How relevant are the drug–drug interactions between antiretroviral boosted-based regimens and calcium channel blockers in real life?

How relevant are the drug–drug interactions between antiretroviral boosted-based regimens and... Sir, The improved survival achieved by HIV-infected patients has complicated their medical care as increasing numbers of comorbidities lead to polypharmacy. The burden of taking multiple medications has been associated with an increased risk of adverse drug events, non-adherence and drug–drug interactions (DDIs), potentially compromising the efficacy of ART.1 In order to address these issues, we set up a special outpatient clinical service [Gestione Ambulatoriale Politerapie (GAP)] in September 2016 with the aim of managing of polypharmacy in HIV-infected patients.2 We here focus on the potential DDIs between ritonavir- or cobicistat-based antiretroviral regimens and calcium channel blockers (CCBs), which are widely used antihypertensive drugs. However, as they are mainly metabolized by cytochrome P450 3A (CYP3A) isoenzymes, whose activity is significantly inhibited by ritonavir or cobicistat, concomitant treatment with boosted antiretroviral regimens should be carefully monitored in clinical practice because of the high risk of side effects.3 This retrospective, observational study considered all of our patients who had received ritonavir- or cobicistat-based regimens combined with CCBs for at least 6 months. The risk of DDIs due to the individual drug combinations was retrieved from the Liverpool website (www.hiv-druginteractions.org) and their clinical relevance was verified by assessing blood pressure (BP) after starting the combined therapy. BP is always measured during the course of each outpatient visit (scheduled every 4 months) by the attending physician and periodically monitored by the patients at home (the patients are asked to report any abnormal BP measurements at their next visit). Clinically relevant hypotension was defined as the presence of a significant drop in BP to <90/60 mmHg, accompanied by at least one of the following symptoms: dizziness or lightheadedness, abnormal heart rhythm and the loss of consciousness. Moreover, in order to identify alterations in the PR interval, we used the patients’ medical records to examine the electrocardiographic assessments made at least twice a year in hypertensive patients. The data are expressed as median values with IQRs. It was considered unnecessary to apply for Ethics Committee approval because, under Italian law, it is required only in the case of prospective clinical trials of medical products for clinical use (Articles 6 and 9 of Legislative Decree 211/2003); however, all of the patients gave their written informed consent to the medical procedures/interventions undertaken for routine clinical purposes. Forty-four out of the 620 patients screened during the first 15 months of the GAP were being treated with CCBs (Table 1): they had a median age of 65 years (IQR 59–73), were mainly male (84%) and Caucasians (95%) and had been receiving CCBs for a median of 1867 days (IQR 870–4255). Twenty-three had been on boosted antiretroviral regimens for a median of 2925 days (IQR 1140–4317), 4 of whom subsequently changed antiretroviral regimens for purposes of treatment simplification; the remaining 21 were on booster-free regimens. As shown in Table 1, there was no difference in median systolic or diastolic BP between the patients on boosted or non-boosted antiretroviral regimens and none of the patients experienced any episodes of hypotension or alterations in PR interval after starting combined antiretroviral and CCB treatment. Remarkably, 39 patients were concomitantly receiving a median of 1 other antihypertensive drug (IQR 1–2). The small number of patients and the heterogeneity of the CCBs used in the two groups precluded any statistical comparison of the daily CCB doses. Table 1 CCB doses and median BP values in HIV-infected patients treated or not with boosted antiretrovirals On boosted antiretrovirals Not on boosted antiretrovirals Patients, n 23 21 Amlodipine dose (mg/day) 5 (5–8.8) (n = 14) 10 (5–10) (n = 12) Barnidipine dose (mg/day) 10 (n = 1) 20 (n = 1) Diltiazem dose (mg/day) 60, 120, 300 (n = 3) 0 Felodipine dose (mg/day) 10 (n = 1) 0 Lacidipine dose (mg/day) 0 4 (n = 1) Lercanidipine dose (mg/day) 20 (n = 1) 10, 20 (n = 2) Nifedipine dose (mg/day) 20, 30 (n = 2) 30 (28–38) (n = 4) Verapamil dose (mg/day) 240 (n = 1) 80 (n = 1) SBP (mmHg), median (IQR) 120 (120–130) 130 (120–133) DBP (mmHg), median (IQR) 80 (78–80) 80 (78–85) Minimum SBP (mmHg), median (IQR) 115 (110–120) 120 (115–120) Minimum DBP (mmHg), median (IQR) 70 (70–80) 75 (70–80) On other anti-hypertensive medications, percentage of patients 91.3 85.7 On boosted antiretrovirals Not on boosted antiretrovirals Patients, n 23 21 Amlodipine dose (mg/day) 5 (5–8.8) (n = 14) 10 (5–10) (n = 12) Barnidipine dose (mg/day) 10 (n = 1) 20 (n = 1) Diltiazem dose (mg/day) 60, 120, 300 (n = 3) 0 Felodipine dose (mg/day) 10 (n = 1) 0 Lacidipine dose (mg/day) 0 4 (n = 1) Lercanidipine dose (mg/day) 20 (n = 1) 10, 20 (n = 2) Nifedipine dose (mg/day) 20, 30 (n = 2) 30 (28–38) (n = 4) Verapamil dose (mg/day) 240 (n = 1) 80 (n = 1) SBP (mmHg), median (IQR) 120 (120–130) 130 (120–133) DBP (mmHg), median (IQR) 80 (78–80) 80 (78–85) Minimum SBP (mmHg), median (IQR) 115 (110–120) 120 (115–120) Minimum DBP (mmHg), median (IQR) 70 (70–80) 75 (70–80) On other anti-hypertensive medications, percentage of patients 91.3 85.7 SBP, systolic BP; DBP, diastolic BP. Actual doses or median (IQR) doses are given. Table 1 CCB doses and median BP values in HIV-infected patients treated or not with boosted antiretrovirals On boosted antiretrovirals Not on boosted antiretrovirals Patients, n 23 21 Amlodipine dose (mg/day) 5 (5–8.8) (n = 14) 10 (5–10) (n = 12) Barnidipine dose (mg/day) 10 (n = 1) 20 (n = 1) Diltiazem dose (mg/day) 60, 120, 300 (n = 3) 0 Felodipine dose (mg/day) 10 (n = 1) 0 Lacidipine dose (mg/day) 0 4 (n = 1) Lercanidipine dose (mg/day) 20 (n = 1) 10, 20 (n = 2) Nifedipine dose (mg/day) 20, 30 (n = 2) 30 (28–38) (n = 4) Verapamil dose (mg/day) 240 (n = 1) 80 (n = 1) SBP (mmHg), median (IQR) 120 (120–130) 130 (120–133) DBP (mmHg), median (IQR) 80 (78–80) 80 (78–85) Minimum SBP (mmHg), median (IQR) 115 (110–120) 120 (115–120) Minimum DBP (mmHg), median (IQR) 70 (70–80) 75 (70–80) On other anti-hypertensive medications, percentage of patients 91.3 85.7 On boosted antiretrovirals Not on boosted antiretrovirals Patients, n 23 21 Amlodipine dose (mg/day) 5 (5–8.8) (n = 14) 10 (5–10) (n = 12) Barnidipine dose (mg/day) 10 (n = 1) 20 (n = 1) Diltiazem dose (mg/day) 60, 120, 300 (n = 3) 0 Felodipine dose (mg/day) 10 (n = 1) 0 Lacidipine dose (mg/day) 0 4 (n = 1) Lercanidipine dose (mg/day) 20 (n = 1) 10, 20 (n = 2) Nifedipine dose (mg/day) 20, 30 (n = 2) 30 (28–38) (n = 4) Verapamil dose (mg/day) 240 (n = 1) 80 (n = 1) SBP (mmHg), median (IQR) 120 (120–130) 130 (120–133) DBP (mmHg), median (IQR) 80 (78–80) 80 (78–85) Minimum SBP (mmHg), median (IQR) 115 (110–120) 120 (115–120) Minimum DBP (mmHg), median (IQR) 70 (70–80) 75 (70–80) On other anti-hypertensive medications, percentage of patients 91.3 85.7 SBP, systolic BP; DBP, diastolic BP. Actual doses or median (IQR) doses are given. In order to exclude the possibility that our findings may have been biased by the exclusion of patients who prematurely stopped combined antiretroviral and CCB treatment, which may have underestimated the clinical impact of this DDI, we also looked at the database of our infectious diseases clinics (7326 HIV-infected patients treated since 1985, of whom 2014 are still being followed up). A search for HIV-infected patients who had previously discontinued CCB treatment for any reason identified a total of 14 patients treated with amlodipine (n = 7), barnidipine (n = 3), diltiazem (n = 2) or nifedipine (n = 2), 8 of whom concomitantly received boosted ART. One patient decided to discontinue his CCB without advice from his physician, 10 patients discontinued CCB because it was not efficacious (advice given by their physicians) and 3 patients simplified their antihypertensive therapy (advice given by their physicians); none of them discontinued their CCB because of hypotension and/or cardiac toxicity. Only a few case reports and pharmacokinetic studies of healthy volunteers have considered the co-administration of boosted antiretrovirals and CCBs, which is why the quality of the evidence concerning this DDI is rated ‘low’ by the Liverpool website.3–5 Nevertheless, it conservatively suggests that the combination of boosting agents with CCBs should be administered extremely cautiously because the high risk of increasing the plasma concentrations of CCBs metabolized by CYP3A may lead to hypotension and/or a prolonged PR interval. Our search for real-life data in the GAP database identified nearly 7% of HIV-infected patients treated with CCBs, equally divided between those who were concomitantly treated with ritonavir or cobicistat and those on non-boosted antiretroviral regimens, none of whom experienced any episodes of hypotension or PR alterations. The discrepancy between the predicted DDI and clinical outcomes may be due to the wide therapeutic index of CCBs, the possibility of adjusting drug doses on the basis of easily assessable pharmacodynamic markers (daily variations in BP) and/or the non-detection of plasma CCB concentrations associated with toxic electrophysiological and haemodynamic effects.6 However, it cannot be ruled out that the small number of patients on individual CCBs and the consequent collapsing of data relating to a heterogeneous drug class have partially biased our findings. In conclusion, we provide some useful insights into the previously under-studied DDIs between boosted antiretrovirals and CCBs, which are frequently co-administered in HIV-infected patients. The findings of this albeit small cohort study seem to suggest that such DDIs can be adequately managed by adjusting CCB doses and clinically monitoring BP and electrocardiographic assessment; it is likely that no discontinuation of the CCBs or change in antiretroviral regimen is required. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. References 1 Edelman EJ , Gordon KS , Glover J et al. The next therapeutic challenge in HIV: polypharmacy . Drugs Aging 2013 ; 30 : 613 – 28 . Google Scholar CrossRef Search ADS PubMed 2 Gervasoni C , Resnati C , Formenti T et al. The relevance of drug-drug interactions in clinical practice: the case of concomitant boosted protease inhibitors plus alpha-1 blocker administration . Antivir Ther 2018 ; doi:10.3851/IMP3214. 3 Glesby MJ , Aberg JA , Kendall MA et al. Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers . Clin Pharmacol Ther 2005 ; 78 : 143 – 53 . Google Scholar CrossRef Search ADS PubMed 4 Rossi DR , Rathbun RC , Slater LN. Symptomatic orthostasis with extended-release nifedipine and protease inhibitors . Pharmacotherapy 2002 ; 22 : 1312 – 6 . Google Scholar CrossRef Search ADS PubMed 5 Baeza MT , Merino E , Boix V et al. Nifedipine-lopinavir/ritonavir severe interaction: a case report . AIDS 2007 ; 21 : 119 – 20 . Google Scholar CrossRef Search ADS PubMed 6 Echizen H , Eichelbaum M. Clinical pharmacokinetics of verapamil, nifedipine and diltiazem . Clin Pharmacokinet 1986 ; 11 : 425 – 49 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

How relevant are the drug–drug interactions between antiretroviral boosted-based regimens and calcium channel blockers in real life?

Journal of Antimicrobial Chemotherapy , Volume Advance Article (8) – Apr 19, 2018

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Abstract

Sir, The improved survival achieved by HIV-infected patients has complicated their medical care as increasing numbers of comorbidities lead to polypharmacy. The burden of taking multiple medications has been associated with an increased risk of adverse drug events, non-adherence and drug–drug interactions (DDIs), potentially compromising the efficacy of ART.1 In order to address these issues, we set up a special outpatient clinical service [Gestione Ambulatoriale Politerapie (GAP)] in September 2016 with the aim of managing of polypharmacy in HIV-infected patients.2 We here focus on the potential DDIs between ritonavir- or cobicistat-based antiretroviral regimens and calcium channel blockers (CCBs), which are widely used antihypertensive drugs. However, as they are mainly metabolized by cytochrome P450 3A (CYP3A) isoenzymes, whose activity is significantly inhibited by ritonavir or cobicistat, concomitant treatment with boosted antiretroviral regimens should be carefully monitored in clinical practice because of the high risk of side effects.3 This retrospective, observational study considered all of our patients who had received ritonavir- or cobicistat-based regimens combined with CCBs for at least 6 months. The risk of DDIs due to the individual drug combinations was retrieved from the Liverpool website (www.hiv-druginteractions.org) and their clinical relevance was verified by assessing blood pressure (BP) after starting the combined therapy. BP is always measured during the course of each outpatient visit (scheduled every 4 months) by the attending physician and periodically monitored by the patients at home (the patients are asked to report any abnormal BP measurements at their next visit). Clinically relevant hypotension was defined as the presence of a significant drop in BP to <90/60 mmHg, accompanied by at least one of the following symptoms: dizziness or lightheadedness, abnormal heart rhythm and the loss of consciousness. Moreover, in order to identify alterations in the PR interval, we used the patients’ medical records to examine the electrocardiographic assessments made at least twice a year in hypertensive patients. The data are expressed as median values with IQRs. It was considered unnecessary to apply for Ethics Committee approval because, under Italian law, it is required only in the case of prospective clinical trials of medical products for clinical use (Articles 6 and 9 of Legislative Decree 211/2003); however, all of the patients gave their written informed consent to the medical procedures/interventions undertaken for routine clinical purposes. Forty-four out of the 620 patients screened during the first 15 months of the GAP were being treated with CCBs (Table 1): they had a median age of 65 years (IQR 59–73), were mainly male (84%) and Caucasians (95%) and had been receiving CCBs for a median of 1867 days (IQR 870–4255). Twenty-three had been on boosted antiretroviral regimens for a median of 2925 days (IQR 1140–4317), 4 of whom subsequently changed antiretroviral regimens for purposes of treatment simplification; the remaining 21 were on booster-free regimens. As shown in Table 1, there was no difference in median systolic or diastolic BP between the patients on boosted or non-boosted antiretroviral regimens and none of the patients experienced any episodes of hypotension or alterations in PR interval after starting combined antiretroviral and CCB treatment. Remarkably, 39 patients were concomitantly receiving a median of 1 other antihypertensive drug (IQR 1–2). The small number of patients and the heterogeneity of the CCBs used in the two groups precluded any statistical comparison of the daily CCB doses. Table 1 CCB doses and median BP values in HIV-infected patients treated or not with boosted antiretrovirals On boosted antiretrovirals Not on boosted antiretrovirals Patients, n 23 21 Amlodipine dose (mg/day) 5 (5–8.8) (n = 14) 10 (5–10) (n = 12) Barnidipine dose (mg/day) 10 (n = 1) 20 (n = 1) Diltiazem dose (mg/day) 60, 120, 300 (n = 3) 0 Felodipine dose (mg/day) 10 (n = 1) 0 Lacidipine dose (mg/day) 0 4 (n = 1) Lercanidipine dose (mg/day) 20 (n = 1) 10, 20 (n = 2) Nifedipine dose (mg/day) 20, 30 (n = 2) 30 (28–38) (n = 4) Verapamil dose (mg/day) 240 (n = 1) 80 (n = 1) SBP (mmHg), median (IQR) 120 (120–130) 130 (120–133) DBP (mmHg), median (IQR) 80 (78–80) 80 (78–85) Minimum SBP (mmHg), median (IQR) 115 (110–120) 120 (115–120) Minimum DBP (mmHg), median (IQR) 70 (70–80) 75 (70–80) On other anti-hypertensive medications, percentage of patients 91.3 85.7 On boosted antiretrovirals Not on boosted antiretrovirals Patients, n 23 21 Amlodipine dose (mg/day) 5 (5–8.8) (n = 14) 10 (5–10) (n = 12) Barnidipine dose (mg/day) 10 (n = 1) 20 (n = 1) Diltiazem dose (mg/day) 60, 120, 300 (n = 3) 0 Felodipine dose (mg/day) 10 (n = 1) 0 Lacidipine dose (mg/day) 0 4 (n = 1) Lercanidipine dose (mg/day) 20 (n = 1) 10, 20 (n = 2) Nifedipine dose (mg/day) 20, 30 (n = 2) 30 (28–38) (n = 4) Verapamil dose (mg/day) 240 (n = 1) 80 (n = 1) SBP (mmHg), median (IQR) 120 (120–130) 130 (120–133) DBP (mmHg), median (IQR) 80 (78–80) 80 (78–85) Minimum SBP (mmHg), median (IQR) 115 (110–120) 120 (115–120) Minimum DBP (mmHg), median (IQR) 70 (70–80) 75 (70–80) On other anti-hypertensive medications, percentage of patients 91.3 85.7 SBP, systolic BP; DBP, diastolic BP. Actual doses or median (IQR) doses are given. Table 1 CCB doses and median BP values in HIV-infected patients treated or not with boosted antiretrovirals On boosted antiretrovirals Not on boosted antiretrovirals Patients, n 23 21 Amlodipine dose (mg/day) 5 (5–8.8) (n = 14) 10 (5–10) (n = 12) Barnidipine dose (mg/day) 10 (n = 1) 20 (n = 1) Diltiazem dose (mg/day) 60, 120, 300 (n = 3) 0 Felodipine dose (mg/day) 10 (n = 1) 0 Lacidipine dose (mg/day) 0 4 (n = 1) Lercanidipine dose (mg/day) 20 (n = 1) 10, 20 (n = 2) Nifedipine dose (mg/day) 20, 30 (n = 2) 30 (28–38) (n = 4) Verapamil dose (mg/day) 240 (n = 1) 80 (n = 1) SBP (mmHg), median (IQR) 120 (120–130) 130 (120–133) DBP (mmHg), median (IQR) 80 (78–80) 80 (78–85) Minimum SBP (mmHg), median (IQR) 115 (110–120) 120 (115–120) Minimum DBP (mmHg), median (IQR) 70 (70–80) 75 (70–80) On other anti-hypertensive medications, percentage of patients 91.3 85.7 On boosted antiretrovirals Not on boosted antiretrovirals Patients, n 23 21 Amlodipine dose (mg/day) 5 (5–8.8) (n = 14) 10 (5–10) (n = 12) Barnidipine dose (mg/day) 10 (n = 1) 20 (n = 1) Diltiazem dose (mg/day) 60, 120, 300 (n = 3) 0 Felodipine dose (mg/day) 10 (n = 1) 0 Lacidipine dose (mg/day) 0 4 (n = 1) Lercanidipine dose (mg/day) 20 (n = 1) 10, 20 (n = 2) Nifedipine dose (mg/day) 20, 30 (n = 2) 30 (28–38) (n = 4) Verapamil dose (mg/day) 240 (n = 1) 80 (n = 1) SBP (mmHg), median (IQR) 120 (120–130) 130 (120–133) DBP (mmHg), median (IQR) 80 (78–80) 80 (78–85) Minimum SBP (mmHg), median (IQR) 115 (110–120) 120 (115–120) Minimum DBP (mmHg), median (IQR) 70 (70–80) 75 (70–80) On other anti-hypertensive medications, percentage of patients 91.3 85.7 SBP, systolic BP; DBP, diastolic BP. Actual doses or median (IQR) doses are given. In order to exclude the possibility that our findings may have been biased by the exclusion of patients who prematurely stopped combined antiretroviral and CCB treatment, which may have underestimated the clinical impact of this DDI, we also looked at the database of our infectious diseases clinics (7326 HIV-infected patients treated since 1985, of whom 2014 are still being followed up). A search for HIV-infected patients who had previously discontinued CCB treatment for any reason identified a total of 14 patients treated with amlodipine (n = 7), barnidipine (n = 3), diltiazem (n = 2) or nifedipine (n = 2), 8 of whom concomitantly received boosted ART. One patient decided to discontinue his CCB without advice from his physician, 10 patients discontinued CCB because it was not efficacious (advice given by their physicians) and 3 patients simplified their antihypertensive therapy (advice given by their physicians); none of them discontinued their CCB because of hypotension and/or cardiac toxicity. Only a few case reports and pharmacokinetic studies of healthy volunteers have considered the co-administration of boosted antiretrovirals and CCBs, which is why the quality of the evidence concerning this DDI is rated ‘low’ by the Liverpool website.3–5 Nevertheless, it conservatively suggests that the combination of boosting agents with CCBs should be administered extremely cautiously because the high risk of increasing the plasma concentrations of CCBs metabolized by CYP3A may lead to hypotension and/or a prolonged PR interval. Our search for real-life data in the GAP database identified nearly 7% of HIV-infected patients treated with CCBs, equally divided between those who were concomitantly treated with ritonavir or cobicistat and those on non-boosted antiretroviral regimens, none of whom experienced any episodes of hypotension or PR alterations. The discrepancy between the predicted DDI and clinical outcomes may be due to the wide therapeutic index of CCBs, the possibility of adjusting drug doses on the basis of easily assessable pharmacodynamic markers (daily variations in BP) and/or the non-detection of plasma CCB concentrations associated with toxic electrophysiological and haemodynamic effects.6 However, it cannot be ruled out that the small number of patients on individual CCBs and the consequent collapsing of data relating to a heterogeneous drug class have partially biased our findings. In conclusion, we provide some useful insights into the previously under-studied DDIs between boosted antiretrovirals and CCBs, which are frequently co-administered in HIV-infected patients. The findings of this albeit small cohort study seem to suggest that such DDIs can be adequately managed by adjusting CCB doses and clinically monitoring BP and electrocardiographic assessment; it is likely that no discontinuation of the CCBs or change in antiretroviral regimen is required. Funding This study was carried out as part of our routine work. Transparency declarations None to declare. References 1 Edelman EJ , Gordon KS , Glover J et al. The next therapeutic challenge in HIV: polypharmacy . Drugs Aging 2013 ; 30 : 613 – 28 . Google Scholar CrossRef Search ADS PubMed 2 Gervasoni C , Resnati C , Formenti T et al. The relevance of drug-drug interactions in clinical practice: the case of concomitant boosted protease inhibitors plus alpha-1 blocker administration . Antivir Ther 2018 ; doi:10.3851/IMP3214. 3 Glesby MJ , Aberg JA , Kendall MA et al. Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers . Clin Pharmacol Ther 2005 ; 78 : 143 – 53 . Google Scholar CrossRef Search ADS PubMed 4 Rossi DR , Rathbun RC , Slater LN. Symptomatic orthostasis with extended-release nifedipine and protease inhibitors . Pharmacotherapy 2002 ; 22 : 1312 – 6 . Google Scholar CrossRef Search ADS PubMed 5 Baeza MT , Merino E , Boix V et al. Nifedipine-lopinavir/ritonavir severe interaction: a case report . AIDS 2007 ; 21 : 119 – 20 . Google Scholar CrossRef Search ADS PubMed 6 Echizen H , Eichelbaum M. Clinical pharmacokinetics of verapamil, nifedipine and diltiazem . Clin Pharmacokinet 1986 ; 11 : 425 – 49 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Apr 19, 2018

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