The path of least resistance: aggressive or moderate treatment?

The evolution of resistance to antimicrobial chemotherapy is a major and growing cause of human mortality and morbidity. Comparatively little attention has been paid to how different patient treatment strategies shape the evolution of resistance. In particular, it is not clear whether treating individual patients aggressively with high drug dosages and long treatment durations, or moderately with low dosages and short durations can better prevent the evolution and spread of drug resistance. Here, we summarize the very limited available empirical evidence across different pathogens and provide a conceptual framework describing the information required to effectively manage drug pressure to minimize resistance evolution.

[1]  S. Zinner,et al.  Concentration-resistance relationships with Pseudomonas aeruginosa exposed to doripenem and ciprofloxacin in an in vitro model. , 2013, The Journal of antimicrobial chemotherapy.

[2]  D. Paterson,et al.  Antibiotic resistance—What’s dosing got to do with it? , 2008, Critical care medicine.

[3]  R. Hogg,et al.  Differential impact of adherence on long-term treatment response among naive HIV-infected individuals , 2008, AIDS.

[4]  P. V. van Helden,et al.  Reinfection and mixed infection cause changing Mycobacterium tuberculosis drug-resistance patterns. , 2005, American journal of respiratory and critical care medicine.

[5]  H. Babiker,et al.  Current views on the population structure of plasmodium falciparum: Implications for control. , 1997, Parasitology today.

[6]  Paul W. Ewald.  Imperfect Vaccines and the Evolution of Pathogen Virulence , 2004 .

[7]  O. Pybus,et al.  Unifying the Epidemiological and Evolutionary Dynamics of Pathogens , 2004, Science.

[8]  A. Jakob.  Short-Course Antibiotic Treatment in Acute Exacerbations of Chronic Bronchitis and COPD : a Meta-Analysis of Double-Blind Studies , 2008 .

[9]  Stephan Harbarth,et al.  Conserving antibiotics for the future: new ways to use old and new drugs from a pharmacokinetic and pharmacodynamic perspective. , 2011, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[10]  P. Harrigan,et al.  Predictors of HIV drug-resistance mutations in a large antiretroviral-naive cohort initiating triple antiretroviral therapy. , 2005, The Journal of infectious diseases.

[11]  E. Govorkova.  Consequences of resistance: in vitro fitness, in vivo infectivity, and transmissibility of oseltamivir‐resistant influenza A viruses , 2013, Influenza and other respiratory viruses.

[12]  David L. Smith,et al.  “One-Size-Fits-All”? Optimizing Treatment Duration for Bacterial Infections , 2012, PloS one.

[13]  B G Williams,et al.  Multigenic drug resistance among inbred malaria parasites , 1997, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[14]  Troy Day,et al.  The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy , 2011, Proceedings of the National Academy of Sciences.

[15]  E. Holmes,et al.  Intra- and Interhost Evolutionary Dynamics of Equine Influenza Virus , 2010, Journal of Virology.

[16]  Andreas Handel,et al.  Antiviral resistance and the control of pandemic influenza: the roles of stochasticity, evolution and model details. , 2009, Journal of theoretical biology.

[17]  M. Fried,et al.  Intermittent treatment to prevent pregnancy malaria does not confer benefit in an area of widespread drug resistance. , 2011, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[18]  J. Bartlett.  Association between adherence to antiretroviral therapy and human immunodeficiency virus drug resistance , 2004 .

[19]  S Bonhoeffer,et al.  Production of resistant HIV mutants during antiretroviral therapy. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[20]  Linus Sandegren,et al.  Selection of Resistant Bacteria at Very Low Antibiotic Concentrations , 2011, PLoS pathogens.

[21]  Alex R. Hall,et al.  The population genetics of antibiotic resistance: integrating molecular mechanisms and treatment contexts , 2010, Nature Reviews Genetics.

[22]  Yanping Wang,et al.  Human intestinal bacteria as reservoirs for antibiotic resistance genes. , 2004, Trends in microbiology.

[23]  G. Kibiki,et al.  The complexity of the adherence‐response relationship in tuberculosis treatment: why are we still in the dark and how can we get out? , 2011, Tropical medicine & international health : TM & IH.

[24]  Troy Day,et al.  Aggressive Chemotherapy and the Selection of Drug Resistant Pathogens , 2013, PLoS pathogens.

[25]  A. Kamali,et al.  Safety, Adherence and Acceptability of Intermittent Tenofovir/Emtricitabine as HIV Pre-Exposure Prophylaxis (PrEP) among HIV-Uninfected Ugandan Volunteers Living in HIV-Serodiscordant Relationships: A Randomized, Clinical Trial , 2013, PloS one.

[26]  H. Goossens,et al.  Outpatient antibiotic use in Europe and association with resistance: a cross-national database study , 2005, The Lancet.

[27]  Silvie Huijben,et al.  CHEMOTHERAPY, WITHIN‐HOST ECOLOGY AND THE FITNESS OF DRUG‐RESISTANT MALARIA PARASITES , 2010, Evolution; international journal of organic evolution.

[28]  V. Calvez,et al.  Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus: an open-label pilot study , 2001, The Lancet.

[29]  Xilin Zhao,et al.  A unified anti-mutant dosing strategy. , 2008, The Journal of antimicrobial chemotherapy.

[30]  R. Marre,et al.  Changes in Escherichia coli resistance patterns during and after antibiotic therapy: a longitudinal study among outpatients in Germany. , 2008, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[31]  M. Toleman,et al.  The emergence of pan-resistant Gram-negative pathogens merits a rapid global political response. , 2012, The Journal of antimicrobial chemotherapy.

[32]  Lars Råberg,et al.  Decomposing health: tolerance and resistance to parasites in animals , 2009, Philosophical Transactions of the Royal Society B: Biological Sciences.

[33]  Nicholas J White,et al.  Antimalarial drug resistance. , 2004, The Journal of clinical investigation.

[34]  A. Benedetti,et al.  Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis , 2009, PLoS medicine.

[35]  O. Cars,et al.  Bacteria with increased mutation frequency and antibiotic resistance are enriched in the commensal flora of patients with high antibiotic usage. , 2003, The Journal of antimicrobial chemotherapy.

[36]  H. Goossens,et al.  Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study , 2007, The Lancet.

[37]  F. Maggiolo,et al.  Effect of Adherence to HAART on Virologic Outcome and on the Selection of Resistance-Conferring Mutations in NNRTI- or PI-Treated Patients , 2007, HIV clinical trials.

[38]  I. Gyssens,et al.  Effect of Dosing and Dosing Frequency on the Efficacy of Ceftizoxime and the Emergence of Ceftizoxime Resistance during the Early Development of Murine Abscesses Caused by Bacteroides fragilis and Enterobacter cloacae Mixed Infection , 2007, Antimicrobial Agents and Chemotherapy.

[39]  O. Cars,et al.  A European study on the relationship between antimicrobial use and antimicrobial resistance. , 2002, Emerging infectious diseases.

[40]  E. Sergent,et al.  On the necessity of having a term to express the resistance of carriers of germs to superimposed infections , 1925 .

[41]  F. Nowrouzian,et al.  Tetracycline Resistance in Escherichia coli and Persistence in the Infantile Colonic Microbiota , 2006, Antimicrobial Agents and Chemotherapy.

[42]  T. Buckley,et al.  Antibiotic Administration Routes Significantly Influence the Levels of Antibiotic Resistance in Gut Microbiota , 2013, Antimicrobial Agents and Chemotherapy.

[43]  Bernhards Ogutu,et al.  A controlled, parallel, cluster-randomized trial of community-wide screening and treatment of asymptomatic carriers of Plasmodium falciparum in Burkina Faso , 2013, Malaria Journal.

[44]  J. Hughes,et al.  Preserving the lifesaving power of antimicrobial agents. , 2011, JAMA.

[45]  T. Wellems,et al.  The threat of artemisinin-resistant malaria. , 2011, The New England journal of medicine.

[46]  M. Lipsitch,et al.  Antimicrobial Use and Antimicrobial Resistance: A Population Perspective , 2002, Emerging Infectious Diseases.

[47]  D. Arnot,et al.  Unstable malaria in Sudan: the influence of the dry season. Clone multiplicity of Plasmodium falciparum infections in individuals exposed to variable levels of disease transmission. , 1998, Transactions of the Royal Society of Tropical Medicine and Hygiene.

[48]  B. Balkau,et al.  Low dosage and long treatment duration of beta-lactam: risk factors for carriage of penicillin-resistant Streptococcus pneumoniae. , 1998, JAMA.

[49]  F. Nosten,et al.  Emergence of artemisinin-resistant malaria on the western border of Thailand: a longitudinal study , 2012, The Lancet.

[50]  B. Levin,et al.  Population dynamics of tuberculosis treatment: mathematical models of the roles of non-compliance and bacterial heterogeneity in the evolution of drug resistance. , 1998, The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease.

[51]  D. Bangsberg,et al.  Paradoxes of adherence and drug resistance to HIV antiretroviral therapy. , 2004, The Journal of antimicrobial chemotherapy.

[52]  V. Tam,et al.  The Relationship between Quinolone Exposures and Resistance Amplification Is Characterized by an Inverted U: a New Paradigm for Optimizing Pharmacodynamics To Counterselect Resistance , 2006, Antimicrobial Agents and Chemotherapy.

[53]  J. Pasipanodya,et al.  Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability. , 2011, The Journal of infectious diseases.

[54]  P. Ehrlich.  Address in Pathology, ON CHEMIOTHERAPY , 1913, British medical journal.

[55]  M. Pusic,et al.  Short-term late-generation antibiotics versus longer term penicillin for acute streptococcal pharyngitis in children. , 2012, The Cochrane database of systematic reviews.

[56]  H. Dupont,et al.  Rifaximin: In vitro and in vivo Antibacterial Activity – A Review , 2005, Chemotherapy.

[57]  O. Cars,et al.  Optimizing drug exposure to minimize selection of antibiotic resistance. , 2007, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[58]  Alan E Hubbard,et al.  Gel versus capillary electrophoresis genotyping for categorizing treatment outcomes in two anti-malarial trials in Uganda , 2010, Malaria Journal.

[59]  D. Moore,et al.  Efficacy of short-course antibiotic regimens for community-acquired pneumonia: a meta-analysis. , 2007, The American journal of medicine.

[60]  B. Levin,et al.  Concentration-Dependent Selection of Small Phenotypic Differences in TEM β-Lactamase-Mediated Antibiotic Resistance , 2000, Antimicrobial Agents and Chemotherapy.

[61]  Benjamin Kerr,et al.  Evolutionary rescue from extinction is contingent on a lower rate of environmental change , 2013, Nature.

[62]  N. Savill,et al.  VACCINATION AND REDUCED COHORT DURATION CAN DRIVE VIRULENCE EVOLUTION: MAREK’S DISEASE VIRUS AND INDUSTRIALIZED AGRICULTURE , 2013, Evolution; international journal of organic evolution.

[63]  B. Foxman,et al.  The role of horizontal gene transfer in the spread of trimethoprim-sulfamethoxazole resistance among uropathogenic Escherichia coli in Europe and Canada. , 2006, The Journal of antimicrobial chemotherapy.

[64]  A. P. Arzamastsev,et al.  ABT492 and levofloxacin: comparison of their pharmacodynamics and their abilities to prevent the selection of resistant Staphylococcus aureus in an in vitro dynamic model. , 2004, The Journal of antimicrobial chemotherapy.