Correspondence
For more on the index developed by WHO see http:// www.whocc.no/ See Online for appendix
1180
(west Africa and Central America) were obtained from IMS Health’s MIDAS database, except for Denmark (Danish Medicines Agency) and Sweden (National Cooperation of Swedish Pharmacies). Data were provided in kilograms and were converted into defined daily doses (DDDs) according to the 2005 version of the ATC/DDD index developed by WHO’s Collaborating Centre for Drug Statistics Methodology. Data we identified for antibiotic use (appendix) compared well with previously reported data, including from the USA; 3 the only major exception was data from Spain for which the differences were attributable to the use of different data sources.4 Changes in antibiotic use noted between 2004 (our data) and 20111 should be interpreted with caution, but do emphasise the need for continuous surveillance from the same data source and with a standardised method, such as in ESAC-Net. We were surprised by the low use of antibiotics, as per the IMS Health’s MIDAS database, in most low-income and middle-income countries. Only a few studies have been published from these countries, but for example, a study from India5 suggested the overuse and inappropriate choice of antibiotics for acute, uncomplicated infections of the respiratory tract. In parallel, in low-resource settings poor access to antibiotic treatment for childhood pneumonia, especially through the public health sector, has been reported.6 Antibiotics obtained from informal providers can account for a substantial proportion of antibiotic use in many countries;7 thus alternative methods would be needed to measure the use of antibiotics that are not distributed through registered outlets. In April, 2014, WHO published its first report8 into global surveillance of antimicrobial resistance. Restricted availability of publicly accessible national and global data on antibiotic use is a major obstacle to the design of effective interventions to ensure
the rational use of these drugs. We encourage reporting of data for antibiotic use will stimulate reporting and development of simple computer techniques to transform sales data into meaningful rates of use. We declare no competing interests.
Liselotte Diaz Högberg, Arno Muller, *Anna Zorzet, Dominique L Monnet, Otto Cars [email protected] ReAct—Action on Antibiotic Resistance, Uppsala University, Uppsala SE-751 05, Sweden (LDH [former affiliation], AM, AZ, OC); European Centre for Disease Prevention and Control, Stockholm, Sweden (LDH [present affiliation], DLM [present affiliation]); and Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark (DLM [former affiliation]); We thank Läkemedelsindustriföreningen (LIF) for a grant to IMS Health to provide the data, Peter Stephens (IMS Health) who answered queries about the database, and Louise Silwer who contributed to an early analysis of the data. 1
2
3
4
5
6
7
8
Versporten A, Bolokhovets G, Ghazaryan L, et al. Antibiotic use in eastern Europe: a crossnational database study in coordination with the WHO Regional Office for Europe. Lancet Infect Dis 2014; 14: 381–87. Van Boeckel TP, Gandra S, Ashok A, et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis 2014; 14: 742–50. Goossens H, Ferech M, Coenen S, Stephens P, European Surveillance of Antimicrobial Consumption Project Group. Comparison of outpatient systemic antibacterial use in 2004 in the United States and 27 European countries. Clin Infect Dis 2007; 44: 1091–95. Erratum: Clin Infect Dis 2007; 44: 1259. Campos J, Ferech M, Lázaro E, et al. Surveillance of outpatient antibiotic consumption in Spain according to sales data and reimbursement data. J Antimicrob Chemother 2007; 60: 698–701. Kotwani A, Holloway K. Antibiotic prescribing practice for acute, uncomplicated respiratory tract infections in primary care settings in New Delhi, India. Trop Med Int Health 2014; 19: 761–68. WHO, UNICEF. Countdown to 2015. Building a future for women and children: the 2012 report. Washington DC; World Health Organization, UNICEF, 2012. http://www. countdown2015mnch.org/ documents/2012Report/2012-complete-noprofiles.pdf (accessed May 5, 2014). Morgan DJ, Okeke IN, Laxminarayan R, Perencevich EN, Weisenberg S. Nonprescription antimicrobial use worldwide: a systematic review. Lancet Infect Dis 2011; 11: 692–701. WHO. Antimicrobial resistance: global report on surveillance. Geneva: World Health Organization, 2014. http://www.who.int/ drugresistance/documents/surveillancereport/ en/ (accessed May 1, 2014).
Therapeutic drug monitoring of antibiotics Jason Roberts and colleaugues 1 provided an excellent guideline for dosing antibiotics in the critically ill patient. However, I am concerned about the adjustment of antibiotic dose guided by therapeutic drug moni toring. According to the consensus statement, “During the first or subsequent dose intervals, one or more blood samples could be taken to estimate the patient’s pharmacokinetic variables for the antibiotic”. Unfortunately, many people still interpret this as waiting until the third dose of drug to measure serum concentrations. The idea of measuring serum drug concentrations for individualised dosing with the third dose of drug probably comes from the work in the 1960s to 1970s when computerised programs for pharmacokinetic analysis were not available and, thus, it was easier to wait until the drug had reached steady state in the patient to obtain peak and trough concentrations. Thus, dose adjustment could be done using a simple dose proportional method. Marilyn Martinez and colleagues 2 suggest that dose adjustment of antibiotics should be done as soon as possible to reduce the development of resistance and optimise the therapeutic success. Our data for the treatment of Gram-negative pneumonia with aminoglycosides 3 lend support to the notion that the sooner antibiotic dosing is optimised, the sooner the patient’s surrogate markers of infection will improve. Most hospitals in developed countries have assays for aminoglyco sides and vancomycin. Inexpensive software is available to allow physicians and pharmacists to calculate individual pharmacokinetics and adjust doses promptly. Because the critically ill patient is at great
www.thelancet.com/infection Vol 14 December 2014
Correspondence
risk of morbidity and mortality from bacterial infection, it makes sense to obtain appropriately timed measurements and serum concentrations during the first dose (no need to obtain true peak or trough concentrations because the computer program can calculate the true maximum and minimum serum concentrations) with prompt individualised dose adjustment. For vancomycin, this will obviate the need to use trough concentrations to estimate the area under the curve (AUC), which has been shown to be inaccurate.4 Two serum concentrations can be used to calculate an appropriate AUC. In most institutions, there should be no problem with providing this type of service 24 h a day year round. For vancomycin and aminoglycosides, first-dose pharmacokinetic monitoring in critically ill patients with stable renal function should be the standard. Additional consideration should be given to doing first-dose pharmacokinetics for rapid dose adjustment in patients who are not in the intensive care unit. I declare no competing interests.
Joseph S Bertino Jr [email protected] Bertino Consulting, Schenectady, NY 12303, USA 1
2
3
4
Roberts JA, Abdul-Aziz M, Lipman J, et al, on behalf of The International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 2014; 14: 498–509. Martinez MN, Papich MG, Drusano GL. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemo 2012; 56: 2795–805. Kashuba ADM, Nafziger AN, Drusano GL, Bertino JS Jr. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram negative bacteria. Antimicrob Agents Chemother 1999; 43: 623–29. Neely MN, Youn G, Jones B, et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob Agents Chemother 2014; 58: 309–16.
Author’s reply Timely administration of effective antibiotic therapy can increase the likelihood of treatment success for critically ill patients. However, optimised dosing is challenging in these patients because of various pharmacokinetic and pharmacodynamic factors. 1 Although therapeutic exposures are associated with clinical cure,2 preclinical infection model data show that higher antibiotic exposures can also suppress the emergence of antibiotic resistance.3 Therefore, low antibiotic concentrations need to be minimised, and use of therapeutic drug monitoring (TDM) can rapidly ensure achievement of target exposures. To this end, Joseph Bertino’s comments represent the ideal for TDM, in which initial measurement of antibiotic concentrations occurs during the first dosing interval and are used for early dose optimisation. In our collaborative review,4 we emphasised this point by stating “During the first or a subsequent dosage interval, one or more blood samples could be taken to estimate the patient’s individual PK parameters for the antibiotic”. This wording was used to allow for practicalities associated with blood sampling, such that if TDM was to be done in a clinical unit where it is done infrequently, or out of hours, then accurate TDM could be done when an appropriate member of the clinical team can supervise the process. Particularly, for antibiotics with short half-lives, such as β lactams, which might have a dosing interval of every 4 h, or for vancomycin, for which a unit might use a 6 h dosing interval, accurate timing of sampling and coordination with the pathology laboratory might not be possible during the first dose. In fact, since antibiotics are often commenced during the night shift in intensive care units, this situation is common. However, for antibiotics with a longer dosing interval, such as once-daily aminoglycosides, or vancomycin when administered every 12 h, TDM sampling should be possible in most cases during the first dosing interval because of a
www.thelancet.com/infection Vol 14 December 2014
wider sampling window. Despite these practical issues, we support Bertino’s comments that accurate TDM should be undertaken as early a possible in the treatment course and preferably during the first dosing interval. Regular TDM should subsequently occur to ensure therapeutic concentrations are maintained throughout the entire course of therapy. I declare no competing interests. I am funded by a Career Development Fellowship from the National Health and Medical Research Council of Australia (APP1048652).
Jason A Roberts, on behalf of The International Society of Anti-Infective Pharmacology (ISAP) and the PK/PD Study Group of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) [email protected] Burns, Trauma, and Critical Care Research Centre, University of Queensland, Herston, Brisbane, QLD 4029, Australia; Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia; and Institute of Translational Medicine, University of Liverpool, Liverpool, UK 1
2
3
4
Lipman J, Udy AA, Roberts JA. Do we understand the impact of altered physiology, consequent interventions and resultant clinical scenarios in the intensive care unit? The antibiotic story. Anaesth Intensive Care 2011; 39: 999–1000. Muller AE, Punt N, Mouton JW. Optimal exposures of ceftazidime predict the probability of microbiological and clinical outcome in the treatment of nosocomial pneumonia. J Antimicrob Chemother 2013; 68: 900–06. Vanscoy B, Mendes RE, Castanheira M, et al. Relationship between ceftolozane-tazobactam exposure and drug resistance amplification in a hollow-fiber infection model. Antimicrob Agents Chemother 2013; 57: 4134–38. Roberts JA, Abdul-Aziz MH, Lipman J, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 2014; 14: 498–509.
1181
For more on the index developed by WHO see http:// www.whocc.no/ See Online for appendix
1180
(west Africa and Central America) were obtained from IMS Health’s MIDAS database, except for Denmark (Danish Medicines Agency) and Sweden (National Cooperation of Swedish Pharmacies). Data were provided in kilograms and were converted into defined daily doses (DDDs) according to the 2005 version of the ATC/DDD index developed by WHO’s Collaborating Centre for Drug Statistics Methodology. Data we identified for antibiotic use (appendix) compared well with previously reported data, including from the USA; 3 the only major exception was data from Spain for which the differences were attributable to the use of different data sources.4 Changes in antibiotic use noted between 2004 (our data) and 20111 should be interpreted with caution, but do emphasise the need for continuous surveillance from the same data source and with a standardised method, such as in ESAC-Net. We were surprised by the low use of antibiotics, as per the IMS Health’s MIDAS database, in most low-income and middle-income countries. Only a few studies have been published from these countries, but for example, a study from India5 suggested the overuse and inappropriate choice of antibiotics for acute, uncomplicated infections of the respiratory tract. In parallel, in low-resource settings poor access to antibiotic treatment for childhood pneumonia, especially through the public health sector, has been reported.6 Antibiotics obtained from informal providers can account for a substantial proportion of antibiotic use in many countries;7 thus alternative methods would be needed to measure the use of antibiotics that are not distributed through registered outlets. In April, 2014, WHO published its first report8 into global surveillance of antimicrobial resistance. Restricted availability of publicly accessible national and global data on antibiotic use is a major obstacle to the design of effective interventions to ensure
the rational use of these drugs. We encourage reporting of data for antibiotic use will stimulate reporting and development of simple computer techniques to transform sales data into meaningful rates of use. We declare no competing interests.
Liselotte Diaz Högberg, Arno Muller, *Anna Zorzet, Dominique L Monnet, Otto Cars [email protected] ReAct—Action on Antibiotic Resistance, Uppsala University, Uppsala SE-751 05, Sweden (LDH [former affiliation], AM, AZ, OC); European Centre for Disease Prevention and Control, Stockholm, Sweden (LDH [present affiliation], DLM [present affiliation]); and Department of Microbiology and Infection Control, Statens Serum Institut, Copenhagen, Denmark (DLM [former affiliation]); We thank Läkemedelsindustriföreningen (LIF) for a grant to IMS Health to provide the data, Peter Stephens (IMS Health) who answered queries about the database, and Louise Silwer who contributed to an early analysis of the data. 1
2
3
4
5
6
7
8
Versporten A, Bolokhovets G, Ghazaryan L, et al. Antibiotic use in eastern Europe: a crossnational database study in coordination with the WHO Regional Office for Europe. Lancet Infect Dis 2014; 14: 381–87. Van Boeckel TP, Gandra S, Ashok A, et al. Global antibiotic consumption 2000 to 2010: an analysis of national pharmaceutical sales data. Lancet Infect Dis 2014; 14: 742–50. Goossens H, Ferech M, Coenen S, Stephens P, European Surveillance of Antimicrobial Consumption Project Group. Comparison of outpatient systemic antibacterial use in 2004 in the United States and 27 European countries. Clin Infect Dis 2007; 44: 1091–95. Erratum: Clin Infect Dis 2007; 44: 1259. Campos J, Ferech M, Lázaro E, et al. Surveillance of outpatient antibiotic consumption in Spain according to sales data and reimbursement data. J Antimicrob Chemother 2007; 60: 698–701. Kotwani A, Holloway K. Antibiotic prescribing practice for acute, uncomplicated respiratory tract infections in primary care settings in New Delhi, India. Trop Med Int Health 2014; 19: 761–68. WHO, UNICEF. Countdown to 2015. Building a future for women and children: the 2012 report. Washington DC; World Health Organization, UNICEF, 2012. http://www. countdown2015mnch.org/ documents/2012Report/2012-complete-noprofiles.pdf (accessed May 5, 2014). Morgan DJ, Okeke IN, Laxminarayan R, Perencevich EN, Weisenberg S. Nonprescription antimicrobial use worldwide: a systematic review. Lancet Infect Dis 2011; 11: 692–701. WHO. Antimicrobial resistance: global report on surveillance. Geneva: World Health Organization, 2014. http://www.who.int/ drugresistance/documents/surveillancereport/ en/ (accessed May 1, 2014).
Therapeutic drug monitoring of antibiotics Jason Roberts and colleaugues 1 provided an excellent guideline for dosing antibiotics in the critically ill patient. However, I am concerned about the adjustment of antibiotic dose guided by therapeutic drug moni toring. According to the consensus statement, “During the first or subsequent dose intervals, one or more blood samples could be taken to estimate the patient’s pharmacokinetic variables for the antibiotic”. Unfortunately, many people still interpret this as waiting until the third dose of drug to measure serum concentrations. The idea of measuring serum drug concentrations for individualised dosing with the third dose of drug probably comes from the work in the 1960s to 1970s when computerised programs for pharmacokinetic analysis were not available and, thus, it was easier to wait until the drug had reached steady state in the patient to obtain peak and trough concentrations. Thus, dose adjustment could be done using a simple dose proportional method. Marilyn Martinez and colleagues 2 suggest that dose adjustment of antibiotics should be done as soon as possible to reduce the development of resistance and optimise the therapeutic success. Our data for the treatment of Gram-negative pneumonia with aminoglycosides 3 lend support to the notion that the sooner antibiotic dosing is optimised, the sooner the patient’s surrogate markers of infection will improve. Most hospitals in developed countries have assays for aminoglyco sides and vancomycin. Inexpensive software is available to allow physicians and pharmacists to calculate individual pharmacokinetics and adjust doses promptly. Because the critically ill patient is at great
www.thelancet.com/infection Vol 14 December 2014
Correspondence
risk of morbidity and mortality from bacterial infection, it makes sense to obtain appropriately timed measurements and serum concentrations during the first dose (no need to obtain true peak or trough concentrations because the computer program can calculate the true maximum and minimum serum concentrations) with prompt individualised dose adjustment. For vancomycin, this will obviate the need to use trough concentrations to estimate the area under the curve (AUC), which has been shown to be inaccurate.4 Two serum concentrations can be used to calculate an appropriate AUC. In most institutions, there should be no problem with providing this type of service 24 h a day year round. For vancomycin and aminoglycosides, first-dose pharmacokinetic monitoring in critically ill patients with stable renal function should be the standard. Additional consideration should be given to doing first-dose pharmacokinetics for rapid dose adjustment in patients who are not in the intensive care unit. I declare no competing interests.
Joseph S Bertino Jr [email protected] Bertino Consulting, Schenectady, NY 12303, USA 1
2
3
4
Roberts JA, Abdul-Aziz M, Lipman J, et al, on behalf of The International Society of Anti-Infective Pharmacology and the Pharmacokinetics and Pharmacodynamics Study Group of the European Society of Clinical Microbiology and Infectious Diseases. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 2014; 14: 498–509. Martinez MN, Papich MG, Drusano GL. Dosing regimen matters: the importance of early intervention and rapid attainment of the pharmacokinetic/pharmacodynamic target. Antimicrob Agents Chemo 2012; 56: 2795–805. Kashuba ADM, Nafziger AN, Drusano GL, Bertino JS Jr. Optimizing aminoglycoside therapy for nosocomial pneumonia caused by gram negative bacteria. Antimicrob Agents Chemother 1999; 43: 623–29. Neely MN, Youn G, Jones B, et al. Are vancomycin trough concentrations adequate for optimal dosing? Antimicrob Agents Chemother 2014; 58: 309–16.
Author’s reply Timely administration of effective antibiotic therapy can increase the likelihood of treatment success for critically ill patients. However, optimised dosing is challenging in these patients because of various pharmacokinetic and pharmacodynamic factors. 1 Although therapeutic exposures are associated with clinical cure,2 preclinical infection model data show that higher antibiotic exposures can also suppress the emergence of antibiotic resistance.3 Therefore, low antibiotic concentrations need to be minimised, and use of therapeutic drug monitoring (TDM) can rapidly ensure achievement of target exposures. To this end, Joseph Bertino’s comments represent the ideal for TDM, in which initial measurement of antibiotic concentrations occurs during the first dosing interval and are used for early dose optimisation. In our collaborative review,4 we emphasised this point by stating “During the first or a subsequent dosage interval, one or more blood samples could be taken to estimate the patient’s individual PK parameters for the antibiotic”. This wording was used to allow for practicalities associated with blood sampling, such that if TDM was to be done in a clinical unit where it is done infrequently, or out of hours, then accurate TDM could be done when an appropriate member of the clinical team can supervise the process. Particularly, for antibiotics with short half-lives, such as β lactams, which might have a dosing interval of every 4 h, or for vancomycin, for which a unit might use a 6 h dosing interval, accurate timing of sampling and coordination with the pathology laboratory might not be possible during the first dose. In fact, since antibiotics are often commenced during the night shift in intensive care units, this situation is common. However, for antibiotics with a longer dosing interval, such as once-daily aminoglycosides, or vancomycin when administered every 12 h, TDM sampling should be possible in most cases during the first dosing interval because of a
www.thelancet.com/infection Vol 14 December 2014
wider sampling window. Despite these practical issues, we support Bertino’s comments that accurate TDM should be undertaken as early a possible in the treatment course and preferably during the first dosing interval. Regular TDM should subsequently occur to ensure therapeutic concentrations are maintained throughout the entire course of therapy. I declare no competing interests. I am funded by a Career Development Fellowship from the National Health and Medical Research Council of Australia (APP1048652).
Jason A Roberts, on behalf of The International Society of Anti-Infective Pharmacology (ISAP) and the PK/PD Study Group of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) [email protected] Burns, Trauma, and Critical Care Research Centre, University of Queensland, Herston, Brisbane, QLD 4029, Australia; Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia; and Institute of Translational Medicine, University of Liverpool, Liverpool, UK 1
2
3
4
Lipman J, Udy AA, Roberts JA. Do we understand the impact of altered physiology, consequent interventions and resultant clinical scenarios in the intensive care unit? The antibiotic story. Anaesth Intensive Care 2011; 39: 999–1000. Muller AE, Punt N, Mouton JW. Optimal exposures of ceftazidime predict the probability of microbiological and clinical outcome in the treatment of nosocomial pneumonia. J Antimicrob Chemother 2013; 68: 900–06. Vanscoy B, Mendes RE, Castanheira M, et al. Relationship between ceftolozane-tazobactam exposure and drug resistance amplification in a hollow-fiber infection model. Antimicrob Agents Chemother 2013; 57: 4134–38. Roberts JA, Abdul-Aziz MH, Lipman J, et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 2014; 14: 498–509.
1181
