{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T17:16:48Z","timestamp":1791047808611,"version":"4.1.0"},"reference-count":44,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2010,6,3]],"date-time":"2010-06-03T00:00:00Z","timestamp":1275523200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"DOI":"10.1371\/journal.pcbi.1000796","type":"journal-article","created":{"date-parts":[[2010,6,3]],"date-time":"2010-06-03T16:20:43Z","timestamp":1275582043000},"page":"e1000796","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":131,"title":["Optimal Drug Synergy in Antimicrobial Treatments"],"prefix":"10.1371","volume":"6","author":[{"given":"Joseph Peter","family":"Torella","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remy","family":"Chait","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roy","family":"Kishony","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2010,6,3]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","first-page":"S122","DOI":"10.1038\/nm1145","article-title":"Antibacterial resistance worldwide: causes, challenges and responses.","volume":"10","author":"SB Levy","year":"2004","journal-title":"Nat Med"},{"key":"ref2","article-title":"Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy","year":"2005"},{"key":"ref3","first-page":"365","article-title":"Antibiotics in Laboratory Medicine","author":"SK Pillai","year":"2005"},{"key":"ref4","doi-asserted-by":"crossref","first-page":"390","DOI":"10.2165\/00003495-199652030-00005","article-title":"Combination antimicrobial therapy for bacterial infections - Guidelines for the clinician.","volume":"52","author":"MJ Rybak","year":"1996","journal-title":"Drugs"},{"key":"ref5","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/nchembio817","article-title":"Systems biology and combination therapy in the quest for clinical efficacy.","volume":"2","author":"JB Fitzgerald","year":"2006","journal-title":"Nat Chem Biol"},{"key":"ref6","first-page":"285","article-title":"The problem of synergism and antagonism of combined drugs.","volume":"3","author":"S Loewe","year":"1953","journal-title":"Arzneimittel-Forschung-Drug Research"},{"key":"ref7","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0031-6997(25)00026-2","article-title":"What is synergy?","volume":"41","author":"MC Berenbaum","year":"1989","journal-title":"Pharmacol Rev"},{"key":"ref8","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/S0031-6997(25)06847-4","article-title":"The search for synergy - a critical review from a response-surface perspective.","volume":"47","author":"WR Greco","year":"1995","journal-title":"Pharmacol Rev"},{"key":"ref9","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/nrd1609","article-title":"Multicomponent therapeutics for networked systems.","volume":"4","author":"CT Keith","year":"2005","journal-title":"Nat Rev Drug Discov"},{"key":"ref10","doi-asserted-by":"crossref","first-page":"14918","DOI":"10.1073\/pnas.0800944105","article-title":"Drug interactions modulate the potential for evolution of resistance.","volume":"105","author":"JB Michel","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref11","doi-asserted-by":"crossref","first-page":"13977","DOI":"10.1073\/pnas.0805965105","article-title":"Accelerated evolution of resistance in multidrug environments.","volume":"105","author":"M Hegreness","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref12","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1128\/JB.65.4.454-465.1953","article-title":"The role of bacterial resistance in antibiotic synergism and antagonism.","volume":"65","author":"M Klein","year":"1953","journal-title":"J Bacteriol"},{"key":"ref13","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1038\/nature05685","article-title":"Antibiotic interactions that select against resistance.","volume":"446","author":"R Chait","year":"2007","journal-title":"Nature"},{"key":"ref14","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1128\/AAC.26.6.797","article-title":"Selection of multiple antibiotic-resistance by quinolones, beta-lactams, and aminoglycosides with special reference to cross-resistance between unrelated drug classes.","volume":"26","author":"CC Sanders","year":"1984","journal-title":"Antimicrob Agents Chemother"},{"key":"ref15","doi-asserted-by":"crossref","first-page":"9451","DOI":"10.1073\/pnas.0609839104","article-title":"Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing.","volume":"104","author":"MM Mwangi","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"key":"ref16","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1128\/AAC.33.8.1318","article-title":"Cross-resistance to fluoroquinolones in Multiple-Antibiotic-Resistant (MAR) Escherichia coli selected by tetracycline or chloramphenicol - decreased drug accumulation associated with membrane changes in addition to OmpF reduction.","volume":"33","author":"SP Cohen","year":"1989","journal-title":"Antimicrob Agents Chemother"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1046\/j.1365-2796.2002.01026.x","article-title":"Evolution and spread of antibiotic resistance.","volume":"252","author":"BH Normark","year":"2002","journal-title":"J Intern Med"},{"key":"ref18","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1126\/science.2479983","article-title":"Multiple Mutations in HIV-1 Reverse Transcriptase Confer High-Level Resistance to Zidovudine (AZT).","volume":"246","author":"BA Larder","year":"1989","journal-title":"Science"},{"key":"ref19","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.0020137","article-title":"The Role of Compensatory Mutations in the Emergence of Drug Resistance.","volume":"2","author":"A Handel","year":"2006","journal-title":"PLoS Comput Biol"},{"key":"ref20","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1016\/S0025-7125(05)70294-7","article-title":"Antibiotic synergy and antagonism.","volume":"84","author":"JF Acar","year":"2000","journal-title":"Med Clin North Am"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1172\/JCI200316814","article-title":"Application of a mathematical model to prevent in vivo amplification of antibiotic-resistant bacterial populations during therapy.","volume":"112","author":"N Jumbe","year":"2003","journal-title":"J Clin Invest"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1086\/516284","article-title":"Pharmacokinetic\/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men.","volume":"26","author":"WA Craig","year":"1998","journal-title":"Clin Infect Dis"},{"key":"ref23","first-page":"S233","article-title":"Does the dose matter?; 2001","author":"WA Craig"},{"key":"ref24","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1056\/NEJM195303192481201","article-title":"\u201cContinuous\u201d vs. \u201cdiscontinuous\u201d therapy with penicillin; the effect of the interval between injections on therapeutic efficacy.","volume":"248","author":"H Eagle","year":"1953","journal-title":"N Engl J Med"},{"key":"ref25","doi-asserted-by":"crossref","first-page":"3670","DOI":"10.1128\/AAC.48.10.3670-3676.2004","article-title":"Pharmacodynamic functions: A multiparameter approach to the design of antibiotic treatment regimens.","volume":"48","author":"RR Regoes","year":"2004","journal-title":"Antimicrob Agents Chemother"},{"key":"ref26","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1016\/0169-5347(96)20067-9","article-title":"Resource competition and within-host disease dynamics.","volume":"11","author":"VH Smith","year":"1996","journal-title":"Trends Ecol Evol"},{"key":"ref27","doi-asserted-by":"crossref","first-page":"2895","DOI":"10.1016\/S0264-410X(00)00046-3","article-title":"Competition among Streptococcus pneumoniae for intranasal colonization in a mouse model.","volume":"18","author":"M Lipsitch","year":"2000","journal-title":"Vaccine"},{"key":"ref28","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jhin.2005.01.008","article-title":"Competition between methicillin-sensitive and -resistant Staphylococcus aureus in the anterior nares.","volume":"61","author":"M Dall'Antonia","year":"2005","journal-title":"J Hosp Infect"},{"key":"ref29","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1038\/ng1755","article-title":"Functional classification of drugs by properties of their pairwise interactions.","volume":"38","author":"P Yeh","year":"2006","journal-title":"Nat Genet"},{"key":"ref30","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/nrmicro2133","article-title":"Drug interactions and the evolution of antibiotic resistance.","volume":"7","author":"PJ Yeh","year":"2009","journal-title":"Nat Rev Microbiol"},{"key":"ref31","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1128\/IAI.39.2.676-685.1983","article-title":"Mechanisms that control bacterial populations in continuous-flow culture models of mouse large intestinal flora.","volume":"39","author":"R Freter","year":"1983","journal-title":"Infect Immun"},{"key":"ref32","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1097\/00001432-199506000-00004","article-title":"The role of iron in infection.","volume":"8","author":"ED Weinberg","year":"1995","journal-title":"Curr Opin Infect Dis"},{"key":"ref33","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1371\/journal.pbio.0060014","article-title":"The evolution of quorum sensing in bacterial biofilms.","volume":"6","author":"CD Nadell","year":"2008","journal-title":"PLoS Biol"},{"key":"ref34","doi-asserted-by":"crossref","first-page":"992","DOI":"10.2175\/106143095X133220","article-title":"Competition for substrate and space in biofilms.","volume":"67","author":"TC Zhang","year":"1995","journal-title":"Water Environ Res"},{"key":"ref35","doi-asserted-by":"crossref","first-page":"1771","DOI":"10.1128\/AAC.44.7.1771-1777.2000","article-title":"Mutation frequencies and antibiotic resistance.","volume":"44","author":"JL Martinez","year":"2000","journal-title":"Antimicrob Agents Chemother"},{"key":"ref36","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1128\/AAC.42.2.478","article-title":"Estimate of the frequency of human immunodeficiency virus type 1 protease inhibitor resistance within unselected virus populations in vitro.","volume":"42","author":"SP Tucker","year":"1998","journal-title":"Antimicrob Agents Chemother"},{"key":"ref37","doi-asserted-by":"crossref","first-page":"2053","DOI":"10.1128\/AAC.00873-06","article-title":"Concentration-dependent synergy and antagonism within a triple antifungal drug combination against Aspergillus species: Analysis by a new response surface model.","volume":"51","author":"J Meletiadis","year":"2007","journal-title":"Antimicrob Agents Chemother"},{"key":"ref38","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1128\/AAC.39.5.1173","article-title":"Concentration-dependent synergy and antagonism between cefoperazone and imipenem against methicillin-resistant Staphylococcus aureus.","volume":"39","author":"KH Rand","year":"1995","journal-title":"Antimicrob Agents Chemother"},{"key":"ref39","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1128\/AAC.41.2.363","article-title":"The population dynamics of antimicrobial chemotherapy.","volume":"41","author":"M Lipsitch","year":"1997","journal-title":"Antimicrob Agents Chemother"},{"key":"ref40","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.1097\/CCM.0b013e318180fe62","article-title":"Antibiotic resistance - What&apos;s dosing got to do with it?","volume":"36","author":"JA Roberts","year":"2008","journal-title":"Crit Care Med"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"2499","DOI":"10.1128\/AAC.47.8.2499-2506.2003","article-title":"Selection of resistant Streptococcus pneumoniae during penicillin treatment in vitro and in three animal models.","volume":"47","author":"JD Knudsen","year":"2003","journal-title":"Antimicrob Agents Chemother"},{"key":"ref42","article-title":"Evolution of Resistance to Targeted Anti-Cancer Therapies during Continuous and Pulsed Administration Strategies.","volume":"5","author":"J Foo","year":"2009","journal-title":"PLoS Comput Biol"},{"key":"ref43","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1371\/journal.pbio.0060074","article-title":"Modelling within-host spatiotemporal dynamics of invasive bacterial disease.","volume":"6","author":"AJ Grant","year":"2008","journal-title":"PLoS Biol"},{"key":"ref44","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1111\/j.1461-0248.2006.00921.x","article-title":"Ecological and evolutionary principles in immunology.","volume":"9","author":"D Wodarz","year":"2006","journal-title":"Ecol Lett"}],"updated-by":[{"DOI":"10.1371\/annotation\/4117feb8-90b6-474f-aba8-0da4aa4b7c21","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2010,7,9]],"date-time":"2010-07-09T00:00:00Z","timestamp":1278633600000}},{"DOI":"10.1371\/annotation\/80bc1e50-d623-464f-817f-a5e776b75717","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2010,6,11]],"date-time":"2010-06-11T00:00:00Z","timestamp":1276214400000}}],"container-title":["PLoS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/dx.plos.org\/10.1371\/journal.pcbi.1000796","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,21]],"date-time":"2025-02-21T11:33:09Z","timestamp":1740137589000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1000796"}},"subtitle":[],"editor":[{"given":"Philip E.","family":"Bourne","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2010,6,3]]},"references-count":44,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2010,6,3]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1000796","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.13550956.14929056","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2010,6,3]]}}}