Efficacy of high doses of penicillin versus amoxicillin in the treatment of uncomplicated community acquired pneumonia in adults. A non-inferiority controlled clinical trial

1 Title Efficacy of high doses of penicillin versus amoxicillin in the treatment of adults with non-severe community-acquired pneumonia. A randomised controlled noninferiority trial. Título Eficacia de altas dosis de penicilina frente a amoxicilina en el tratamiento de la neumonía no complicada adquirida en la comunidad en adultos. Ensayo clínico controlado de no inferioridad. Short running title Penicillin versus amoxicillin in pneumonia. Authors Carl Llor, GP1; Almudena Pérez, GP2; Eugenia Carandell, GP3; Anna García-Sangenís, monitor4; Javier Rezola, GP3; Marian Llorente, GP3; Salvador Gestoso, GP3; Francesc Bobé, GP5; Miguel Román-Rodríguez, GP3; Josep M. Cots, GP2; Silvia Hernández, GP5; Jordi Cortés, statistician4; Marc Miravitlles, pneumologist6; Rosa Morros, pharmacologist4 1Primary Care Centre Via Roma, Barcelona, Spain 2Primary Care Centre La Marina, Barcelona, Spain 3Primary Care Centre Son Pisà, Palma de Mallorca, Spain 4Institut Universitari d'Investigació en Atenció Primària Jordi Gol, Barcelona, Spain. 5Primary Care Centre Jaume I, Tarragona, Spain 6Pneumology Department. Hospital Universitari Vall d’Hebron, CIBER de Enfemedades Respiratorias (CIBERES), Barcelona, Spain. © 2018. This manuscript version is made available under the CC-BYNC-ND 4.0 license http://creativecommons.org/licenses/by-ncnd/4.0/ 2 Address for correspondence Carl Llor Primary Healthcare Centre Via Roma c. Manso 19, 3rd floor. 08015 Barcelona, Spain. Email: [email protected] Funding The project received a research grant from the Carlos III Institute of Health, Ministry of Economy and Competitiveness (Spain), awarded in the 2011 call under the Health Strategy Action 20132016, within the National Research Program oriented to Societal Challenges, within the Technical, Scientific and Innovation Research National Plan 2008-2011, with reference PI11/02471, co-funded with European Union ERDF funds. It was also supported by the Spanish Clinical Research Network (SCReN), PT13/0002/0030. The funding bodies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests Dr Llor reports receiving research grants from the European Commission (Sixth and Seventh Programme Frameworks), Catalan Society of Family Medicine, Instituto de Salud Carlos III (Spanish Ministry of Health) and Alere and has received research fees from GlaxoSmithKline in the last 3 years. Dr Román-Rodríguez reports that he has received research grants or fees for speaking in the last 3 years from the Instituto de Salud Carlos III (Spanish Ministry of Health) and the following pharmaceutical companies: Astra Zeneca, Boehringer-Ingelheim, Chiesi, GSK, Menarini, Mundipharma, Novartis, Pfizer, Rovi, and Teva. MM has received speaker fees from Almirall, Boehringer Ingelheim, Pfizer, AstraZeneca, Chiesi, GlaxoSmithKline, Menarini, Teva, Grifols and Novartis, and consulting fees from Almirall, Boehringer Ingelheim, Pfizer, GlaxoSmithKline, Gebro Pharma, CLS Behring, Cipla, Medimmune, Teva, Takeda, Novartis and Grifols. The other authors declare no competing interests. The other authors declare no competing interests in relation to this work. 3 Abstract Introduction. In some northern European countries community-acquired pneumonia (CAP) is treated with penicillin. This study was aimed at evaluating whether high-dose penicillin V is as effective as high-dose amoxicillin for the treatment of non-severe CAP. Design. Multicentre, parallel, double-blind, controlled, randomised clinical trial. Setting. 31 primary care centres in Spain. Participants. Patients from 18 to 75 years of age without significant associated comorbidity attending the physician with symptoms of lower respiratory tract infection and radiological confirmation of CAP were randomised to receive either penicillin V 1.6 million units or amoxicillin 1,000 mg thrice-daily during 10 days. Main measurements. The main outcome was clinical cure at 14 days and the primary hypothesis was that penicillin V would be no inferior to amoxicillin with regard to this outcome, with a margin of 15% for the difference in proportions. EudraCT register 2012-003511-63. Results. 43 subjects (amoxicillin: 28; penicillin: 15) were randomised. Clinical cure was observed in 10 (90.9%) patients assigned to penicillin and in 25 (100%) patients assigned to amoxicillin with a difference of – 9.1% (95% CI, - 41.3% to 6.4%; p=0.951) for noninferiority. In the intention-to-treat analysis amoxicillin was found to be 28.6% superior to penicillin (95% CI, 7.3% to 58.1%; p=0.009 for superiority). The number of adverse events was similar in both groups. Conclusions. We observed a trend favouring high-dose amoxicillin versus high-dose penicillin in adults with uncomplicated CAP. The main limitation of this trial was the low statistical power because of the low number of patients included. Keywords: Community-acquired Pneumonia; Randomized Controlled Trial; Penicillin; Amoxicillin; Adults 4 Eficacia de dosis altas de penicilina frente a amoxicilina en el tratamiento de la neumonía no complicada adquirida en la comunidad en adultos. Ensayo clínico controlado de no inferioridad. Introducción. En algunos países la neumonía adquirida en la comunidad (NAC) se trata con penicilina. Este estudio tuvo como objetivo evaluar si penicilina V a dosis altas es igual de efectiva que amoxicilina a dosis altas en la NAC no complicada. Diseño. Ensayo clínico paralelo, doble ciego, controlado y multicéntrico, Emplazamiento. 31 centros de salud en España. Participantes. Se reclutaron pacientes de 18 a 75 años de edad sin comorbilidad asociada importante con síntomas de infección respiratoria inferior y confirmación radiológica de neumonía, que fueron asignados aleatoriamente a 1,6M unidades de penicilina V o amoxicilina 1.000 mg, tres veces al día, durante 10 días. Mediciones principales. La variable de resultado principal fue curación clínica a los 14 días y se planteó la hipótesis de que penicilina no era inferior a amoxicilina con un margen de 15% para la diferencia de proporciones. Registro EudraCT 2012-003511-63. Resultados. Se aleatorizaron 43 personas (amoxicilina: 28; penicilina: 15). Se observó curación clínica en 10 pacientes asignados a penicilina (90,9%) y en 25 asignados a amoxicilina (100%), observándose una diferencia de -9.1% (IC95%: -41.3 a 6,4%; p=0,951) para no inferioridad. En el análisis por intención de tratar, amoxicilina fue 28,6% superior a penicilina V (IC95%: 7,3% a 58,1%; p=0,009 para superioridad). El número de eventos adversos fue similar en ambos grupos. Conclusiones. Se observó una tendencia de un mayor beneficio de amoxicilina frente a penicilina en adultos con NAC no complicada. La principal limitación fue la baja potencia estadística debido al bajo número de pacientes incluidos. Palabras clave: Neumonía adquirida en la comunidad; Ensayo clínico aleatorio; Penicilina; Amoxicilina; Adultos. 5 Introduction Community-acquired pneumonia (CAP) remains a burden in the modern world [1]. Respiratory bacteria constitute the major group of causative organisms. In approximately 50% of the cases the pathogen cannot be identified; however, Streptococcus pneumoniae is the organism most frequently isolated throughout all the studies and settings, even among outpatients [2,3]. In some European countries, mainly those in Northern Europe, pneumonia is treated with penicillin V since the resistance of pneumococci to this antibiotic is low [4]. However, in most European countries amoxicillin is the first-choice antibiotic for uncomplicated cases [5-7]. Four reasons justify the present study. Firstly, the cut-off points which determine whether a pneumococcus is susceptible or resistant to penicillin changed in 2008 [8], and according to some recently published studies pneumococcal resistance to penicillin (minimum inhibitory concentration [MIC] >2 µg/ml) has fallen drastically [9]. Secondly, there is no correlation between pneumococcal infection by a strain resistant to penicillin and therapeutic failure with βlactams prescribed at adequate doses [10]. Thirdly, the use of narrow-spectrum antibiotics is needed because of the dearth of new antimicrobials and the link observed between the consumption of broad-spectrum antibiotics and the emergence and spread of antibacterial resistance [11]; and fourthly, no clinical study comparing amoxicillin and penicillin V in pneumonia in adults has been published to date. Thus, the aim of the present trial was to determine whether high-dose penicillin V was as effective as high-dose amoxicillin for the treatment of uncomplicated CAP in a Mediterranean adult population. Material and methods We performed a prospective, parallel-group, randomised, double-blind, trial in primary healthcare centres in Spain carried out from November 2013 to April 2016. All patients provided written informed consent. The study protocol has been published elsewhere [12]. Patients aged 18 to 75 without significant associated comorbidity attending a primary care physician with signs and symptoms of lower respiratory tract infection and radiological confirmation of the diagnosis of pneumonia were invited to participate. We permitted the 6 inclusion and randomisation of patients without radiological confirmation if there was a high suspicion of pneumonia as suggested in previous studies [13], that is, patients with lower respiratory tract infection, temperature higher than 38.5ºC and productive cough; however, chest X-ray had to be done in the following 24 hours, and if there was no radiological confirmation of pneumonia, patients were excluded. Due to difficulties in the recruitment of patients an amendment to the previous protocol was made, broadening the age range of subjects, considering some other comorbidities and also taking into account patients who had taken urinary antiseptics in the previous days [12]. Exclusion criteria were subjects under 18 or over 75 years of age, severe impairment of signs (impairment of consciousness, respiratory rate >30 breaths/minute, heart rate >125 beats/minute, systolic blood pressure <90 mm Hg, diastolic blood pressure <60 mm Hg, temperature >40ºC, oxygen saturation <92%), hypersensitivity to β-lactams, important alteration on chest X-ray, such as alveolar infiltrate in more than one lobe or bilateral, pleural effusion and/or pulmonary cavitation, problems to comply with treatment at home, lack of tolerance to oral treatment, significant comorbidity including bronchial asthma, renal failure, hepatic cirrhosis, heart failure, chronic obstructive pulmonary disease, ischaemic heart disease, stroke and/or type 1 diabetes mellitus, immunosuppression, terminal disease, pregnancy or lactation, hospitalization in the last month, consumption of antibiotics in the last two weeks, difficulty to attend the programmed visits or refusal to participate in the study. It was a double-blind two arms clinical study; participants and investigators remained blinded to the treatment received. Patients were randomly assigned to receive either penicillin V 1,600,000 IU (two 800,000 IU pills) or amoxicillin 1,000 mg (two 500 mg pills) thrice a day during 10 days. Subject numbers were assigned sequentially as each subject entered the study. The subjects were assigned to a study drug through a randomisation schedule based on the randomisation plan. Since this was a multicentre study a block procedure was planned for the allocation of the study medication. Each container included 66 pills (60 pills for the treatment plus 6 extra pills). The dose of penicillin used in the study was not marketed in our country, and consequently, the study drugs were entirely prepared and labelled by the Pharmacy Unit of the Hospital Universitari Son Espases (Palma de Mallorca). As the medication was prepared by a Pharmacy 7 Service, the batches were small and every batch required stability analysis every 6 months. Furthermore, two pills per intake were needed due to the high penicillin dose, meaning that we had to double the number of batches and 6-month stability analyses, thereby exceeding the initial budget. Considering the high dose of penicillin used, a data and safety monitoring board was created to ensure patient safety and treatment efficacy during recruitment. However, the difficulties in drug preparation, the limited budget and the elevated number of centres opened to minimize the low inclusion rate made it impossible to maintain the 4 block per centre distribution, and finally the medication was allocated following a simple randomisation according to centre needs. Use of antithermic drugs or analgesics (acetaminophen, acetylsalicylic acid or ibuprofen), bronchodilators or any other medication, except oral systemic antibiotics, that the patient was talking was allowed. Variables The main outcome was clinical cure at 14 days, defined as the absence of fever, resolution or improvement of cough, improvement of general well-being and resolution or reduction of crackles indicating that no other antimicrobial treatment was necessary. Any clinical result other than the anterior was considered as treatment failure. Secondary outcomes were efficacy at day 30 after the initiation of antibiotic treatment, radiological resolution or improvement one month after the initiation of the treatment, complete clinical resolution at day 14 defined as the total resolution of acute symptoms and signs related to the infection, and the presence of adverse events. The radiologists responsible for diagnosing pneumonia and confirming the radiological cure were blind to the clinical data and the treatment administered. On fulfilling the inclusion criteria, the nature of the study was explained to the patient and informed consent was obtained. All the eligible patients had a chest X-ray (posteroanterior and lateral views) demonstrating pneumonic infection. The study scheme and the visit program were explained to the patients, and they were then randomised to one of the 2 treatment groups and the medication was given. At the first follow-up visit, scheduled at day 3 (by phone or at the 8 centre), worsening of the clinical situation was evaluated to determine whether a change in the antibiotic treatment was necessary. Likewise, compliance and possible secondary effects of the treatment were evaluated. At the second follow-up visit, at day 14, the clinical evolution of the signs and symptoms was evaluated. Likewise, possible secondary effects of the treatment were evaluated. On the last follow-up visit, scheduled at day 30, the clinical outcome of the signs and symptoms of the pneumonia was evaluated and a new chest X-ray was performed (posteroanterior and lateral views) to confirm radiological resolution. The medication was discontinued in the case of significant adverse events. The variables were registered in an electronic case report form designed by the Fundació Institut Català de Farmacologia, Barcelona. Sample size calculation and statistical analyses The objective of the study was to demonstrate that penicillin V was not inferior to amoxicillin. Considering a success rate of 85% for the group treated with amoxicillin [14,15], a total of 105 patients were required in each treatment group (total of 210) to detect a noninferiority margin of 15% at maximum between the two treatments with a minimum power of 80% considering an alpha error of 2.5% for a unilateral hypothesis and maximum possible losses of 15%. The intention-to-treat (ITT) population included all randomised patients with confirmation of pneumonic infection receiving at least one dose of the study drug and the per-protocol (PP) population included patients adherent to protocol with adequate treatment compliance and absence of major protocol violations. Descriptive results of the outcomes were reported as number and percentages. To evaluate the differences on baseline characteristics, Fisher’s exact tests for categorical variables and nonparametric tests for continuous measures were carried out. Comparisons between groups were performed using exact binomial distribution for the efficacy endpoints and adverse events [16], 95% confidence intervals (CI) for the differences in success percentages were estimated and pvalues provided. All analyses were conducted with R statistical package, version 3.2.5. 9 Ethics approval The study was approved by the Institutional Review Board (IDIAP Jordi Gol Clinical Investigation Ethic Committee) and the Spanish Agency of Medicines and Health Products. Written informed consent was obtained from all participants. Trial registration: EudraCT number 2012-003511-63. Results The required sample size of 210 patients could not be achieved although 31 centres were opened (10 centres were initially planned). A total of 43 subjects were screened and randomised (28 patients in the amoxicillin arm and 15 patients in the penicillin arm) and constituted the safety population. The demographic and clinical characteristics of the randomised population were well matched between the groups (Table 1). A total of 4 patients were excluded from the ITT population: 3 had a normal chest X-ray and one more was mistakenly given expired medication and was withdrawn the following day. A total of 3 patients were lost during follow-up and were all excluded from the PP population. The flow of patients in the study and causes of exclusion are presented in the general scheme of the study. We cannot prove that penicillin V was not inferior to amoxicillin as clinical cure was observed in 10 patients assigned to penicillin (90.9%) and in 25 patients assigned to amoxicillin (100%) in the PP population with a difference of – 9.1% (95% CI, - 41.3% to 6.4%; p=0.951 for noninferiority). A total of 39 subjects (25 in the amoxicillin arm and 14 in the penicillin V arm) fulfilled all the criteria for the ITT population, and in this group amoxicillin was found to be superior to penicillin, with a difference of 28.6% (95% CI, 7.3% to 58.1%; p=0.009 for superiority) (Fig. 1). All the results of this section refer to superiority comparisons in the ITT population (Fig. 1). Amoxicillin was found to be 28.6% superior to penicillin in terms of clinical resolution on day 30 (95% CI, 7.3% to 58.1%; p=0.009) and in terms of total resolution one month after the index visit (34.9% superior, 95% CI, 6.2% – 62.5%; p=0.002). Radiological resolution among patients assigned to amoxicillin was 27.3% superior to patients allocated to penicillin V (95% CI, 4.5% to 16 17. Llor C, Moragas A. Dificultades de selección en los ensayos clínicos en atención primaria. Cuando no se llega al tamaño muestral. Aten Primaria. 2013;45:71–3. 18. Gilbert DN. Clinical end points of therapy for patients with mild community-acquired pneumonia. Clin Infect Dis. 2008;47(Suppl 3):S140–4. 19. Atkinson M, Lakhanpaul M, Smyth A, Vyas H, Weston V, Sithole J, et al. Comparison of oral amoxicillin and intravenous benzyl penicillin for community acquired pneumonia in children (PIVOT trial): a multicentre pragmatic randomised controlled equivalence trial. Thorax. 2007;62:1102–6. 20. Addo-Yobo E, Chisaka N, Hassan M, Hibberd P, Lozano JM, Jeena P, et al. Oral amoxicillin versus injectable penicillin for severe pneumonia in children aged 3 to 59 months: a randomised multicentre equivalency study. Lancet. 2004;364:1141–8. 21. Tsarouhas N, Shaw KN, Hodinka RL, Bell LM. Effectiveness of intramuscular penicillin versus oral amoxicillin in the early treatment of outpatient pediatric pneumonia. Pediatr Emerg Care. 1998;14:338–41. 22. Rojas MX, Granados C. Oral antibiotics versus parenteral antibiotics for severe pneumonia in children (Review). Cochrane Database Syst Rev. 2006;(2):CD004979. 23. Agweyu A, Gathara D, Oliwa J, Muinga N, Edwards T, Allen E, et al; Severe Pneumonia Study Group. Oral amoxicillin versus benzyl penicillin for severe pneumonia among Kenyan children: a pragmatic randomized controlled noninferiority trial. Clin Infect Dis. 2015;60:1216–24. 24. Pakhale S, Mulpuru S, Verheij TJ, Kochen MM, Rohde GG, Bjerre LM. Antibiotics for community-acquired pneumonia in adult outpatients. Cochrane Database Syst Rev. 2014;(10):CD002109. 25. Knudsen JD, Odenholt I, Erlendsdottir H, Gottfredsson M, Cars O, Frimodt-Møller N, et al. Selection of resistant Streptococcus pneumoniae during penicillin treatment in vitro and in three animal models. Antimicrob Agents Chemother. 2003;47:2499–506. 17 26. Oakes M, Human RP, Meers PD. Serum-levels of four antibiotics administered orally to patients in general practice. Lancet. 1973;1:222–4. 27. Bryan CS, Talwani R, Stinson MS. Penicillin dosing for pneumococcal pneumonia. Chest. 1997;112:1657–64. 28. Fredlund H, Bodin L, Bäck E, Holmberg H, Krook A, Rydman H. Antibiotic therapy in pneumonia: a comparative study of parenteral and oral administration of penicillin. Scand J Infect Dis. 1987;19:459–66. 29. British Medical Association; Pharmaceutical Society of Great Britain: British National Formulary 59. London: BMJ Publishing Group Ltd and Royal Pharmaceutical Society, 2010; pp. 231–352. 30. Pallarés R, Linares J, Vadillo M, Cabellos C, Manresa F, Viladrich PF, et al. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med. 1995;333:474–80. 31. Metlay JP, Hofmann J, Cetron MS, Fine MJ, Farley MM, Whitney C, et al. Impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia. Clin Infect Dis. 2000;30:520–8. 18 Table 1. Baseline characteristics of the patients randomized into two groups to receive either amoxicillin or penicillin V. Values are numbers (percentages) unless stated otherwise. Amoxicillin (n=28) Penicillin V (n=15) Male sex 14 (50.0) 5 (33.3) Age, mean (SD) 49.0 (14.3) 46.6 (17.4) Smoking status: Current smoker 4 (14.3) 3 (20.0) Former smoker 4 (14.3) 4 (26.7) Non smoker 20 (71.4) 8 (53.3) Excessive consumption of alcohol 3 (10.7) 1 (6.7) High blood pressure 3 (10.7) 3 (20.0) Diabetes mellitus 1 (3.6) 0 (-) Hypercholesterolemia 7 (25.0) 3 (20.0) Cough 28 (100) 14 (93.3) Days with cough before randomization visit, mean (SD) 6.2 (4.7) 10.1 (8.7) Joint and muscle aches 14 (50.0) 8 (53.3) Expectoration 24 (85.7) 12 (80.0) Sputum color: Uncolored 1 (3.6) 4 (26.7) Yellow or green 21 (75.0) 6 (40.0) Rust 2 (7.1) 1 (6.7) Diarrhea 2 (7.1) 2 (13.3) Dyspnea 8 (28.6) 6 (40.0) Chest pain 13 (46.4) 7 (46.7) General malaise 20 (71.4) 13 (86.7) 19 Clinical examination: Temperature, mean ºF (SD) 99.1 (33.8) 99.1 (33.3) Systolic blood pressure, mean of mm Hg (SD) 128.0 (16.1) 125.1 (13.9) Diastolic blood pressure, mean of mm Hg (SD) 77.9 (10.1) 74.7 (11.6) Pulse, mean per minute (SD) 85.5 (14.9) 83.3 (9.0) Respiratory rate, mean per minute (SD) 19.3 (4.0) 18.5 (3.6) Pulse oximetry, mean of saturation (SD) 96.8 (1.7) 97.0 (1.7) General crackles 1 (3.6) 1 (6.7) Focal crackles 23 (82.1) 12 (80.0) Ronchi 7 (25.0) 3 (20.0) Wheezing 6 (21.4) 2 (13.3) Treatment administered: Analgesics 21 (75.0) 14 (93.3) Non-steroidal anti-inflammatory drugs 12 (42.9) 8 (53.3) Antitussives 8 (28.6) 2 (13.3) Bronchodilators 7 (25.0) 0 (-) Mucolytics 6 (21.4) 4 (26.7) SD: standard deviation