microL. Treatment with meropenem and vancomycin was ineffective and high fever persisted. Methicillin-resistant Staphylococcus aureus (MRSA) and MDRP were isolated from blood culture and combination therapy with aztreonam and amikacin was selected for MDRP based on 'Break-point Checkerboard Plate' results. Linezolid was used for MRSA. The patient recovered successfully from MDRP and MRSA sepsis.     

Subtraction serum bactericidal assay: a method for estimating in vivo effects of antibiotic combinations.

The subtraction serum bactericidal assay has been developed to assess the effects of the individual components of antibiotic combinations in serum specimens from patients with serious bacterial infection. The technique can be performed easily with conventional microtiter technology, and the results compare favorably with those obtained by conventional in vitro determinations of the additive and synergistic activity of fixed antibiotic combinations against various Enterobacteriaceae. Three combinations of gentamicin and ampicillin were used, and synergistic or additive activity was demonstrated against each of the 11 clinical isolates tested, but only with one or two of the antibiotic combinations. This finding suggests the clinical importance of a test that can determine the effects of the actual concentrations of individual antibiotics that are achieved in patients with serious infections that are being treated with antibiotic combinations.     

Antibiotic therapy for Pseudomonas aeruginosa bacteremia: outcome correlations in a prospective study of 200 patients

PURPOSE AND PATIENTS AND METHODS: We performed a prospective clinical study of 200 consecutive patients with Pseudomonas aeruginosa bacteremias to analyze in vitro susceptibility and synergistic testing of antibiotics the patients received and clinical parameters to assess their relationship to survival. RESULTS: No significant correlation between in vitro susceptibility testing (minimal inhibitory concentrations/minimal bactericidal concentrations) and outcome could be demonstrated. Similarly, improved outcome could not be demonstrated for patients receiving antibiotic combinations that were synergistic in vitro (either time-kill or checker-board) versus those combinations that were not. There was also no correlation between results obtained by time-kill curve and checkerboard synergistic testing, i.e., combinations found to be synergistic by one method were not necessarily synergistic by the other method. Clinical parameters associated with improved survival were a urinary portal of entry and absence of neutropenia. Conversely, survival was significantly decreased when the portal was the respiratory tract. The mortality rate between patients receiving combination therapy (27%) and monotherapy (47%) was significant (p less than 0.02); this significant relationship held true for most subgroups including malignancy, nosocomial infection, and infection site. CONCLUSION: Increasing effort should be placed on ensuring timely administration of combination therapy to patients with P. aeruginosa bacteremia since the use of combination therapy was even more important in determining outcome than was underlying disease.     

Accelerated evolution of resistance in multidrug environments

The emergence of resistance during multidrug chemotherapy impedes the treatment of many human diseases, including malaria, TB, HIV, and cancer. Although certain combination therapies have long been known to be more effective in curing patients than single drugs, the impact of such treatments on the evolution of drug resistance is unclear. In particular, very little is known about how the evolution of resistance is affected by the nature of the interactions—synergy or antagonism—between drugs. Here we directly measure the effect of various inhibitory and subinhibitory drug combinations on the rate of adaptation. We develop an automated assay for monitoring the parallel evolution of hundreds of Escherchia coli populations in a two-dimensional grid of drug gradients over many generations. We find a correlation between synergy and the rate of adaptation, whereby evolution in more synergistic drug combinations, typically preferred in clinical settings, is faster than evolution in antagonistic combinations. We also find that resistance to some synergistic combinations evolves faster than resistance to individual drugs. The accelerated evolution may be due to a larger selective advantage for resistance mutations in synergistic treatments. We describe a simple geometric model in which mutations conferring resistance to one drug of a synergistic pair prevent not only the inhibitory effect of that drug but also its enhancing effect on the other drug. Future study of the profound impact that synergy and other drug-pair properties can have on the rate of adaptation may suggest new treatment strategies for combating the spread of antibiotic resistance.     

Multiple synergistic interactions between atovaquone and antifolates against Plasmodium falciparum in vitro: a rational basis for combination therapy

The use of synergistic drug combinations for the treatment of drug-resistant malaria is a major strategy to slow the selection and spread of Plasmodium falciparum resistant strains. In order to investigate synergistic compounds, with different modes of action, as alternative candidates for combination therapy, we used standard in vitro P. falciparum cultures and an established synergy testing method to define interactions among dapsone (DDS), atovaquone (ATQ), chlorproguanil (CPG) and its triazine metabolite chlorcycloguanil (CCG). Strong synergy was observed in the combinations DDS/CCG and ATQ/CPG. Multiple combination of these drugs, DDS/CCG/CPG/ATQ also exhibited high synergy although not higher than that of either of the two drug combinations separately. The use of this triple combination DDS/CPG/ATQ, even without an increase in synergy over their double combinations, ATQ/CPG and DDS/CCG, would contribute towards slowing the selection pressure since these drugs act against different targets and would delay the selection of parasites resistant to the three drugs, extending the useful therapeutic life of these valuable compounds.     

Drug interactions modulate the potential for evolution of resistance

Antimicrobial treatments increasingly rely on multidrug combinations, in part because of the emergence and spread of antibiotic resistance. The continued effectiveness of combination treatments depends crucially on the frequency with which multidrug resistance arises. Yet, it is unknown how this propensity for resistance depends on cross-resistance and on epistatic interactions—ranging from synergy to antagonism—between the drugs. Here, we analyzed how interactions between pairs of drugs affect the spontaneous emergence of resistance in the medically important pathogen Staphylococcus aureus. Resistance is selected for within a window of drug concentrations high enough to inhibit wild-type growth but low enough for some resistant mutants to grow. Introducing an experimental method for high-throughput colony imaging, we counted resistant colonies arising across a two-dimensional matrix of drug concentrations for each of three drug pairs. Our data show that these different drug combinations have significantly different impacts on the size of the window of drug concentrations where resistance is selected for. We framed these results in a mathematical model in which the frequencies of resistance to single drugs, cross-resistance, and epistasis combine to determine the propensity for multidrug resistance. The theory suggests that drug pairs which interact synergistically, preferred for their immediate efficacy, may in fact favor the future evolution of resistance. This framework reveals the central role of drug epistasis in the evolution of resistance and points to new strategies for combating the emergence of drug-resistant bacteria.     

Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations

BMS-354825 (dasatinib) and AMN107 (nilotinib) are potent alternate Abl inhibitors with activity against many imatinib mesylate-resistant BCR-ABL kinase domain (KD) mutants, except T315I. We used N-ethyl-N-nitrosourea (ENU)-exposed Ba/F3-p210(BCR-ABL) cells to compare incidence and types of KD mutants emerging in the presence of imatinib mesylate, dasatinib, and nilotinib, alone and in dual combinations. Although ENU is expected to induce mutations in multiple proteins, resistant clones were almost exclusively BCR-ABL KD mutant at relevant concentrations of nilotinib and dasatinib, consistent with a central role of KD mutations for resistance to these drugs. Twenty different mutations were identified with imatinib mesylate, 10 with nilotinib (including only 1 novel mutation, E292V) and 9 with dasatinib. At intermediate drug levels the spectrum narrowed to F317V and T315I for dasatinib and Y253H, E255V, and T315I for nilotinib. Thus, cross-resistance is limited to T315I, which is also the only mutant isolated at drug concentrations equivalent to maximal achievable plasma trough levels. With drug combinations maximal suppression of resistant clone outgrowth was achieved at lower concentrations compared with single agents, suggesting that such combinations may be equipotent to higher-dose single agents. However, sequencing uniformly revealed T315I, consistent with the need for a T315I inhibitor, to completely block resistance.     

Synergistic effect of two combinations of antituberculous drugs against Mycobacterium tuberculosis

Fluoroquinolones such as ofloxacin are promising drugs to treat drug-resistant tuberculosis (TB) and have been proposed for shortening the treatment of TB. The objectives were to study the synergistic effect of the combinations of three drugs and to evaluate the in?vitro interactions of the following combinations against Mycobacterium tuberculosis: A) isoniazid, rifampicin, and ethambutol and B) ofloxacin, rifampicin, and ethambutol using an adaptation of the two-dimensional chequerboard assay. A total of 12 isolates resistant to isoniazid or to isoniazid-streptomycin and 11 drug-susceptible isolates were tested. The fractional inhibitory concentration (FICI) was calculated as follows: FICI?=?FIC(A)?+?FICB?+?FIC(C)?=?A/MIC(A)?+?B/MIC(B)?+?C/MIC(C) where A, B and C were the MICs of each antibiotic in combination and MIC(A), MIC(B) and MIC(C) were the individual MICs. The FICI was interpreted as synergism when the value was ≤0.75. In combination A, 11 drug-susceptible isolates decreased the individual MIC one to three dilutions, showing indifferent activity in 81.8% (FICI?=?0.88-1.6) and synergistic activity in 18.1% (FICI?=?0.6). In combination B, 21 out of the 23 isolates studied (91.3%) showed synergism (FICI?=?0.31-0.62). In conclusion, adaptation of the two-dimensional chequerboard assay is a reliable method to study in?vitro three-drug combinations. Both three-drug combinations tested may be useful against drug-resistant isolates, although the combination including ofloxacin showed better efficacy, being of potential use in drug-susceptible and isoniazid-resistant isolates.     

Activities of colistin- and minocycline-based combinations against extensive drug resistant <Emphasis Type="Italic">Acinetobacter baumannii</Emphasis> isolates from intensive care unit patients

Background  

Extensive drug resistance of Acinetobacter baumannii is a serious problem in the clinical setting. It is therefore important to find active antibiotic combinations that could be effective in the treatment of infections caused by this problematic 'superbug'. In this study, we analyzed the in vitro activities of three colistin-based combinations and a minocycline-based combination against clinically isolated extensive drug resistant Acinetobacter baumannii (XDR-AB) strains.     

多药耐药铜绿假单胞菌院内感染危险因素及预后因素分析

目的 分析多药耐药铜绿假单胞菌(MDRP)产生的危险因素，并探讨影响MDRP院内感染预后的因素。方法 采用病例对照研究方法。收集北京协和医院1999年1月～2002年12月MDRP引起的院内感染44例，并随机选择同时期敏感铜绿假单胞菌院内感染68例作为对照，采用单因素(t检验，χ^2检验)及多因素Logistic回归进行分析。结果 对112例铜绿假单胞菌院内感染单因素分析发现，下列因素与MDRP感染有关：高龄、高APACHE Ⅱ(acute physiology and chronic health evaluation)评分、2种以上细菌混合感染、院内获得性肺炎(HAP)、机械通气、患有慢性阻塞性肺疾病(COPD)、分离出MCIRP前15天用过氟喹喏酮、分离出MDRP前15天用过亚胺培南／美罗培南。但多因素Logistic回归分析仅确定了2项独立危险因素：机械通气[比值比(OR)=8．19]，分离出MDRP前15天用过亚胺培南／美罗培南(OR，44．80)。44例MDRP院内感染，死亡24例，好转20例，病死率为55％。单因素分析发现，下列因素与MDRP感染死亡相关：高APACHEⅡ评分、机械通气、未恢复对抗铜绿假单胞菌抗生素的敏感性。多因素Logistic回归分析发现了1项独立危险因素：未恢复对抗铜绿假单胞菌抗生素的敏感性(OR=10．70)。结论 机械通气，以及亚胺培南／美罗培南的使用是MDRP感染的危险因素。MDRP未恢复对抗铜绿假单胞菌抗生素的敏感性是MDRP感染预后差的危险因素。     

Synergistic effects of ethnomedicinal plants of Apocynaceae family and antibiotics against clinical isolates of Acinetobacter baumannii

Objective:To investigate the efficacy of 17 ethnomedicinal plants belonging to Apocynaceae family used in combination with 16 conventional antibiotics against non-multidrug resistant-,multidrug resistant(MDR)-.and extensive drug resistant(XDR) Acinetobacter baumannii(A.haumannii).Methods:Antibacterial activity and resistance modifying ability of 272combinations were determined by growth inhibition assays and further confirmed by time-kill assay.Results:Among the combinations of the antibiotics with Apocynaceae ethanol extracts on this pathogen,15(5%) had synergistic effects,23(8%) had partial synergistic effects and 234(86%) had no effects.Synergistic activity was observed mostly when the Apocynaceae extracts were combined with rifampicin or cefazolin.Interestingly.10 out of 17 combinations between the extracts and rifampicin displayed synergistic or partial synergistic behaviors.Holarrhena antidysenterica extract was additionally tested to restore rifampicin activity against clinical isolates of MDR and XDR A.haumannii.With respect to total or partial synergy,70%was XDR A.haumannii isolates and 66%was MDR A.haumannii isolates.Conclusions:Holarrhena antidysenterica extract clearly demonstrated the ability to restore rifampicin activity against both A.haumannii ATCC19606 and clinically isolated A.haumannii.Additional studies examining its active principles as well as nieclianisms of actions such as the effects on efflux pumps and outer membrane permeability alterations are recommended.     

In vitro activity of artemisinin in combination with clotrimazole or heat-treated amphotericin B against Plasmodium falciparum

Currently available artemisinin-based combination therapies (ACTs) for malaria are inadequate. There remains an enormous unmet need for alternate artemisinin-based combination therapies. One of the fastest methods to identify promising artemisinin-based combination therapies is to look for synergistic or additive antimalarial interaction between artemisinin and an alternate drug against P. falciparum in vitro. Amphotericin B and clotrimazole are known drugs for treatment of human fungal infections. We repurposed clotrimazole or heat-treated amphotericin B in fixed ratio combination with artemisinin for antimalarial properties. Isobologram results show synergistic/additive interaction in both of the cases at therapeutically safe concentrations. Artemisinin, clotrimazole, and their synergistic combinations also decrease hemozoin production in parasitized erythrocytes. New permeation pathways induced in infected cells remain unaffected by drug combinations as indicated by sorbitol lysis. It would be interesting to extend the studies' in vivo system.     

Mortality of COPD Patients Infected with Multi-Resistant Pseudomonas aeruginosa : A Case and Control Study

Abstract Background:   The incidence of infections caused by multiresistant Pseudomonas aeruginosa (MDRP) is increasing, especially in critically ill patients. The relevance of MDRP in the prognosis of chronic obstructive pulmonary disease (COPD) acute exacerbation in patients admitted to the hospital’s general ward is not well known. Patients and Methods:   Case and control study. Cases were patients admitted for COPD acute exacerbation in which a MDRP was isolated from spontaneous sputum. MDRP was defined as the absence of susceptibility to three or more antibiotic families (betalactams, quinolones, carbapenems and aminoglycosides). Patients currently or previously admitted to the intensive care unit (ICU), who had a recent surgery, neoplasia or immunosuppressive treatment were excluded from the study. Patients from the control group were admitted for COPD acute exacerbation and matched 1:1 with each case-patient in terms of age, sex, date of admission and degree of airway obstruction. Pseudomonas aeruginosa susceptible to all antimicrobials or other microorganisms was isolated from sputum. Results:   During the study period (2000–2005), 50 casepatients and 50 controls were included. Crude mortality at 2 years was 60% for the case-patients and 28% for the control group. In the logistic regression analysis adjusted for age, FEV₁ and number of previous hospital admissions, MDRP infection was associated to an increased mortality in comparison to patients without MDRP (OR = 6.2; IC 95%: 1.7–22.1; p < 0.01). Conclusions:   In COPD patients admitted to the general ward, acute exacerbation with MDRP in sputum was associated with higher mortality.     

Clinical analysis of drug sensitivity tests of various drug-resistant MTB isolates against different combinations of anti-tuberculosis drugs in vitro

目的 分析耐药MTB分离株对不同组合抗结核药品(简称“不同组合药品”)进行体外药物敏感性试验(简称“药敏试验”)的检测结果,评价不同组合药品的最低抑菌浓度(MIC)及对耐药菌株的抗结核协同作用。方法 搜集同济大学附属上海市肺科医院“十二五”国家科技重大专项入组的148例首次复治肺结核患者,通过对患者痰标本进行BACTEC MGIT 960和改良罗氏法培养获取167株MTB分离株,对75例患者经上述两种方法进行药敏试验结果均为阳性的92株耐药菌株(包括36株MDR-MTB、54株XDR-MTB和2株单耐H菌株),采用MIC三维棋盘法分别以H-R、Mfx-Pa、Mfx-Pa-Rfb、Mfx-Pa-Rft等4种组合药品进行体外药敏试验,计算不同药品组合的协同率。结果 药品未组合前的H、R、Rfb、Rft、Pa体外药敏试验MIC值的中位数(四分位数)[M(Q₁,Q₃)]分别为4(1,8)、24(2,64)、0.5(0.125,1)、4(4,4)、8(4,8)mg/L,均明显高于组合后的H[2(1,4)mg/L]、R[1(0.25,16)mg/L]、与Mfx-Pa组合后的Rfb[0.125(0.03125,0.125)mg/L]、与Mfx-Pa组合后的Rft[1(1,1)mg/L]、与Mfx/Mfx-Rfb/Mfx-Rft组合后的Pa[分别为0.0075(0.0075,0.875)、0.0075(0.0075,0.125)、0.0225(0.0075,0.5)mg/L](Z=-4.855,-6.908,-8.386,-8.632,-8.094,-8.335,-7.771,P值均<0.001);且H-R、Mfx-Pa、Mfx-Pa-Rfb、Mfx-Pa-Rft药品组合后的协同率分别为12.0%(11/92)、5.4%(5/92)、17.4%(16/92)、23.9%(22/92);其中H-R和Mfx-Pa组合分别与Mfx-Pa-Rfb和Mfx-Pa-Rft组合的协同率比较,差异均有统计学意义(χ²=12.670,P=0.002;χ²=19.420,P<0.001;χ²=18.640,P<0.001;χ²=28.500,P<0.001)。结论 组合药品中H、R、Rfb、Rft、Pa的MIC值均低于未组合前该药品的MIC值,说明耐药菌株对组合后上述药品的敏感性增强。三药组合的协同率均优于两药组合,且Mfx-Pa-Rft较Mfx-Pa-Rfb组合表现出更好的协同作用。     

耐药MTB分离株对不同组合抗结核药品体外药物敏感性试验的结果分析

目的 分析耐药MTB分离株对不同组合抗结核药品(简称“不同组合药品”)进行体外药物敏感性试验(简称“药敏试验”)的检测结果,评价不同组合药品的最低抑菌浓度(MIC)及对耐药菌株的抗结核协同作用。方法 搜集同济大学附属上海市肺科医院“十二五”国家科技重大专项入组的148例首次复治肺结核患者,通过对患者痰标本进行BACTEC MGIT 960和改良罗氏法培养获取167株MTB分离株,对75例患者经上述两种方法进行药敏试验结果均为阳性的92株耐药菌株(包括36株MDR-MTB、54株XDR-MTB和2株单耐H菌株),采用MIC三维棋盘法分别以H-R、Mfx-Pa、Mfx-Pa-Rfb、Mfx-Pa-Rft等4种组合药品进行体外药敏试验,计算不同药品组合的协同率。结果 药品未组合前的H、R、Rfb、Rft、Pa体外药敏试验MIC值的中位数(四分位数)[M(Q₁,Q₃)]分别为4(1,8)、24(2,64)、0.5(0.125,1)、4(4,4)、8(4,8)mg/L,均明显高于组合后的H[2(1,4)mg/L]、R[1(0.25,16)mg/L]、与Mfx-Pa组合后的Rfb[0.125(0.03125,0.125)mg/L]、与Mfx-Pa组合后的Rft[1(1,1)mg/L]、与Mfx/Mfx-Rfb/Mfx-Rft组合后的Pa[分别为0.0075(0.0075,0.875)、0.0075(0.0075,0.125)、0.0225(0.0075,0.5)mg/L](Z=-4.855,-6.908,-8.386,-8.632,-8.094,-8.335,-7.771,P值均<0.001);且H-R、Mfx-Pa、Mfx-Pa-Rfb、Mfx-Pa-Rft药品组合后的协同率分别为12.0%(11/92)、5.4%(5/92)、17.4%(16/92)、23.9%(22/92);其中H-R和Mfx-Pa组合分别与Mfx-Pa-Rfb和Mfx-Pa-Rft组合的协同率比较,差异均有统计学意义(χ²=12.670,P=0.002;χ²=19.420,P<0.001;χ²=18.640,P<0.001;χ²=28.500,P<0.001)。结论 组合药品中H、R、Rfb、Rft、Pa的MIC值均低于未组合前该药品的MIC值,说明耐药菌株对组合后上述药品的敏感性增强。三药组合的协同率均优于两药组合,且Mfx-Pa-Rft较Mfx-Pa-Rfb组合表现出更好的协同作用。     

Aerosolized antibiotics in cystic fibrosis

Inhaled antibiotics offer an attractive alternative to systemic administration in cystic fibrosis (CF) for several reasons. Antibiotics can be administered directly to the site of infection with little systemic absorption, thereby minimizing toxicity. Aerosolization will permit chronic administration of antipseudomonal antibiotics while avoiding the risks and inconvenience of intravenous access. Modern aerosolized drug delivery systems enable endobronchial delivery of very high antibiotic concentrations, resulting in clinical improvement even in patients with bacterial organisms that traditionally would have been considered resistant. This article summarizes basic concepts of aerosol drug administration and reviews available data on the administration of a variety of drug classes for both suppressive therapy and acute exacerbations of cystic fibrosis, including toxicity and safety data. The aminoglycosides have been by far the most extensively studied class of antibiotics, culminating in U.S. Food and Drug Administration (FDA) approval of a specifically formulated tobramycin solution for inhalation. The available data on the development of antibiotic resistance and emergence of other organisms with long-term use of this agent are reviewed. Finally, a brief guideline for initiating and monitoring patients on antibiotic aerosols is provided for the clinician caring for CF patients.     

On the rapidity of antibiotic resistance evolution facilitated by a concentration gradient

The rapid emergence of bacterial strains resistant to multiple antibiotics is posing a growing public health risk. The mechanisms underlying the rapid evolution of drug resistance are, however, poorly understood. The heterogeneity of the environments in which bacteria encounter antibiotic drugs could play an important role. E.g., in the highly compartmentalized human body, drug levels can vary substantially between different organs and tissues. It has been proposed that this could facilitate the selection of resistant mutants, and recent experiments support this. To study the role of spatial heterogeneity in the evolution of drug resistance, we present a quantitative model describing an environment subdivided into relatively isolated compartments with various antibiotic concentrations, in which bacteria evolve under the stochastic processes of proliferation, migration, mutation and death. Analytical and numerical results demonstrate that concentration gradients can foster a mode of adaptation that is impossible in uniform environments. It allows resistant mutants to evade competition and circumvent the slow process of fixation by invading compartments with higher drug concentrations, where less resistant strains cannot subsist. The speed of this process increases sharply with the sensitivity of the growth rate to the antibiotic concentration, which we argue to be generic. Comparable adaptation rates in uniform environments would require a high selection coefficient (s > 0.1) for each forward mutation. Similar processes can occur if the heterogeneity is more complex than just a linear gradient. The model may also be applicable to other adaptive processes involving environmental heterogeneity and range expansion.     

老年患者医院获得性肺炎病原菌及耐药性监测

目的 明确广州地区老年医院获得性肺炎(hospital-acquired pneumonia,HAP)患者致病菌的构成情况及耐药情况,以期指导临床治疗.方法 2004年1月至2005年10月在广州市4家医院住院、年龄≥60岁且分离出致病菌的HAP患者共206例,进行致病菌的分离鉴定,采用纸片扩散法进行细菌药敏检测.结果 本组206例老年HAP患者平均年龄(76.6±8.3)岁,平均发病时间为21 d,94.4%为迟发型HAP.共分离致病菌308株,其中革兰阴性细菌占65.3%,革兰阳性细菌占26.3%,白色念珠菌占8.4%.前3位致病菌分别为铜绿假单胞菌(19.2%)、金黄色葡萄球菌(12.7%)、肺炎克雷伯菌(9.1%).革兰阳性菌和革兰阴性菌均耐药情况严重.金黄色葡萄球菌中耐甲氧西林金黄色葡萄球菌比例高达92.3%,溶血性葡萄球菌100%为耐甲氧西林溶血性葡萄球菌.金黄色葡萄球菌对万古霉素耐药率为2.6%.革兰阴性细菌对三代头孢菌素均严重耐药,铜绿假单胞菌呈广泛性严重耐药,有15株铜绿假单胞菌对所有抗生素均耐药.结论 广州地区老年HAP患者细菌耐药性严重,必须加强措施防治其发病.     

Significance of fluoroquinolone-resistant Escherichia coli in urinary tract infections

Antibiotic-resistant urinary tract infections (UTIs) are on the rise. We investigated the recent emergence of representative resistant strains in patients diagnosed with UTIs at Kobe University Hospital between 2000 and 2006, focusing on resistant strains isolated from the urine of UTI patients, especially fluoroquinolone-resistant Escherichia coli (FQRE), multidrug-resistant Pseudomonas aeruginosa (MDRP), and methicillin-resistant Staphylococcus aureus (MRSA). We found 16 MDRP, 108 FQRE, and 251 MRSA UTI cases, reflecting a significant increase in the incidence of FQRE. Our data demonstrated that isolated ratios of FQRE rose as much as 26.3% in 2006 and that there were significantly more isolated cases in 2003 - 2006 than in 2000 - 2002. The data show a significant trend toward FQRE emergence. This trend should be considered when treating UTI.     

Efficacy of artemisinin and mefloquine combinations against Plasmodium falciparum. In vitro simulation of in vivo pharmacokinetics

The activity of artemisinin in combination with mefloquine was tested in vitro against a chloroquine‐sensitive (F32) strain of Plasmodium falciparum . A method of repetitive dosing and extending the culture observation period to 28–30 days was used to mimic the in vivo pharmacokinetic situation. Plasmodium falciparum was exposed to artemisinin from 10⁻⁸ to 10⁻⁵  m , mefloquine from 3×10⁻⁹ to 10⁻⁵  m and their combinations. The exposure time for artemisinin was 3 hours twice daily and for mefloquine 24 hours. The drug‐dosing duration was 3 days.
Neither artemisinin nor mefloquine alone provided radical clearance of P. falciparum , even when maximum concentrations (10⁻⁵  m ) were applied. The antiparasitic activity of artemisinin and mefloquine were significantly higher when dosed alone. Effective concentrations for different degrees of inhibition (EC 50, 90 and 99) of both artemisinin and mefloquine respectively were significantly lower when used in combination. At concentrations normally reached in vivo , this effect was clearly synergistic ( P =0.016)
Our in vitro model of intermittent dosing of artemisinin and mefloquine combinations for 3 days provides significant evidence of positive interaction between the two compounds. Lower combination concentrations around the MIC‐values for the individual compounds showed synergistic effect, and high concentrations showed additive effect. This indicates that such drug combinations may provide radical clearance at concentrations lower than those required for single‐drug treatment.