Combined Action Of Antibiotics Research Articles

New insights into the effects of antibiotics and copper on microbial community diversity and carbon source utilization.

Residual antibiotics (ABs) and heavy metals (HMs) are continuously released from soil, reflecting their intensive use and contamination of water and soil, posing an environmental problem of great concern. Relatively few studies exist of the functional diversity of soil microorganisms under the combined action of ABs and HMs. To address this deficiency, BIOLOG ECO microplates and the Integrated Biological Responses version 2 (IBRv2) method were used to comprehensively explore the effects of single and combined actions of copper (Cu) and enrofloxacin (ENR), oxytetracycline (OTC), and sulfadimidine (SM2) on the soil microbial community. The results showed that the high concentration (0.80mmol/kg) compound group had a significant effect on average well color development (AWCD) and OTC showed a dose-response relationship. The results of IBRv2 analysis showed that the single treatment group of ENR or SM2 had a significant effect on soil microbial communities, and the IBRv2 of E1 was 5.432. Microbes under ENR, SM2, and Cu stress had more types of available carbon sources, and all treatment groups were significantly more enriched with microorganisms having D-mannitol and L-asparagine as carbon sources. This study confirms that the combined effects of ABs and HMs can inhibit or promote the function of soil microbial communities. In addition, this paper will provide new insights into IBRv2 as an effective method to evaluate the impacts of contaminants on soil health.

Minimal biophysical model of combined antibiotic action.

Phenomenological relations such as Ohm's or Fourier's law have a venerable history in physics but are still scarce in biology. This situation restrains predictive theory. Here, we build on bacterial "growth laws," which capture physiological feedback between translation and cell growth, to construct a minimal biophysical model for the combined action of ribosome-targeting antibiotics. Our model predicts drug interactions like antagonism or synergy solely from responses to individual drugs. We provide analytical results for limiting cases, which agree well with numerical results. We systematically refine the model by including direct physical interactions of different antibiotics on the ribosome. In a limiting case, our model provides a mechanistic underpinning for recent predictions of higher-order interactions that were derived using entropy maximization. We further refine the model to include the effects of antibiotics that mimic starvation and the presence of resistance genes. We describe the impact of a starvation-mimicking antibiotic on drug interactions analytically and verify it experimentally. Our extended model suggests a change in the type of drug interaction that depends on the strength of resistance, which challenges established rescaling paradigms. We experimentally show that the presence of unregulated resistance genes can lead to altered drug interaction, which agrees with the prediction of the model. While minimal, the model is readily adaptable and opens the door to predicting interactions of second and higher-order in a broad range of biological systems.

Enhanced killing of multiresistant strains of Staphylococcus aureus and Acinetobacter baumannii through a combined action of antibiotics and bacteriocins

A search for multidrug-resistant bacteria was conducted in 1,143 clinical samples in Morocco from which 244 isolates were tested against 29 different antibiotics. This showed a prevalence of resistant strains of 68.4%. The spectra of resistance ranged from 1 to 21. Ampicillin, Ticarcilin, Amoxicillin, Piperacillin and Ciproflaxin were the most frequently resisted. Eight antibiotics were tested against two selected strains, S. aureus 400037 from conjunctive mucosa and A. baumannii 280291 urine, which showed resistance to concentrations up to 240 µg.ml-1. A. baumannii 280291 also resisted the two bacteriocins nisin A and pediocin PA-1, while S. aureus 400037 showed relative sensitivity to nisin A with a MIC of 125 µg.ml-1 but was insensitive to pediocin PA-1. However, the combined use of antibiotics and bacteriocins showedpotentiating effects of bacteriocins on antibiotics or synergistic effects between the two antimicrobials. Combinations with nisin A resulted for instance in a sensitisation of S. aureus 400037 to penicillin G, amoxicillin, ampicillin, cefaclor and ciprofloxacin with MIC values as low as 0.19; 0.78; 0.31; 3.75 and 0.62 µg.ml-1 respectively. Against A. baumannii 280291, the MIC value of gentamycin decreased from 60 to 3.75 µg.ml-1, in the presence of nisin. Similar results were obtained when antibiotics were combined with pediocin PA-1 and such effects were even stronger when both bacteriocins were used along with antibiotics. The present study shows that pathogenic bacteria that developed high levels of resistance to a wide array of antibiotics can be rendered sensitive to the same antibiotics simply by combining them with bacteriocins.

Analysis by Means of 1H NMR Spectroscopy of Heteroassociaion in Water Solution of Antitumor Antibiotics Daunomycin and Actinomycin D

Heteroassociation of aromatic antitumor antibiotics daunomycin (DAU) and actinomycin D (AMD) was investigated using 1D and 2D 1H NMR spectroscopy (at 500 MHz) and molecular mechanics procedure with the goal of establishing the mechanism of the combined action of antibiotics in the system AMD-DAU. The experimental data were processed applying a modified statistical and thermodynamic model of the molecules heteroassociation. Proceeding from this model the values were obtained of induced proton chemical shifts, equilibrium constant and thermodynamic parameters of complexing reaction between DAU and AMD. By means of molecular mechanics with the use of X-PLOR software and of the analysis results of the induced proton chemical shifts in the molecules the most probable spatial structure, 1:1, was established for the heterocomplex of DAU and AMD. Heterocomplexes of daunomycin and actinomycin D form due to stacking interaction between the aromatic chromophores with possible additional stabilization of the complexes by an intermolecular hydrogen bond.

Microbial Kinetics of Drug Action against Gram-Positive and Gram-Negative Organisms III: Effect of Lincomycin and Clindamycin Combinations on Staphylococcus aureus and Escherichia coli

The functional dependencies of apparent first-order generation rate constants, kapp, of drug-affected cultures on drug concentrations indicate that lincomycin and clindamycin possess the same mechanism of action, which is bacteriostatic, against Staphylococcus aureus. Clindamycin also possesses another mechanism of action, which is bactericidal, at high concentration levels. However, clindamycin possesses only one of the two mechanisms of lincomycin action, which is bacteriostatic, against Escherichia coli. The relative potency of action of a clindamycin-lincomycin combination against Staph. aureus is variable, and the effective ratio ranges between 5:1 and 9:1; the effective ratio against E. coli is fixed at 6:1 over a wide concentration range. This difference is attributed to differences in bioavailability and/or binding characteristics of the drugs for bioreceptors, as a consequence of structural modifications in the drug molecules, and to differences in modes of action in the respective organisms. Mixtures containing equipotent fractions of clindamycin and lincomycin show “equivalence” or “indifference” of effects on Staph. aureus. The combined action of the mixtures can be quantitatively predicted from the separate dose-response curves of either component drug alone. Therefore, it is concluded that clindamycin and lincomycin may bind to the same receptor site that is engaged in microbial protein synthesis to inhibit the generation of Staph. aureus. However, combinations of clindamycin and lincomycin are less active than the a priori equipotent concentration of either drug alone in their action against E. coli, demonstrating unequivocally an antagonism of effects. Furthermore, the degree of antagonism is dependent on the order of addition of the drugs, which is attributed to the possibility that clindamycin and lincomycin bind differently on active and allosteric loci of the same receptor site functionally engaged in protein synthesis in E. coli. A rational approach to the quantification and prediction of combined antibiotic action must, therefore, be based not only on the kinetics and mechanisms of action as well as on the dose-response relationship over a wide concentration range for the separate antibiotics but also on the strain and species of the test organism.

Kinetics and Mechanisms of Action of Drugs on Microorganisms XV: Effect of Erythromycin on the Action of Lincomycin (Phase II) and the 7(S)-Chloro Analogs of Lincomycin against Escherichia coli

Lincomycin-affected Escherichia coli cultures show two phases of steady-state generation. The initial (Phase I) steady-state generation, expressed as In N = kapp.It + constant, is followed after several generations by an ultimate (Phase II) steady-state generation, In N = kapp.IIt + constant, at the same dose level, where kapp.I >kapp.II. Cultures affected with erythromycin or the 7(S)-chloro analogs of lincomycin show only one steady-state generation. A fixed potency ratio of erythromycin lactobionate-lincomycin hydro-chloride (Phase I) as 1:5 (on weight basis) is operative over a wide drug concentration range. Combinations of erythromycin and lincomycin are quantifiable on the basis of this potency factor as kineti-cally equivalent in action to the equipotent lincomycin (in Phase I action) or erythromycin alone. However, the potency factor for erythromycin and lincomycin (Phase II) varies with the concentration level. Therefore, combinations of erythromycin and lincomycin, which a priori have the same potency as equivalent lincomycin alone (in Phase I action), are less potent in the Phase II action. This is attributed to an artifact of diluted lincomycin effect in Phase II action of the mixture and not to antagonism of effects. Combinations of erythromycin and the 7(S)-chloro analogs of lincomycin demonstrate a priori antagonism of effects because of possible allosteric interactions which decrease the effects of one drug in the presence of the other at their site of action. It is emphasized that the dose-response relationship over a wide concentration range, as well as the kinetics and mechanisms of the separate drug action, must be considered in the quantification and prediction of combined action of antibiotics.

Methods of testing combined antibiotic bactericidal action and the significance of the results

A DESCRIPTION IS GIVEN OF TWO METHODS OF MEASURING COMBINED ANTIBIOTIC BACTERICIDAL ACTION: a test in liquid medium with subculture and the cellophane transfer method. It is emphasized that information so obtained is necessary in order to predict the effect of combined treatment, particularly in bacterial endocarditis due to organisms not fully sensitive to penicillin. Eight case histories are given, in all of which such a prediction was fulfilled, one of failure and seven of success from the use of five different combinations. The cellophane transfer method was applied to the study of the nature of combined antibiotic action on multiple strains of several bacterial species. The results were rarely uniform for any given combination and species: the necessity for individual tests as a guide to treatment is thus confirmed.Modifications of the theory of combined action formulated by Jawetz are proposed.

Antibiotic combinations; antibacterial action of plasma after ingestion of novobiocin or penicillin G or both.

THIS paper reports another in a series of studies designed to throw some light on the combined action of antibiotics in vivo by controlled observations on the antibacterial action of blood after the administration of antibiotics to the same subjects singly and in combinations.§ The present study deals with the combination of novobiocin with penicillin and, like most of the others, was carried out in normal men given the same total amount of each agent separately or of both together in equal parts. The plasma obtained at intervals after each dose was assayed for antibacterial action against 4 different bacterial . . .

The participation of polymyxin B in combined antibiotic action.

Article1 July 1954THE PARTICIPATION OF POLYMYXIN B IN COMBINED ANTIBIOTIC ACTIONERNEST JAWETZ, M.D., Ph.D., VIRGINIA COLEMAN, B.A., JANET B. GUNNISON, M.A.ERNEST JAWETZ, M.D., Ph.D.Search for more papers by this author, VIRGINIA COLEMAN, B.A.Search for more papers by this author, JANET B. GUNNISON, M.A.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-41-1-79 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptThe polymyxins are a group of stable basic polypeptides isolated fromBacillus polymyxa.1Depending upon their amino acid composition, they have been designated by letters A, B, C, D and E. Polymyxins A and D possess significant nephrotoxic action and are no longer employed in therapy. Polymyxins B and E produce annoying, though harmless, neurotoxic side effects but are not significantly nephrotoxic if administered intramuscularly in doses not exceeding 2.5 mg./kg./day to persons with good renal function.2, 3These drugs are rapidly bactericidal for gram-negative organisms and have been particularly useful in the management of infections due toPseudomonas aeruginosa.3,...Bibliography1. Stansly PG: The polymyxins, Am. J. Med. 1: 807, 1949. CrossrefGoogle Scholar2. HopperJawetzHinman JEF: Polymyxin B in chronic pyelonephritis: observations on the safety of the drug and on its influence on the renal infection, Am. J. M. Sc. 225: 302, 1953. CrossrefGoogle Scholar3. Jawetz E: Infections with Pseudomonas aeruginosa treated with polymyxin B, Arch. Int. Med. 89: 90, 1952. CrossrefGoogle Scholar4. Yow EM: Development of Proteus and Pseudomonas infections during antibiotic therapy, J. A. M. A. 149: 1184, 1952. CrossrefMedlineGoogle Scholar5. PulaskiBakerRosenbergConnell EJHJMLJF: Laboratory and clinical studies of polymyxin B and E, J. Clin. Investigation 28: 1028, 1949. CrossrefGoogle Scholar6. PriceRandallWelchChandler CWWAHVL: Studies of the combined action of antibiotics and sulfonamides, Am. J. Pub. Health 39: 340, 1949. CrossrefGoogle Scholar7. BlissWarthLong EAPTPH: Studies of combinations of antibiotics in vitro and in experimental infections in mice, Bull. Johns Hopkins Hosp. 90: 149, 1952. MedlineGoogle Scholar8. NeterKunzMorgan EEHED: Synergistic effects of polymyxin B and Terramycin on bacteria encountered in urinary tract infections, J. Urol. 67: 773, 1952. CrossrefMedlineGoogle Scholar9. JawetzGunnison EJB: Studies on antibiotic synergism and antagonism: a scheme of combined antibiotic action, Antibiotics and Chemotherapy 2: 243, 1952. Google Scholar10. Jawetz E: In preparation. Google Scholar11. GunnisonShevkyBruffColemanJawetz JBMCJAVRE: Studies on antibiotic synergism and antagonism: the effect in vitro of combinations of antibiotics on bacteria of varying resistance to single antibiotics, J. Bact. 66: 150, 1953. CrossrefMedlineGoogle Scholar12. JawetzGunnison EJB: Antibiotic synergism and antagonism: an assessment of the problem, Pharmacol. Rev. 5: 175, 1953. MedlineGoogle Scholar13. JawetzGunnison EJB: An experimental basis of combined antibiotic action (Report to the Council on Pharmacy and Chemistry of the A. M. A.), J. A. M. A. 150: 693, 1952. CrossrefMedlineGoogle Scholar14. RantzRandall LAE: Antibiotic synergism and Staphylococcus aureus , Antibiotics and Chemotherapy 2: 645, 1952. Google Scholar15. DowlingLepperJackson HFMHGG: When should antibiotics be used in combination? J. A. M. A. 151: 813, 1953. CrossrefMedlineGoogle Scholar16. Haviland JW: Advances in antibiotic therapy, Ann. Int. Med. 39: 307, 1953. LinkGoogle Scholar17. KleinSchorr MSE: The role of bacterial resistance in antibiotic synergism and antagonism, J. Bact. 65: 454, 1953. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: San Francisco, California*Received for publication November 6, 1953.Supported in part by grants from the National Institutes of Health (E-214), Burroughs, Wellcome and Co., and Chas. Pfizer and Co.From the Departments of Microbiology, Medicine and Pediatrics, University of California School of Medicine, San Francisco. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byA SYNERGIC PERSPECTIVEPolymyxins and CirculinPolymyxins and CirculinANTIBIOTICS ISOLATED FROM THE GENUS BACILLUS (BACILLACEAE)1 Polypeptide Antibiotics of Medicinal InterestOtogenic MeningitisPolymyxin, Colistin and BacitracinThe activity of some antibiotic combinations onSalmonellaPolymyxin, Neomycin and Bacitracin: Applied Pharmacology 1 July 1954Volume 41, Issue 1Page: 79-88KeywordsAdverse reactionsAmino acidsAntibioticsBacillusMicrobiologyPediatricsPolymyxinsPolypeptidesPseudomonasPseudomonas infections Issue Published: 1 July 1954 PDF downloadLoading ...

Laboratory aspects of combined antibiotic treatment.

Since Ungar's observation in 1943 that penicillin and sulphonamides enhance each other's action, the subject of synergism and antagonism between antibacterial sub stances has received much attention and has recently been extensively reviewed by Garrod (1953). Tests have been made both in vitro and in vivo, and it is certain that some interaction between antibiotics exists and is likely to be therapeutically important. Clinical experience, though limited, confirms this view; on the one hand, it appears that in the treatment of enterococcal endocarditis a combination of penicillin and streptomycin is more efficient than either drug alone (Hunter, 1950; Robbins and Tompsett, 1951 ; Cates et al., 1951), and, on the other hand, in pneumococcal meningitis, penicillin and aureomycin used together are less effective than penicillin alone (Lepper and Dowling, 1951). Interaction occurs in at least three of the manifesta tions of the antibiotic action: inhibition of growth, lethal effect, and emergence of resistant variants. Growth-inhibition tests are simple to perform, but when used to investigate the combined action of antibiotics often fail to correlate with findings in vivo (Jawetz, Gunnison, Speck, and Coleman, 1951; Chopra and Gupta, 1951 ; Bliss et al., 1952). The estimation of the bactericidal effect of a pair of drugs, as opposed to bac teriostatic effect, is much more laborious, but interaction shown in this way may have more therapeutic significance (Hunter, 1950; Gunnison, Jawetz, and Coleman, 1950; Garrod, 1953). The emergence of resistant variants is also bound up with bactericidal action. The present paper records an investigation -of the lethal action of com binations of antibiotics, using a technique simpler than those previously described. The terms synergism and antagonism are defined as follows: a combination of drugs is synergistic when its lethal effect is greater than that of the more lethal drug alone, and antagonistic when its effect is less. Synergism, defined in this way, includes the term additive described by other authors. There may, of course, be no interaction, in which case the effect of the more lethal drug is dominant. A number of different methods have been used in studying the bactericidal effects of mixtures of antibiotics. Generally, complete viable counts have been made at intervals on cultures containing several different con centrations of antibiotics. In order to carry out testing on a larger scale, some workers have used simplified viable counts (Bigger, 1944; Nichols, 1948; Rantz and Randall, 1952), and others the turbidimetric estimation of growth from surviving bacteria (Thomas and Hayes, 1947; Burnell and Kirby, 1951). All these methods are unsuitable for routine testing in a busy clinical labora tory. The simplified viable count method of Martin et al. (1952), recommended by Garrod (1953), tests the action of a pair of antibiotics at one concentration only. This is likely to be misleading, as there are reports that concentrations are important (Hobby and Dawson, 1946; Bliss et al., 1952). The conditions under which antibiotics act in the body are varied, and it is probable that when a patient receives two drugs their relative con centration fluctuates widely. Agar diffusion methods used to detect inhibitory levels have the great advantage of allowing a range of relative concentrations to be tested easily, and as they are also widely employed for routine sensitivity tests it is not surprising that attempts have been made to show interaction by such methods (Peyre and Velu, 1952; King et al., 1953 ; Garrod, 1953). These attempts have, however, been based on interactions at the inhibitory level, and we believe that the appearances of inhibition on solid media can give misleading information. A further step is required to show whether the growth one sees is alive or whether in fact it has been killed. The technique we have used is an agar diffusion method amplified by a simple form of sampling to reveal the l thal action of the antibiotics.

Participation of erythromycin and carbomycin in combined antibiotic action in vitro.

Participation of erythromycin and carbomycin in combined antibiotic action in vitro.

Advances in antibiotic therapy.

Excerpt Although the field of antibiotics is developing so rapidly as to render it almost kaleidoscopic, during recent months several topics of general interest have come into sharp focus. The subj...

Proposed scheme for combined antibiotic action

Proposed scheme for combined antibiotic action

An experimental basis of combined antibiotic action.

The increasing number of available potent antimicrobial agents tempts the physician to use several of these drugs simultaneously in the same patient. This practice is often justified with the statement, "if one drug should not influence the disease-producing micro-organisms, the other one will." Such indiscriminate combined therapy has led to diminishing emphasis on specific etiologic diagnosis which should be the basis of antimicrobial treatment.¹On the basis of the claim "if one drug is good, two should be better," combinations are frequently administered although little is known about their effect. To approach the problem rationally it is important to assemble experimental facts on the behavior of combinations of antimicrobial drugs. Better clinical management might be built on such a foundation. The present report, however, is limited strictly to the effects of drug combinations observed in the laboratory under controlled conditions and in no way implies that the same principles