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Drug synergy in experimental African trypanosomiasis.

The possibilities of trypanocidal drug synergy have been examined in vitro and in vivo using a monomorphic laboratory strain of Trypanosoma rhodesiense. Twenty-seven different drug pair combinations were chosen from among 12 representative trypanocides on the basis of surmized or reported synergy, evidence of collateral sensitivity in resistant strains, and known differences in modes of action or in field use. In vitro synergy test were made with a transfer plate technique which allows direct isobol determination by microtest tray superimposition. All pairs showing synergy in vitro were tested further in mice. Statistically significant synergy was shown only by suramin and tryparsamide, suramin and Puromycin, and suramin and Berenil. Although six other pairs, of which three contained suramin, showed higher than addictive cure rates, these rates fell short of statistical significance.

Animals↗

Involvement of the mitochondrion respiratory chain in the synergy achieved by treatment of human ovarian carcinoma cell lines with both tumor necrosis factor-alpha and cis-diamminedichloroplatinum.

BACKGROUND: Previous studies have demonstrated that treatment of human tumor cell lines with a combination of cis-diamminedichloroplatinum (CDDP) and tumor necrosis factor-alpha (TNF-alpha) results in additive/synergistic cytotoxic effects and reverses tumor cell resistance to TNF drugs. Free radical intermediates are induced by both TNF-alpha and CDDP; however, the role of free radicals in synergy is not known. This study investigated the effect of two inhibitors on synergy, phenoxan (Phe) and butylated hydroxyanisole (BHA), which inhibit Complex I and Complex I and II of the mitochondrion respiratory chain, respectively. METHODS: Three human ovarian carcinoma cell lines of different sensitivity to TNF-alpha and/or CDDP were selected for the study and consisted of 222, a TNF/CDDP-sensitive line, 222TR (TNF-resistant), a TNF-resistant, CDDP-sensitive line, and AD10, a TNF-sensitive, CDDP-resistant line. Cytotoxicity was determined by the microculture tetrazolium dye assay. RESULTS: Synergy in cytotoxicity was achieved in all three lines treated with a combination of TNF-alpha and CDDP. Cytotoxicity by either TNF-alpha or CDDP or by both TNF-alpha and CDDP was inhibited in the presence of either Phe or BHA. Pretreatment of tumor cells with either Phe or BHA for up to 4 hours, washed and followed by the addition of the cytotoxic agents (alone or combined), resulted in no inhibitory effect. Pretreatment of the cells with the cytotoxic agent for up to 2 hours, washed and then followed by the addition of Phe, resulted in significant inhibition of cytotoxicity. In contrast to Phe, the addition of BHA as late as 12 hours post pretreatment of the cells with the cytotoxic agent(s) still inhibited cytotoxicity. These results demonstrated that free radicals are involved in cytotoxicity mediated by a single agent, and in synergy with both agents. Further, the results demonstrated that Phe acts at an early stage of the cytotoxic pathway and that BHA acts at both an early and a late stage of the cytotoxic pathway. CONCLUSIONS: These results demonstrated that both TNF-alpha and CDDP rapidly stimulate the induction of free radicals but a lag of several hours was necessary to initiate the irreversible program of cell death. Further, the studies demonstrated that synergy and reversal of drug resistance in ovarian tumor cells by TNF-alpha and CDDP, used in combination, share the same pathway of cytotoxicity as that mediated by TNF-alpha or CDDP used as a single agent.

Antineoplastic Agents↗

Coordinated series of studies to evaluate characteristics and mechanisms of acute coronary syndromes in high-risk patients randomly assigned to enoxaparin or unfractionated heparin: design and rationale of the SYNERGY Library.

Clinical trials and accompanying substudies in patients with acute coronary syndromes (ACS) have over the last several years yielded a wealth of knowledge about the pathophysiology and management of this high-risk condition. The Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is a large-scale, randomized, controlled trial evaluating the effect of enoxaparin and unfractionated heparin on death and myocardial infarction in high-risk patients presenting with non-ST-segment elevation ACS. The SYNERGY Library has been designed as a coordinated series of investigations with simultaneous data acquisition on the same cohort of approximately 500 SYNERGY patients at 60 centers in North America. Specifically, electrocardiograms, coronary arteriograms, inflammatory markers, coagulation studies, and genetic samples will be collected and processed at core laboratory facilities, and the results will be stored in a central repository. This novel strategy for substudy investigation is unprecedented in cardiovascular clinical trials. The goal is to gain significant understanding about this patient population, discover new principles of pathophysiology, identify novel pharmacologic targets, and streamline further drug development. It is hoped that the SYNERGY Library will serve as a model for future substudy design to maximize academic insight within the framework of a large-scale, multicenter trial.

Angina, Unstable↗

Using relative risk models for estimating synergy between two risk factors.

The synergy between two risk factors measures the extent to which each of them is more harmful in combination with the other than when acting alone. Relative risk models which describe interaction between risk factors with a few parameters are well adapted to the quantification of synergy. A simple measure of synergy and a method for its estimation with the help of relative risk models are proposed. This concept of synergy provides a simple interpretation of the non-linear parameter of several classical relative risk models. The discussion is illustrated with examples taken from cancer epidemiology of the upper aerodigestive tract.

Alcohol Drinking↗

Mutagenic synergy between paraoxon and plant-activated m-phenylenediamine or 2-acetoxyacetylaminofluorene.

Paraoxon (diethyl-p-nitrophenylphosphate) is the toxic, but non-mutagenic metabolite of the organophosphorus ester insecticide parathion. Although this agent has been used as a deacetylase inhibitor in many studies, we discovered a mutagenic synergy when paraoxon was incubated with plant-activated m-phenylenediamine (mPDA) or with direct-acting 2-acetoxyacetylaminofluorene (2AAAF) and S. typhimurium tester strains. Using non-toxic concentrations of plant-activated mPDA and paraoxon a 10-fold increase in the mutant yield of S. typhimurium was observed. The mutagenicity of the plant-activated mPDA product required that O-acetyltransferase (OAT) be expressed by the S. typhimurium tester strain. However, the paraoxon-dependent mutagenic synergy was observed using the direct-acting arylamine metabolite, 2AAAF, with strains YG1024, TA98 and TA98/1,8-DNP6 regardless of their OAT activity. This mutagenic synergy is dependent upon the presence of an activated acetylated form of the arylamine. The data presented here demonstrate that this mutagenic synergy is limited to paraoxon and not to the parent compound (parathion) or to a major metabolite of parathion (p-nitrophenol).

Acetoxyacetylaminofluorene↗

Development of functional synergies for speech motor coordination in childhood and adolescence.

Adults produce rapid, interleaved sequences of speech sounds by controlling the relative motions in time and space of the oral articulators. The control and coordination of these effectors appear to be automatic, effortless, and usually error free. If speech production is viewed within the framework of classical motor control theories, we can infer that adults have organized functional synergies (consistent patterns of activation of muscle collectives) that act as stable subunits. In this study, the development of these stable functional synergies is examined. Motion of the upper lip, lower lip, and jaw was recorded during sentence production in 180 children and adults (aged 4-22 years). Two indices of oral motor coordination were computed, which reflect the degree of trial-to-trial consistency in intereffector relationships and thus the stability of the underlying functional synergies. Major findings are: (a) The time course of development for speech motor coordination is protracted, (b) speech motor control processes are not adultlike until after age 14 years for both females and males, (c) boys (until age 5 years) show a slower maturational course of speech motor development, and (d) late childhood (the 7- to 12-year period) is characterized by a plateau in the development of these coordinative synergies for speech production. We posit that multiple factors are likely to contribute to the protracted development of oral motor coordination for speech, including maturation of components of the motor system itself and maturation of the brain subsystems for language processing.

Adolescent↗

Reciprocal inhibition, synergies, and movements.

This paper presents a conceptual scheme relating discrete motor entities, such as muscles, joints, synergies and reflexes, to a continuous space of movements. Synergies are first derived as combinations of muscles, with reference to Ia reciprocal inhibition. Derived synergies may be modified into bases (in the linear space sense) for movements. The empirical example discussed is human postural synergies. The methods presented provide a relatively simple means for describing the control of bending and twisting movements about a joint by multiple muscles, joined by modifiable spinal interconnections.

Humans↗

Synergy and antagonism of combinations with quinolones.

Combinations of fluoroquinolones with other antimicrobial agents have been extensively investigated. Combinations of fluoroquinolones with aminoglycosides, beta-lactams, imidazoles, macrolides and clindamycin infrequently show synergy against Enterobacteriaceae and gram-positive bacteria. These combinations rarely show antagonism. Combinations of rifampin with fluoroquinolones tested against Staphylococcus aureus have been reported to show synergy and antagonism, and in vitro results have not correlated with results of animal infection experiments. Against Pseudomonas aeruginosa combinations of antipseudomonas penicillins or imipenem with fluoroquinolones are synergistic for 20% to 50% of isolates in vitro and also are synergistic in animal models of infection, whereas combinations of aminoglycosides with fluoroquinolones rarely show synergy against Pseudomonas aeruginosa. Against anaerobic species such as Bacteroides fragilis combinations of fluoroquinolones with clindamycin, anti-anaerobic penicillins, cephalosporins or imidazoles are occasionally synergistic but usually indifferent. Ciprofloxacin and ofloxacin combined with antituberculosis agents have activity against Mycobacterium tuberculosis and atypical mycobacteria. In general, fluoroquinolones should be combined with other agents not to achieve synergy, which is extremely variable, but to provide activity against bacteria inadequately inhibited by the fluoroquinolones.

4-Quinolones↗

Kinematic synergy adaptation to an unstable support surface and equilibrium maintenance during forward trunk movement.

The aim of this investigation was to study the adaptation to an unstable support surface of kinematic synergy responsible for equilibrium control during upper trunk movements. Eight adult subjects were asked to bend their upper trunk forward to an angle of 35 degrees and then to hold the final position for 3 s, first in a standard condition, with two feet on the ground and the second, on a rocking platform swinging in the sagittal plane. The movement characteristics (duration, amplitude, and mean angular velocity of the trunk), the time course of the antero-posterior center of mass (CM) shift during the movement, and the EMG pattern of the main muscles involved in the movement were studied under the two experimental conditions. Kinematic synergy was quantified by performing a principal component analysis on the hip, knee, and ankle angle changes occurring during the movement. The results indicate that (1) the CM shift from the very onset of the movement remains controlled during performance of the forward trunk movement when the equilibrium constraints were increased; (2) the principal component analysis of the hip, knee, and ankle angle changes occurring during the movement showed a transition from one principal component (PC(1)) in the standard condition to two components in the rocking platform condition; (3) the greatest contribution of PC(1) (weight coefficients) was located at the hip level in both the standard and rocking platform conditions, while the greatest contribution of PC(2) in the rocking platform condition was located at the ankle level; and (4) the EMG pattern underlying kinematic synergy is modified. It is concluded that a simple adaptation of kinematic synergy by changing the weight coefficients of each pair of joints participating in the movement is no longer sufficient when the equilibrium constraints increase and, rather, disturbs equilibrium. The CNS has to provide two parallel controls, one to perform the trunk movement and the other to preserve equilibrium.

Adaptation, Physiological↗

Finger synergies during multi-finger cyclic production of moment of force.

We investigated multi-finger synergies stabilizing the total moment of force and the total force when the subjects produced a quick cyclic change in the total moment of force. The seated subjects performed the task with the fingers of the dominant arm while paced by the metronome at 1.33 Hz. They were required to produce a rhythmic, sine-like change in the total pronation-supination moment of force computed with respect to the midpoint between the middle and ring fingers. The framework of the uncontrolled manifold hypothesis was used to compute indices of stabilization of the total moment and of the total force across 20 cycles. Variance of the total moment showed a cyclic pattern with peaks close to the peak rate of the moment change. Variance of the total force was maximal close to peak moment into supination. Higher magnitudes of the moment directed against the required moment direction (antagonist moment) were produced by individual fingers during supination efforts as compared to pronation efforts. Indices of multi-finger synergies showed across-trials stabilization of the total moment over the whole cycle but not of the total force. These indices were smaller during supination efforts. We conclude that the central nervous system facilitates multi-finger synergies stabilizing the total rotational action across a variety of tasks. Synergies stabilizing the total force are not seen in tasks that do not explicitly require accurate force control. Pronation efforts are performed more efficiently and with better stabilization of the action.

Adult↗

Axial synergies during human upper trunk bending.

Upper trunk bending movements were accompanied by opposite movements of the lower body segments. These axial kinematic synergies maintained equilibrium during the movement performance by stabilizing the center of gravity (CG), which shifted on average across all the subjects by 1 +/- 4 cm in the anteroposterior direction and thus always remained within the support area. The aim of the present investigation was to provide an insight into the central control responsible for the performance of these synergies. The kinematic analysis was performed by the method of principal components (PC) analysis applied to the covariation between ankle, knee and hip joint angles and compared with CG shifts during upper trunk bending. Subjects were asked to perform backward or forward upper trunk bending in response to a tone. They were instructed to move as fast as possible or slowly (2 s), with high or low movement amplitudes. PC analysis showed a strong correlation between hip, knee and ankle joint changes. The first principal component (PC1) representing a multijoint movement with fixed ratios between joint angular changes, accounted, on average, for 99.7% +/- 0.2% of the total angular variance in the forward trunk movements and for 98.4% +/- 1.4% in the backward movements. The instructed voluntary regulation of the amplitude and velocity of the movement was achieved by adapting the bell-shaped profile of the velocity time course without changes in interjoint angular relations. Fixed ratios between changes in joint angles, represented by PC1, ensured localization of the CG within the support area during trunk bending. The ratios given by PC1 showed highly significant dependence on subjects, suggesting the adaptability of the central control to each subject's biomechanical peculiarities. Subject's intertrial variability of PC1 ratios was small, suggesting a stereotyped automatic interjoint coordination. When changing velocity and amplitude of the movement, the ratios remained the same in about half the subjects while in others slight variations were observed. A weak second principal component (PC2) was shown only for fast movements. In forward movements PC2 reflected the early knee flexion that seems related to the disturbances caused by the passive interaction between body segments, rather than to the effect of a central command. In fast backward movements, PC2 reflected the delay in hip extension relative to the movement onset in the ankle and knee that mirrors intersubject differences in the initiation process of the axial synergy. The results suggest that PC1 reflects the centrally controlled multijoint movement, defining the time course and amplitude of the movement and fixing the ratios between changes in joint angles. They support the hypothesis that the axial kinematic synergies result from a central automatic control that stabilizes the CG shift in the anteroposterior direction while performing the upper trunk bending.

Adaptation, Physiological↗

Evaluation of the E test for the assessment of synergy of antibiotic combinations against multiresistant Pseudomonas aeruginosa isolates from cystic fibrosis patients.

The determination of synergistic effects of antimicrobial drug combinations can lead to improved therapeutic options in the antibiotic treatment of cystic fibrosis patients who are chronically infected with multiresistant Pseudomonas aeruginosa isolates. The aim of this study was to evaluate the performance of the E test versus the standard agar dilution checkerboard susceptibility test in the assessment of synergy and, in addition, to determine the activity of two antimicrobial combinations against 163 multiresistant P. aeruginosa isolates from cystic fibrosis patients. The agreement between the checkerboard method and the E test was excellent (>90%) for nonmucoid as well as mucoid isolates from cystic fibrosis patients. The rate of synergy was higher for the antibiotic combination of ceftazidime and tobramycin (28.8% of the cystic fibrosis strains) than for the combination of meropenem and tobramycin (19.0%). However, the probability of synergy for the second antibiotic combination increased significantly when the synergy of the first antibiotic combination had already been demonstrated (Fischer's exact test, p=0.049). The results show that the E test is a valuable and practical method for routine microbiological diagnostics and can aid in the selection of improved antibiotic options in the treatment of cystic fibrosis patients chronically infected with P. aeruginosa.

Anti-Bacterial Agents↗

Synergy of four macrolide antibiotics with chloroquine against chloroquine-resistant Plasmodium falciparum in vitro.

The antimalarial activity of four macrolide antibiotics was investigated against the multidrug resistant K1 strain of Plasmodium falciparum in vitro. ID50 (50% inhibitory concentration) values for erythromycin, spiramycin, tylosin tartrate and oleandomycin phosphate in 48-hour assays were 1.6 X 10(-4)M, 2.5 X 10(-5)M, 1.2 X 10(-5)M and 9 X 10(-6)M respectively, and in 96 hour assays were 10(-5)M, 2.6 X 10(-6)M, 2.6 X 10(-6) and 3 X 10(-6)M, respectively. Comparable values were obtained in assays in which drug effect was quantified from either parasite counts or 14C isoleucine incorporation. Each of the four macrolides displayed synergy with chloroquine at the IC90 (90% inhibitory concentration) level, but at the IC50 level synergy was either less pronounced or absent. For each combination this difference in the degree of synergy was significant at the 95% level of confidence. In replicate assays in which 3H hypoxanthine was the marker of drug effect, synergy between chloroquine and either erythromycin or spiramycin could not be detected.

Animals↗

The misuse of analysis of variance to detect synergy in combination drug studies.

Drug combination studies often examine the possibility of synergy between drugs. Synergy is defined as an effect of a combination of drugs greater than that expected from the effects of the drugs given individually. One technique used by several investigators is the use of analysis of variance (ANOVA) to determine synergy. In this discussion, the argument is made that due to the pharmacology of drug combination studies the conditions necessary to support the use of ANOVA to detect synergy are typically not met. Therefore, the ANOVA technique is invalid for these drug combination studies.

Analysis of Variance↗

Synergy between protamine and vancomycin in the treatment of Staphylococcus epidermidis biofilms.

OBJECTIVES: To test for synergy between protamine and vancomycin by analyzing their bactericidal activities against slime-producing Staphylococcus epidermidis ATCC 35983 under planktonic and biofilm conditions. METHODS: We evaluated the activity of vancomycin and protamine separately against planktonic S epidermidis in broth by measuring the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) for each agent according to the standard macrobroth dilution method. To assess the possibility of synergy between these two agents, planktonic S epidermidis was exposed to vancomycin and protamine together in varying concentrations. Biofilms containing S epidermidis were then prepared and subjected to incubation with vancomycin and protamine separately as well as combined in varying concentrations. The bacterial viability of S epidermidis in the planktonic and biofilm phases after exposure to these two agents was assessed by qualitative culture and determination of viable colony blots. RESULTS: Standard antibacterial susceptibility tests revealed that the MICs of protamine and vancomycin were 1 and 2 micrograms/mL, respectively, and their MBCs were 4 micrograms/mL. The MICs were unchanged when protamine and vancomycin were combined in varying concentrations. Neither agent exhibited significant bactericidal activity against S epidermidis in the biofilm phase at concentrations < or = 32 micrograms/mL. However, a combination of both agents, each at 32 micrograms/mL, resulted in a 7-log decrease in viable bacterial counts. CONCLUSIONS: Protamine alone exhibited significant antibacterial activity against planktonic S epidermidis. No synergy was noted between protamine and vancomycin against S epidermidis in the planktonic phase. However, synergy was demonstrated when a combination of protamine and vancomycin was used on S epidermidis in the biofilm phase. Thus, protamine shows promise as an adjunctive agent to vancomycin in the treatment of S epidermidis in biofilms.

Biofilms↗

Studies of in vitro synergy between several beta-lactam and aminoglycoside antibiotics against endocarditis strains of Pseudomonas aeruginosa.

Ten strains of Pseudomonas aeruginosa isolated from patients with endocarditis (1969-1975) and eight similar strains (1980) were assayed for minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) to several aminoglycosides (gentamicin, tobramycin, amikacin) and beta-lactam antibiotics (ticarcillin, piperacillin, azlocillin, moxalactam and MKO 787). In vitro synergy (1969-1975 series) between beta-lactam and aminoglycoside antibiotics was shown uniformly with azlocillin (100 per cent) followed by moxalactam (80 per cent), piperacillin and ticarcillin (66 per cent) and MKO 787 (13.3 per cent). Results were similar in 1980. Synergy of azlocillin was demonstrated with five strains previously not showing synergy between carbenicillin and an aminoglycoside. In 1980 four of eight patients infected with pseudomonads that were not synergistically affected in vitro were refractory to treatment with the piperacillin-aminoglycoside combination. In vitro synergy of the infecting strain is necessary for successful medical treatment of patients with P. aeruginosa infective endocarditis.

Aminoglycosides↗

Mechanisms underlying the steroidogenic synergy of insulin and luteinizing hormone in porcine granulosa cells: joint amplification of pivotal sterol-regulatory genes encoding the low-density lipoprotein (LDL) receptor, steroidogenic acute regulatory (stAR) protein and cytochrome P450 side-chain cleavage (P450scc) enzyme.

Growth of ovarian Graafian follicles and cytodifferentiation of granulosa and theca cells are regulated by gonadotropins, sex steroids and peptidyl growth factors. For example insulin and intraovarian insulin-like growth factor type I (IGF-I) may amplify the actions of both follicle stimulating hormone (FSH) and luteinizing hormone (LH) in promoting biochemical luteinization and enhancing steroidogenesis. To explore further the notion of interactions between insulinomimetic peptides and LH and to examine the associated mechanisms, we have established porcine granulosa cells in monolayer culture for 48 h in 3% serum with insulin (1 microg/ml), estradiol (0.5 microg/ml), and follicle stimulating hormone (FSH, 5 ng/ml) to allow cell anchorage, facilitate in vitro cytodifferentiation and confer LH responsiveness. To limit any carry-over effects of serum, granulosa cells were stabilized overnight in serum-free medium. Studies were then initiated to assess the impact of insulin on the dose-responsive actions of LH. A maximally effective concentration of insulin (1 microg/ml) synergistically augmented LH's dose-dependent ampilification of progesterone and cAMP accumulation; viz. by approximately twofold (progesterone) and approximately 2.5-fold (cAMP) above that observed in maximally LH-stimulated cultures (P < 0.001). Mechanistically, insulin significantly enhanced the sensitivity of granulosa cells to LH's drive of cAMP accumulation [ED50 for LH 61 +/- 14 ng/ml (control) vs. 10 +/- 1.0 ng/ml (insulin) (P < 0.01)]. Insulin also augmented the maximal stimulatory effect of LH; i.e. LH efficacy rose from 6.5 +/- 0.4 to 17 +/- 1.4 (pmole cAMP/microg DNA/48 h; P < 0.001). Insulin dose-response analysis showed that insulin alone minimally elevated basal, but significantly heightened LH's stimulation of progesterone and cAMP accumulation at (insulin) concentrations as low as 3-10 ng/ml. The molecular mechanisms underlying insulin and LH's synergy were assessed by RNase protection assays with (porcine) cRNA probes encoding the low density lipoprotein receptor (LDL-R), Steroidogenic Acute Regulatory Protein (StAR), P450 cholesterol sidechain cleavage enzyme (P450scc) and (as a possible negative control) Sterol Carrier Protein 2 (SCP-2) [data normalized to constitutive 18S rRNA]. Non linear least-squares analysis was applied to confirm or refute an hypothesis of interactive synergy between LH and insulin on gene expression. LH and insulin alone exerted no effect on StAR message accumulation, and LH alone minimally stimulated P450scc and LDL-R mRNA's accumulation at 48 h. In contrast, insulin in combination with LH augmented StAR mRNA concentrations by approximately 5-10-fold and stimulated LDL-R message levels by threefold above the respective maximally LH-driven values (P < 0.01). Maximal P450scc mRNA expression was enhanced twofold by cotreatment with LH and insulin compared with maximal LH-treated cultures. In contrast SCP-2 mRNA accumulation remained unaffected by any treatment. In summary, we have used a serum-free, in vitro differentiated porcine granulosa cell culture system to assess regulatory interactions between the disparate first messengers, LH and insulin. We observe marked LH-insulin steroidogenic synergy after 48 h of joint hormonal stimulation, and further clarify that the mechanism(s) of synergy include augmentation of cAMP production and increased steady-state concentrations of transcripts of key sterol-regulatory genes; namely, LDL-R, StAR, and P450scc, but not SCP-2. Since the encoded products of these genes variously control sterol substrate uptake, delivery to and utilization in mitochondrial steroidogenesis, we speculate that the concerted actions of insulin-like peptides and LH may contribute to steroidogenic differentiation during the later stages of follicular maturation and the granulosa-luteal cell transition.

Animals↗

Evaluation of antibiotic synergy against Acinetobacter baumannii: a comparison with Etest, time-kill, and checkerboard methods.

Acinetobacter baumannii is becoming increasingly resistant to antibiotics, often requiring combination therapy. Numerous methods exist to detect the presence of in vitro synergy with the time-kill and checkerboard tests being widely used. The Epsilometer test (E test) is a new method that is less labor intensive, but has not been evaluated using a wide range of antimicrobials and organisms. We assessed synergy using the time-kill and checkerboard tests and compared the results to the E test method using 10 clinical isolates of A. baumannii. Antimicrobial combinations evaluated consisted of trovafloxacin or tobramycin in combination with cefepime or piperacillin. Synergy was detected with all combinations by either the checkerboard or time-kill method. Synergy was not detected by the Etest method. The agreement between the time-kill test and Etest method was 72% (range 42-97%); for the time-kill and checkerboard tests, agreement was 51% (range 30-67%). The Etest method appears promising although further testing should be performed with additional antimicrobial agents and organisms.

Acinetobacter↗