Analysis of antibacterial agents consumption in a Brazilian southeastern hospital complex from 2018 to 2021

Abstract

Healthcare during the COVID-19 pandemic may have led to the inappropriate use of antimicrobial agents and contributed to elevated multidrug resistance. The aim of this study was to analyze the consumption of antibacterial agents at a hospital complex from 2018 to 2021. Drug utilization study using antibacterial agents consumption data. The groups of antibacterial agents most consumed in the hospital complex were carbapenems, penicillins + beta-lactamase inhibitors, beta-lactamase-resistant penicillins, glycopeptides, and fluoroquinolones. The drugs with a compound annual growth rate that increased by more than 20% from 2018 to 2021 were amikacin (50.12%), benzylpenicillin (24.33%), oral clarithromycin (51.06%), daptomycin (34.38%), polymyxin B (20.85%), and tigecycline (41.49%). According to the AWaRE classification, the antibacterial agents from the Watch group subjected to AWaRE exhibited increased consumption in all years of the study. On the other hand, there was a reduction in the access category. In turn, the consumption of antibacterial agents in the reserve category also increased. The pattern of antimicrobial consumption in the hospital complex showed increased consumption in medical clinics and intensive care units, with a predominance of carbapenems, penicillins + beta-lactamase inhibitors, beta-lactamase-resistant penicillins, glycopeptides, fluoroquinolones, and polymyxin B, reflecting the care profile and influence of the COVID-19 pandemic.

Keywords:
Antibacterials agents; Defined daily dose; Hospitals; Antibiotics; Drug resistance

INTRODUCTION

Antimicrobials are among the most commonly prescribed medications in hospitals, and their inappropriate use contributes to emerging antimicrobial resistance. This critical public health problem can determine the risk of death, therapeutic failure, increased length of stay, and increased healthcare costs associated with alternative and more expensive antibacterial agents, which can have more severe adverse effects (Nadgir, Biswas, 2023; Pauwels et al., 2021).

A study covering data from 204 countries and territories estimated that 1.2 million deaths were directly attributed to antimicrobial resistance in 2019 (Antimicrobial Resistance Collaborators, 2022). Furthermore, the impact of antimicrobial resistance is expected to increase, with an estimated global rate of approximately 10 million yearly deaths by 2050 if adequate solutions are not found to contain the problem (O’Neill, 2016).

Although it cannot be eradicated, antimicrobial resistance can be managed, and actions to reduce harm through the appropriate use of antibiotics have been promoted by governments and international organizations, such as the World Health Organization (WHO) (Grau et al., 2021).

The COVID-19 pandemic has led to substantial patient morbidity and mortality. It revealed significant hospital care vulnerabilities due to patient overload and tensions in the supply chain, which led to shortages of medicines and other essential care products. Healthcare under these conditions may have led to the inappropriate use of antimicrobials and contributed to elevated multidrug resistance during the pandemic (Patel et al., 2023; Allel et al., 2023; Antunes et al., 2023).

Furthermore, the decreased emergence of new antibacterial agents in recent decades has increased the lack of therapeutic alternatives (Hodoșan et al., 2023). Several analogs of existing substances have been introduced into the market, but only two new classes of antimicrobial agents have been sold. On the other hand, multiresistant bacteria have surfaced, making infections increasingly difficult to address with the antibacterial agents currently on the market (Rolain et al., 2016; Diallo et al., 2020). The appropriate use of antimicrobials available in hospitals remains a crucial effort to prevent and control antimicrobial multidrug resistance (Benkő et al., 2022).

In this setting, antimicrobial stewardship activities are essential for optimizing the use of these medicines and reducing the emergence rate of multiresistant microorganisms. Identifying hospital consumption patterns is crucial for uncovering opportunities for improvement and implementing policies to optimize antimicrobial prescriptions (Grau et al., 2021).

Therefore, this work aimed to analyze the consumption of antibacterial agents by adult patients at a hospital complex located in a Brazilian southeastern capital from 2018 to 2021.

METHODS

Study type

This was a retrospective, cross-sectional drug utilization study using antibacterial agents consumption data from a hospital complex collected from January 2018 to December 2021. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines were adopted for this study.

Study location

The study was conducted at a teaching hospital complex in Belo Horizonte, Minas Gerais state, Brazil, which provides medium- and high-complexity care. The complex has an approximate 500-bed capacity encompassing two hospitals and five outpatient services. It serves patients from all over the state and is a reference in several medium- and high-complexity services, such as transplants, oncology treatment, and ophthalmology. Medication prescriptions are prepared at the institution using an electronic prescription system. The institution has a Hospital Infection Control Committee (HICC), which performs prospective audits of prescriptions for all antimicrobials. Audit and approval by the Pharmacy and Therapeutics Commission (PTC) is also required for high-cost or nonformulary antimicrobial agents.

The evaluation by the HICC or PTC auditor is conducted within 24 hours. The antimicrobial agent is supplied, and the administration route, dose, and duration of treatment approved by the audit are recorded.

Inclusion criteria

This study included data on the consumption of antimicrobials of the J01 group, Antibacterials for systemic use of the WHO ATC classification, used in the adult hospitalization units of the general hospital and the ophthalmological hospital of the hospital complex investigated, intensive care center, and obstetric center, from January 2018 to December 2021.

Exclusion criteria

The study did not analyze data on the consumption of topical antibacterials and systemic antibacterials used in pediatric and neonatal units or outpatient procedures during the period investigated.

Data collection

Monthly and annual consumption data per care unit were collected from medication stock movement reports. The pharmacy department of the investigated hospital complex provided reports to researchers in Excel spreadsheet format. Data relating to the consumption of antibacterials were organized in a database for research purposes.

Antibacterials were classified according to level 4 (chemical) of the WHO Anatomical Therapeutic Chemical Classification (ATC/DDD Index, 2023) and per the WHO’s AWaRE system, which is based on treatment potential, possible impact on therapy, and antibacterial resistance, structured into the following groups: i. “Access - Antibacterials listed as the first and second options for the treatment of common infections and broadly accessible” (Who, 2022); ii. “Watch - Antibacterials specific to patients with well-defined diseases and syndromes whose use should be continuously monitored” (Who, 2022); and iii. “Reserve - Antimicrobials considered as a last resort in the treatment of bacterial infections resistant to multiple antibacterials” (Who, 2022).

The care units were grouped as follows: i. emergency unit: provides urgent and clinical and surgical emergency care; ii. Medical clinic unit: hospitalization units for internal medicine patients and several medical specialties; iii. intensive care unit: hospitalization units for adult patients under intensive and semi-intensive care and coronary care units; iv. surgical clinical unit: hospitalization units for surgical patients in neurology, orthopedics, plastic, oral and maxillofacial surgery, and other specialties; v. gastroenterology and digestive tract surgery unit: hospitalization units for clinical or surgical patients related to the digestive tract; vi. gynecology and obstetrics unit: inpatient units for the clinic and gynecological surgery, rooming-in, and obstetric wing;vii. hematology and transplantation unit: hospitalization units for onco-hematology clinical patients and solid organ and hematological stem cell transplant patients; and viii. Ophthalmology unit: inpatient units of the ophthalmology hospital of the investigated hospital complex.

The bed occupancy rates of the units included in the study to calculate the defined daily dose/1000 patients/ day were collected from reports made available by the Medical Archive and Statistics Service (SAME) and recorded in the database.

Data analysis

Consumption data for each year of the study period were calculated per care unit and for the hospital in DDD/1000 patients/day using the following formula:

$\text{DDD Consumption}=\frac{\left(A/B\right)\times 1000}{C}$

A - Total antibacterial activity consumed in grams

B - Standard daily dose in grams of the antibacterial agent for an adult, in its primary indication, per the ATC/DDD Index 2023 (ATC/DDD Index, 2023)

C - Patient-day value

* The equivalence between units and grams was identified to calculate the DDD for antibacterials whose concentration was expressed in units.

The 90% drug utilization (DU) index was calculated for each ATC chemical group and antibacterial activity for each investigated year. Ninety percent of DUs cover drugs that represent 90% of the total consumed in a health service in a given period (Teichert et al., 2007). The compound annual growth rate (CAGR) was employed to calculate the annual changes in the most consumed antibacterials over the study period via the following formula:

$CARG=\left(\frac{{C_{af}}^{1/\left(nf-ni\right)}}{C_{ai}}\right)-1$

where is the total amount of antibacterials used in the final year, is the total amount used in the start year of the research, nf is the final year, and ni is the start year of the investigated period. Furthermore, the difference between the pandemic period (CAGRp) and the total period (CAGRt) (Wushouer et al., 2023, Medeiros, 2022) was used to obtain the growth rate if there was no influence of the COVID-19 pandemic.

The amount of antibacterial DDD consumed at the hospital complex according to the WHO AWaRE classification from 2018 to 2021 was determined. Independent sample t tests were performed. Statistical significance was defined as a P value < 0.05.

The database was developed using Excel Software, and statistical analysis was performed with the Statistical Package for Social Sciences® (SPSS®) software, version 25.0.

Ethical aspects

The research was conducted per Resolution N° 466/12 of the National Health Council - Ministry of Health (Brasil, 2012). There was no need to seek approval from the Research Ethics Committee, given that the research was conducted with administrative databases, whose information is aggregated and without individual identification. The research unit of the investigated institution approved access to the data and authorized the research.

RESULTS

Table I presents the consumption in DDD/1000 patients/day of systemic antibacterials agents at the hospital complex during the period investigated by the ATC classification chemical group and sorted by ranking. The most consumed ATC groups were J01DH- carbapenems, J01CR-penicillins + beta-lactamase inhibitors, J01CF-beta-lactamase-resistant penicillins, J01XA-glycopeptides, and J01MA-fluoroquinolones. There was no significant change in the consumption of these antibacterial agents, except for fluoroquinolones, which fell to 7^th and 8^th place in 2020 and 2021, respectively.

TABLE I
Groups of antibacterial agents most commonly prescribed per ATC classification at the investigated hospital from 2018 to 2021

ATC	PHARMACOLOGICAL GROUP	Ranking	DDD 2018	Ranking	DDD 2019	Ranking	DDD 2020	Ranking	DDD 2021	Total
J01DH	Carbapenems	1	1187.99	1	1197.56	2	1212.91	1	1758.3	5356.76
J01CR	Penicillins + Beta-lactamase inhibitor	2	1023.75	2	1102.43	1	1295.12	2	1391.43	4812.73
J01CF	Beta-lactamase resistant penicillins	3	899.41	3	880.31	4	838.84	3	1018.73	3637.29
J01MA	Fluoroquinolones	4	774.57	4	800.06	7	567.76	8	660.02	2802.41
J01XA	Glycopeptide antibacterials	5	674.12	5	687.78	3	844.35	4	881.48	3087.73
J01DB	First-generation cephalosporins	6	527.43	7	514.97	14	246.07	12	293.82	1582.29
J01XB	Polymyxins	7	495.85	9	440.13	5	679.1	5	880.83	2495.91
J01DD	Third-generation cephalosporins	8	475.73	10	421.24	6	638.23	7	693.12	2228.32
J01EC	Intermediate-acting sulfonamides	9	428.26	11	355.96	17	192.89	19	30.67	1007.78
J01DE	Fourth-generation cephalosporins	10	395.82	8	476.72	10	413.4	15	246.76	1532.7
J01XD	Imidazole derivatives	11	383.76	12	326.03	12	315.78	11	305.16	1330.73
J01CE	Beta-lactamase sensitive penicillins	12	374.2	6	523.84	9	500.92	6	724.34	2123.3
J01EE	Combinations of sulfonamides and trimethoprim, incl. derivatives	13	324.18	13	276.72	13	266.31	14	280.93	1148.14
J01FA	Macrolides	14	245.71	15	258.08	8	516.12	9	394.45	1414.36
J01GB	Other aminoglycosides	15	202.77	14	271.35	11	365.43	10	370.43	1209.98
J01CA	Penicillins with extended-spectrum	16	148.48	17	144.34	19	115.94	16	227.7	636.46
J01XX	Other antibacterials	17	130.57	16	182.84	16	209.98	13	281.85	805.24
J01FF	Lincosamides	18	112.96	19	109.86	18	179.73	17	112.12	514.67
J01AA	Tetracyclines	19	107.94	18	117.67	15	210.4	18	141.56	577.57
J01DF	Monobactams	20	22.2	20	40.28	21	27.26	20	0.87	90.61
J01XE	Nitrofuran derivatives	21	21.78	21	26.75	20	35.7	21	0	84.23
J01GA	Streptomycins	22	2.08	22	4.42	22	1.29	22	0	7.79
J01BA	Amphenicols	23	0.11	23	0.1	23	0	23	0	0.21

Macrolides (J01XA) increased from 14^th in 2018 to 8^th in 2020, and beta-lactamase-sensitive penicillins (J01CE) increased from 12^th in 2018 to 6^th in 2021. An upward fluctuation in consumption was also detected for polymyxins (J01XB), moving from 7^th in 2018 to 5^th in 2021. In contrast, first-generation cephalosporin (J01DB) consumption decreased from sixth in 2018 to 12^th in 2021 (Table I).

Tables II and III show the consumption of antibacterials of DDD/1000 patient/day, stratified by hospitalization units, and the highest DDD/1000 patient/ day values were identified for J01DH-carbapenems and J01CR-penicillins + beta-lactamase inhibitor in the following units: emergency care, medical clinic, intensive care, and surgical clinic.

TABLE II
DDD consumption of antibacterial agents per ATC classification in the clinical and surgical units of the investigated hospital complex from 2018 to 2021

ATC	PHARMACOLOGICAL GROUP	URGENT AND EMERGENCY CARE UNIT				CLINICAL MEDICAL UNIT				INTENSIVE CARE UNIT				CLINICAL SURGICAL UNIT
		2018	2019	2020	2021	2018	2019	2020	2021	2018	2019	2020	2021	2018	2019	2020	2021
J01AA	Tetracyclines	9.5	4.54	6.05	4.41	3.65	10.17	16.01	15.83	19.71	36.42	49.37	23.88	16.63	39.83	51.14	44.4
J01BA	Amphenicols	0.11	0.1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
J01CA	Penicillins with extended-spectrum	16.99	12.39	4.76	6.45	22.31	33.5	16.27	48.05	19.08	17.38	28.61	28.07	14.06	22.01	9.97	73.46
J01CE	Beta-lactamase sensitive	28.52	66.89	14.37	23.74	10.71	18.03	11.83	12.09	1.59	2.28	2.13	4.85	5.67	2.63	12.74	11.25
J01CF	Beta-lactamase resistant	127.82	182.29	33.15	38.07	202.42	188	176.18	192.95	127.27	133.96	128.5	159.71	306.64	270.09	332.89	435.1
J01CR	Penicillins + Betalactamase inhibitor	224.84	256.56	153.23	180.63	136.25	177.3	264.47	286.01	186.86	176.52	219.11	245.89	149.16	170.49	286.53	288.76
J01DB	First-generation cephalosporins	12.84	9.01	6.98	10.09	8.22	6.02	3.81	9.86	197.67	193.48	47.38	136.74	42.84	43.47	6.29	35.51
J01DD	Third-generation cephalosporins	100.17	94.47	89.08	104.95	48.23	27.2	93.74	137.36	104.78	88.43	194.13	176.7	58.46	55.94	73.73	81.85
J01DE	Fourth-generation cephalosporins	104.78	148.82	65.45	35.61	46	55.2	83.51	35.56	19.79	16.26	9.95	11.38	126.18	189.34	186.16	82.03
J01DF	Monobactams	0.07	0.18	3.34	0.87	2.05	0.73	0.12	0	2.5	11.21	0	0	15.7	28.16	11.61	0
J01DH	Carbapenems	176.52	171.29	103.59	124.75	169.88	136.19	189.91	241.69	321.96	317.53	383.26	723.42	355.08	399.09	321.89	357.07
J01EC	Intermediate-acting sulfonamides	29.33	24.94	14.78	11.51	56.3	77.8	28.1	0.67	63.55	36.9	13.82	1.71	81.12	52.66	19.34	16.78
J01EE	Combinations of sulfonamides and trimethoprim, incl. derivatives	31.42	25.99	14.1	11.91	45.34	47.68	35.95	44.7	47.37	47.03	41.73	57.93	78.16	74.61	73.42	59.38
J01FA	Macrolides	87.84	96.5	73.62	64.59	57.02	53.27	186.73	166.15	36.34	33.31	155.54	89.54	8.5	18.03	37.09	20.86
J01FF	Lincosamides	10.31	7.35	7.89	6.15	24.62	7.58	21.28	4.4	27.46	18.09	35.91	26.99	12.98	14.73	9.35	6.95
J01GA	Streptomycins	0.04	1.04	0	0	1.13	2.53	0.48	0	0.91	0.85	0.66	0	0	0	0	0
J01GB	Other aminoglycosides	29.74	25.02	14.53	18.55	15.93	29.87	17.8	40.09	31.65	39	133.88	142.79	39.22	70.34	69.45	67.16
J01MA	Fluoroquinolones	74.51	47.94	22.39	22.68	46.54	50.67	43.04	46.38	32.94	68.26	45.97	75.69	76.92	77.01	66.12	87.44
J01XA	Glycopeptide antibacterials	90.11	79.99	40.74	49.13	90.19	88.28	106.35	124.23	174.98	171.81	247.52	286.2	215.41	249.51	295.31	233.56
J01XB	Polymyxins	66.17	29.98	26.04	27.37	49.26	31.14	28.09	68.17	229.81	213.97	461.97	648.87	110.76	127.94	100.63	73.06
J01XD	Imidazole derivatives	56.85	43.79	38.21	46.18	31.57	18.4	19.29	26.49	80.47	70.04	66.37	49.87	46.17	47.91	42.59	38.04
J01XE	Nitrofuran derivatives	2.27	1.53	1.74	0	3.02	1.25	2.41	0	0.43	0.79	0.63	0	4.38	3.36	2.6	0
J01XX	Other antibacterials	19.17	8.95	1.59	3.65	20.15	23.44	23.52	33.04	22.5	54.01	47.48	107.17	51.48	76.63	119.19	45.8

TABLE III
DDD consumption of antibacterial agents per ATC classification at the specialized clinical and surgical units of the investigated hospital from 2018 to 2021

ATC	PHARMACOLOGICAL GROUP	GASTROENTEROLOGY AND DIGESTIVE SYSTEM SURGERY UNIT				GYNECOLOGY AND OBSTETRICS UNIT				HEMATOLOGY AND TRANSPLANT UNIT				OPHTHALMOLOGY UNIT
		2018	2019	2020	2021	2018	2019	2020	2021	2018	2019	2020	2021	2018	2019	2020	2021
J01AA	Tetracyclines	2.37	4.93	7.8	23.9	1.87	2.89	3.74	0.77	3.48	4.25	17.4	10.76	50.73	14.64	58.89	17.61
J01BA	Amphenicols	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
J01CA	Penicillins with extendedspectrum	17.46	10.1	11.86	28.09	36.5	25.16	29.92	38.9	12.84	7.69	3.63	0.08	9.24	16.11	10.92	4.6
J01CE	Beta-lactamase sensitive penicillins	0.59	0	22.79	5.56	27.04	122.31	126.54	129.91	0.19	2.12	4.13	1.64	299.89	309.58	306.39	535.3
J01CF	Beta-lactamase resistant penicillins	3.81	77.66	84.2	40.52	28.37	3.5	1.81	7.74	24.03	14.38	20	39.17	79.05	10.43	62.11	105.47
J01CR	Penicillins + Beta-lactamase inhibitor	173.81	169.46	199.41	200.44	51.42	62.52	91.86	64.17	55.65	39.96	43.11	66.41	45.76	49.62	37.4	59.12
J01DB	First-generation cephalosporins	67.8	47.87	17.63	25.45	140.6	118.77	96.57	47.01	2.05	10.26	4.42	5.42	55.41	86.09	62.99	23.74
J01DD	Third-generation cephalosporins	103.37	99.67	106.08	103.01	9.22	18.62	17.72	18.96	11.39	20.96	13.73	19.27	40.11	15.95	50.02	51.02
J01DE	Fourth-generation cephalosporins	17.25	15.91	23.69	16.2	0.89	0.24	2.52	7.29	74.09	47.98	34.03	55.82	6.84	2.97	8.09	2.87
J01DF	Monobactams	0	0	0	0	0	0	0	0	1.88	0	12.19	0	0	0	0	0
J01DH	Carbapenems	64.62	51.04	98.73	132.92	3.13	2.31	2.5	4.38	96.8	119.93	112.77	171.13	0	0.18	0.26	2.94
J01EC	Intermediate-acting sulfonamides	0	0	1.03	0	3.45	1.62	6.53	0	8.69	6.42	7.3	0	185.82	155.62	101.99	0
J01EE	Combinations of sulfonamides and trimethoprim, incl. derivatives	3.93	3.74	7.4	5.9	1.28	0.03	1.75	1.03	108.37	77.03	82.91	76.8	8.31	0.61	9.05	23.28
J01FA	Macrolides	5.5	3.89	8.48	3.41	27.25	36.66	38.6	39.68	13.82	9.05	7.22	1.67	9.44	7.37	8.84	8.55
J01FF	Lincosamides	13.02	12.65	12.72	14.21	16.14	31.61	67.75	31.68	4.4	7.72	5	1.38	4.03	10.13	19.83	20.36
J01GA	Streptomycins	0	0	0.15	0	0	0	0	0	0	0	0	0	0	0	0	0
J01GB	Other aminoglycosides	13.9	11.43	22.04	40.21	20.82	36.82	41.91	39.15	4.27	3.05	20.98	16.35	47.24	55.82	44.84	6.13
J01MA	Fluoroquinolones	52.44	47.48	37.91	52.93	0.99	3.93	1.87	2.06	32.82	14.17	18.16	20.9	457.41	490.6	332.3	351.94
J01XA	Glycopeptide antibacterials	30.59	31.51	63.45	103.5	0.96	1.49	3.48	7.29	59.26	56.49	63.51	65.89	12.62	8.7	23.99	11.68
J01XB	Polymyxins	9.6	10.02	9.82	22.65	0.12	0	0	0	30.13	27.08	52.55	40.71	0	0	0	0
J01XD	Imidazole derivatives	144.45	110.76	105.47	106.09	1.9	11.18	12.96	12.85	13.98	17.1	16.17	24.9	8.37	6.85	14.72	0.74
J01XE	Nitrofuran derivatives	2.29	0.78	6.48	0	9.12	17.84	21.72	0	0.27	1.2	0.12	0	0	0	0	0
J01XX	Other antibacterials	6.77	2.02	15.18	70.57	0	0	0	0	10.5	17.79	3.02	21.62	0	0	0	0

The medical clinic and intensive care units had the highest DDD values for the J01FA-macrolides group. The consumption of J01-glycopeptides was greater in medical clinics, intensive care units, and surgical clinics. The J01XB-Polymyxins group had greater DDD/1000 patient-day in the intensive care unit, with increases in 2020 and 2021. Surgical and medical clinics are among the units with high DDDs for this chemical group of antibacterial agents. We should underscore the increased DDD of J01XX-Other antibacterial agents (daptomycin and linezolid) from 2020 onward in intensive care units, surgical clinics (Table II) and gastroenterology and digestive system surgery units (Table III). The J01AA - tetracyclines group also increased over the years in these units and the medical clinic (Table II).

As in the surgical clinical unit (Table II), the J01CR group-penicillins + beta-lactamase inhibitors-was the most consumed in the gastroenterology and digestive system surgery unit (Table III), showing a growing consumption from 2020 onward. The J01D-carbapenems had the highest hematology and transplantation unit consumption, with a progressive increase from 2019. Consumption was also high in the gastroenterology and digestive system surgery units, but consumption increased only in 2020 (Table III).

Table IV presents the CAGR calculated for the antibacterials corresponding to D90. The CAGRt showed a negative or positive percentage variation of more than 20% from 2018 to 2021 for amikacin (50.12%), benzylpenicillin potassium (24.33%), cefazolin (-21.7%), sulfadiazine (-58.11%), oral clarithromycin (51.06%), daptomycin (34.38%), polymyxin B (20.85%), and tigecycline (41.49%).

TABLE IV
The compound annual growth rate (CAGR) of the most commonly used antibacterial agents per D90 at the hospital complex from 2018 to 2021

Drug	AWaRE	DDD 2018	DDD 2019	DDD 2020	DDD 2021	CAGRt (%)	CAGRp (%)	(%)*
Amicacin	Access	35.55	67.52	88.72	121.77	50.12	34.29	-15.83
Oral amoxicillin + clavulanic acid		205.14	223.26	243.12	175.98	-4.93	-11.22	-6.28
Parenteral amoxicillin + clavulanic acid		142.35	171.43	210.06	207.95	13.32	10.14	-3.19
Parenteral ampicillin		100.95	87.78	80.84	170.77	18.94	39.48	20.54
Benzylpenicillin potassium		359.96	504.25	472.76	696.32	24.33	17.51	-6.81
Cefazoline		509.17	483.02	198.20	242.63	-21.70	-29.13	-7.43
Parenteral clindamicin		73.18	80.50	153.12	86.10	5.51	3.42	-2.09
Gentamicin		167.22	203.83	276.71	248.66	13.99	10.45	-3.54
Metronidazole oral		98.92	86.99	73.37	76.04	-8.31	-6.51	1.81
Parenteral metronidazole		284.84	239.04	242.41	229.12	-6.93	-2.10	4.83
Oxacillin		899.41	880.31	838.84	1018.73	4.20	7.58	3.38
Sulfadiazine		428.26	355.96	192.89	30.67	-58.11	-70.65	-12.54
Sulfamethoxazole + oral trimethoprim		238.55	211.45	252.08	256.82	2.47	10.21	7.74
Oral azithromycin	Watch	141.44	147.58	208.76	117.78	-5.86	-10.66	-4.80
Parenteral azithromycin		8.70	16.57	138.60	11.46	9.52	-16.84	-26.36
Cefepime		395.82	476.72	413.40	246.76	-14.44	-28.05	-13.62
Ceftriaxone		427.71	354.04	588.52	653.42	15.01	35.85	20.84
Oral ciprofloxacin		595.72	588.94	434.06	475.22	-7.19	-10.17	-2.99
Parenteral ciprofloxacin		78.75	81.38	59.53	80.35	0.67	-0.63	-1.30
Oral clarithromycin		51.18	50.79	129.34	178.63	51.06	87.54	36.48
Meropenem		1158.08	1163.99	1202.82	1730.64	14.18	21.94	7.76
Piperacillin + tazobactam		662.24	707.07	771.71	973.47	13.56	17.34	3.78
Teicoplanin		94.53	131.25	152.57	127.60	10.41	-1.40	-11.81
Vancomycin		579.59	556.53	691.78	753.88	9.06	16.39	7.32
Daptomycin	Reserve	109.09	150.49	183.76	267.09	34.38	33.22	-1.16
Polymyxin b		494.47	438.01	674.31	877.81	20.85	41.57	20.71
Tigecycline		35.05	59.78	109.39	100.32	41.49	29.54	-11.94

• *CAGRp - CAGRt

The CAGR analysis for 2019-2021 (CAGRp) revealed a negative or positive percentage variation greater than 20% for amikacin (34.29%), parenteral ampicillin (39.48%), cefazolin (-29.13%), sulfadiazine (-70.65%), cefepime (-28.05%), ceftriaxone (35.85%), oral clarithromycin (87.54%), meropenem (21.94%), daptomycin (33.22%), polymyxin B (41.57%) and tigecycline (29.54%) (Table IV).

The calculation of the difference between CAGRp and CAGRt, which revealed that the possible growth rate was not due to the influence of the pandemic, varied positively or negatively by more than 20% for parenteral ampicillin (20.54%), parenteral azithromycin (-26.36%), ceftriaxone (20.84%), oral clarithromycin (36.48%), and polymyxin B (20.71%) (Table IV).

The consumption of bacteria classified as Watch by AWaRE increased, increasing from 49.3% in 2018 to 52.4% in 2021, where mainly oral clarithromycin, meropenem, and piperacillin-tazobactam accounted for this group. On the other hand, we observed a decline in the Access category, from 43.1% in 2018 to 35.7% in 2021, underscoring the increased consumption of parenteral ampicillin. In turn, the consumption of antibacterial agents in the reserve category also increased, increasing from 7.6% to 11.9%, especially that of polymyxin B, daptomycin, and tigecycline (Figure 1 and Table IV). The consumption of antibacterials classified as Watch by AWaRE significantly differed among years (P value <0.001).

FIGURE 1
DDD consumption of antibacterial agents at the hospital complex according to the WHO AWaRE classification from 2018 to 2021.

DISCUSSION

The consumption of antibacterial agents from 2018 to 2021 in the investigated hospital complex reflects the complexity of care and the influence of the COVID-19 pandemic on the use of antimicrobial agents in hospitals. A meta-analysis investigating the use of antibiotics during the hospitalization of patients with COVID-19 revealed a high frequency of patients who were prescribed antibiotics despite the low bacterial coinfection rate in this group (Langford et al., 2021). These data corroborate the growing concern that COVID-19 may have led to greater use of antimicrobial agents and disruptions in hospital infection control practices. The combination of these factors may have escalated the increase in multidrug resistance (Afshinnekoo et al., 2021; Allel et al., 2023).

The consumption pattern at the hospital complex, with a predominance of carbapenems, penicillins + beta-lactamase inhibitors, beta-lactamase-resistant penicillins, fluoroquinolones, and glycopeptides, is similar to findings in consumption studies in Brazilian hospitals and several other countries (Versporten et al., 2018; Porto et al., 2020; Hodoșan et al., 2023). A systematic review of 154 studies that investigated the use of antimicrobial agents in patients with COVID-19 revealed that beta-lactams (30%), fluoroquinolones (20%), and macrolides (18.9%) were among the most commonly prescribed antimicrobial agents (Langford et al., 2021). A survey conducted in three public hospitals in southeastern Brazil (Pereira et al., 2023) and another in 73 Brazilian intensive care units reported an increase in the use of macrolides during the COVID-19 pandemic (Antunes et al., 2023).

One of the likely explanations for this increase in macrolides in Brazil, which was also detected in the investigated hospital complex, was the controversial use of azithromycin as a treatment option for COVID-19 at the onset of the pandemic, the lack of evidence for which was later demonstrated (Chi et al., 2021). A consistent increase in the consumption of clarithromycin was also observed in the investigated hospital complex. Despite the lack of evidence, outpatient use of azithromycin persisted in Brazil during the pandemic (Pereira et al., 2023; Solanky et al., 2023), resulting in shortages of this antibacterial agent in hospital services (Martins et al., 2022), which may have contributed to increased clarithromycin consumption.

The combination of macrolides (azithromycin or clarithromycin) with beta-lactams or fluoroquinolones is an option for the treatment of community-acquired pneumonia (Metlay et al., 2019), which may explain the increased consumption of clarithromycin and ceftriaxone during the study period. Given the widespread use of macrolides in Brazil during the pandemic, it will be essential to monitor macrolide resistance in the coming years to preserve the effectiveness of this class of antibacterial agents, mainly against S. pneumoniae, S. aureus and Haemophilus spp. (Pereira et al., 2023), as the emergence of resistance of these microorganisms to macrolides, associated with increased consumption, has already been demonstrated in Japan and the United States in studies conducted before the pandemic (Inoue et al., 2005, Jenkins, Brown, Farrell, 2008).

The increased use of broad-spectrum beta-lactams, such as carbapenems and penicillins + beta-lactamase inhibitors (piperacillin + tazobactam), as evidenced in the intensive care unit (ICU) and medical clinics, has increased the risk of contributing to the emergence of carbapenem-resistant enterobacteria, which produce carbapenemases. An alert from the Latin American Network for Antimicrobial Resistance Surveillance was published in 2022. Increased carbapenem-resistant and carbapenemase-producing enterobacteria have been reported in Latin America (Thomas et al., 2022). The magnitude of the impact of the COVID-19 pandemic on the spread of antimicrobial multidrug resistance remains unknown (Allel et al., 2023; Patel et al., 2023). However, given such alerts, we can see the importance of implementing measures to avoid the excessive use of broad-spectrum antibiotics and thus prevent the spread of multidrug resistance.

The increased consumption of tigecycline and polymyxin B, which are antibacterial agents in the reserve group of the AWaRE classification, from 2020 onward may have been caused by the emergence of A. baumannii and K. pneumoniae, which are resistant to other antibacterial agents used in gram-negative infections during the pandemic (Sulayyim et al., 2022). A higher incidence of vancomycin-resistant Staphylococcus aureus was observed in patients with COVID-19, which may have caused an increased use of daptomycin (Sulayyim et al., 2022).

Data on antimicrobial consumption by units highlighted several limitations, such as the reduction in first-generation cephalosporins in surgical units in 2020 due to a decrease in surgeries and an increase in antimicrobial consumption in the ICU and medical clinic, possibly due to the prioritization of beds for COVID-19 care.

However, comparative analyses between the consumption of antibacterials by units must be carried out with caution, as the determinants of use are complex and multifactorial and can be influenced by changes in the provision of healthcare, healthcare-seeking behavior during the pandemic, and the availability of antimicrobials in the hospital during the study period.

According to the AWaRE classification, antibacterials agents from the Watch group were the most commonly used in the hospital complex throughout the studied period, followed by those from the Access and Reserve groups. At the national level, the WHO has set a target to increase the proportion of antibiotic consumption in the Access group to at least 60% and to reduce the use of antibiotics from the Watch and Reserve groups (Who, 2022). Unfortunately, this target is at the primary healthcare level. Thus, there is a need to define specific targets for hospitals. Monitoring the use of Watch and Reserve antimicrobials is also an essential strategy for monitoring and evaluating antibiotic stewardship actions at hospitals.

A systematic review that investigated exposure to AWaRE antibacterials agents and the isolation of multidrug-resistant bacteria revealed a solid rationale for expanding the use of the AWaRE tool to improve the prescription of antibiotics, showing the importance of adopting these measures for antimicrobial resistance control.³³ Thus, accessing antibacterials should be considered the first-choice option, when possible, to limit the use of Watch and Reserve drugs for clinical situations where they are indicated (Pauwels et al., 2021; Sulis et al., 2022).

This study displays the differences in the consumption of all antibacterial classes in a hospital complex. The analysis allowed us to determine the importance of identifying the consumption profile at the local level to guide interventions and optimize the use of antimicrobials at the hospital, contributing to multiresistance prevention and control.

However, this study has several significant limitations: it was unicentric, hindering the generalization of the results to other institutions or the country; additionally, the analysis was not performed at the patient level, preventing stratification by indication, diagnosis, and treatment time. The relationship between the consumption and frequency of multiresistant microorganisms was not investigated, compromising the assessment of the impact of increased consumption. Moreover, we could not identify antibacterials with shortages during the study period, which may have influenced consumer trend analysis. Finally, the data were analyzed yearly, hampering the identification of monthly consumption fluctuations.

CONCLUSION

The standard of consumption of antimicrobials at the hospital complex increased from 2018 to 2021 in medical clinics and intensive care units, with a predominance of carbapenems, penicillins + beta-lactamase inhibitors, beta-lactamase penicillins, glycopeptides, fluoroquinolones, and polymyxin B, reflecting the care profile and influence of the COVID-19 pandemic.

REFERENCES

• Afshinnekoo E, Bhattacharya C, Burguete-García A, Castro-Nallar E, Deng Y, Desnues C, et al. ECOVID-19 drug practices risk antimicrobial resistance evolution. Lancet Microbe. 2021;2(4):e135-e136.
• Allel K, Peters A, Conejeros J, Martínez JRW, Spencer-Sandino M, Riquelme-Neira R, et al. Antibiotic consumption during the coronavirus disease 2019 pandemic and emergence of carbapenemase-producing klebsiella pneumoniae lineages among inpatients in a Chilean Hospital: a time-series study and phylogenomic analysis. Clin Infect Dis. 2023;77(Suppl 1): S20-S28.
• Antimicrobial Resistance Collaborators. Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet. 2022;399(10325):629-655.
• Antunes BBP, Silva AAB, Nunes PHC, Martin-Loeches I, Kurtz P, Hamacher S, et al. Antimicrobial consumption and drug utilization patterns among COVID-19 and non-COVID-19 patients. J Antimicrob Chemother. 2023;78(3):840-849.
• ATC/DDD Index 2023. [cited 2023 Mar 16]. Available from : Available from : https://www.whocc.no/atc_ddd_index/
  » https://www.whocc.no/atc_ddd_index/
• Benkő R, Matuz M, Pető Z, Weist K, Heuer O, Vlahović-Palčevski V, et al. Members of the ESAC-Net AWaRe study group; ESAC-Net AWaRe study group. Trends in the hospital-sector consumption of the WHO AWaRe Reserve group antibiotics in EU/EEA countries and the United Kingdom, 2010 to 2018. 2022;27(41):2101058.
• BRASIL. Conselho Nacional de Saúde. Resolução n° 466, de 12 de dezembro de 2012. Aprova as diretrizes e normas regulamentadoras de pesquisas envolvendo seres humanos. Brasília, DF: CNS, 2013. [cited 2023 Mar 16]. Available from: Available from: https://conselho.saude.gov.br/resolucoes/2012/Reso466.pdf
  » https://conselho.saude.gov.br/resolucoes/2012/Reso466.pdf
• Chi G, Memar Montazerin S, Lee JJ, Kazmi SHA, Shojaei F, Fitzgerald C, et al. Effect of azithromycin and hydroxychloroquine in patients hospitalized with COVID-19: Network meta-analysis of randomized controlled trials. J Med Virol. 2021;93(12):6737-6749.
• Diallo OO, Barona SA, Colsona CAP, Chaudeta H, Rolain JM. Antibiotic resistance surveillance systems: A review. J Global Antimicrob Resist. 2020;23:430-438.
• Grau S, Hernández S, Echeverría-Esnal D, Almendral A, Ferrer R, Limón E, et al. Catalan Infection Control and Antimicrobial Stewardship Program (VINCat-PROA). Antimicrobial Consumption among 66 Acute Care Hospitals in Catalonia: Impact of the COVID-19 Pandemic. Antibiotics (Basel). 2021;10(8):943.
• Hodoșan V, Daina LG, Zaha DC, Cotrău P, Vladu A, Dorobanțu FR, et al. Pattern of antibiotic use among hospitalized patients at a level one multidisciplinary care hospital. Healthcare (Basel). 2023;11(9):1302.
• Inoue M, Kohno S, Kaku M, Yamaguchi K, Igari J, Yamanaka K. PROTEKT 1999-2000: a multicenter study of the antimicrobial susceptibility of respiratory tract pathogens in Japan. Int J Infect Dis. 2005;9(1):27-36.
• Jenkins SG, Brown SD, Farrell DJ. Trends in antibacterial resistance among Streptococcus pneumoniae isolated in the USA: update from PROTEKT US Years 1-4. Ann Clin Microbiol Antimicrob. 2008;7:1.
• Langford BJ, So M, Raybardhan S, Leung V, Soucy JR, Westwood D, et al. Antibiotic prescribing in patients with COVID-19: rapid review and meta-analysis. Clin Microbiol Infect 2021;27:520-31.
• Martins MR, Bezerra VS, Oliveira FNM, Silva ARO, Lima EC. Drug and others products shortage in Brazilian health services in the scenario imposed by COVID-19. Research, Society and Development, [S. l.], 11(5), p. e26711527928, 2022. DOI: 10.33448/rsd-v11i5.27928. [cited 2023 Mar 16]. Available from: Available from: https://rsdjournal.org/index.php/rsd/article/view/27928
  » https://doi.org/10.33448/rsd-v11i5.27928» https://rsdjournal.org/index.php/rsd/article/view/27928
• Medeiros AF. Avaliação do uso de antimicrobianos e resistência microbiana: análise de séries temporais dos resultados de um programa de gerenciamento de antimicrobianos em um hospital público de ensino. [Dissertação]. Belo Horizonte: Universidade Federal de Minas Gerais, Faculdade de Farmácia, Programa de Pós-graduação em Medicamentos e Assistência Farmacêutica. 2022.
• Metlay JP, Waterer GW, Long AC, Anzueto A, Brozek J, Crothers K, et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67.
• Nadgir CA, Biswas DA. Antibiotic resistance and its impact on disease management. Cureus. 2023;15(4):e38251.
• O’Neill J. Review on antimicrobial resistance: tackling drug-resistant infections globally: final report and recommendations. London, UK: Wellcome Trust, 2016:80.
• Patel TS, McGovern OL, Mahon G, Osuka H, Boszczowski I, Munita JM, et al. Trends in inpatient antibiotic use among adults hospitalized during the coronavirus disease 2019 pandemic in Argentina, Brazil, and Chile, 2018-2021. Clin Infect Dis . 2023;77(Suppl 1):S4-S11.
• Pauwels I, Versporten A, Drapier N, Vlieghe E, Goossens H, on behalf of the Global-PPS network. Hospital antibiotic prescribing patterns in adult patients according to the WHO Access, Watch and Reserve classification (AWaRe): results from a worldwide point prevalence survey in 69 countries. J Antimicrob Chemother . 2021;76:1614-1624.
• Pereira ML, Mothé DA, Pinheiro KS, Gonçalves SS, Santos KV. Antibiotic dispensing during the first year of the COVID-19 pandemic in Brazilian public hospitals. Future Microbiol. 2023;18:639-647.
• Porto APM, Goossens H, Versporten A, Costa SF; Brazilian Global-PPS Working Group. Global point prevalence survey of antimicrobial consumption in Brazilian hospitals. J Hosp Infect. 2020;104(2):165-171.
• Rolain J-M, Abat C, Jimeno M-T, Fournier P-E, Raoult D. Do we need new antibiotics? Clin Microbiol Infect 2016;22:408-15.
• Solanky D, McGovern OL, Edwards JR, Mahon G, Patel TS, Lessa FC, et al. Prescribing of outpatient antibiotics commonly used for respiratory infections among adults before and during the coronavirus disease 2019 pandemic in Brazil. Clin Infect Dis . 2023;77(Suppl 1):S12-S19.
• Sulayyim HJA, Ismail R, Hamid AA, Ghafar NA. Antibiotic resistance during COVID-19: A systematic review. Int J Environ Res Public Health. 2022;19(19):1193.
• Sulis G, Sayood S, Katukoori S, Bollam N, George I, Yaeger LH, et al. Exposure to World Health Organization’s AWaRe antibiotics and isolation of multidrug resistant bacteria: a systematic review and meta-analysis. Clin Microbiol Infect . 2022;28(9):1193-1202.
• Teichert M, van der Aalst A, de Wit H, Stroo M, De Smet PA. How useful are prescribing indicators based on the DU90% method to distinguish the quality of prescribing between pharmacotherapy audit meetings with different levels of functioning? Eur J Clin Pharmacol. 2007;63(12):1171-7.
• Thomas GR, Corso A, Pasterán F, Shal J, Sosa A, Pillonetto M, et al. Increased detection of carbapenemase-producing enterobacterales bacteria in Latin America and the Caribbean during the COVID-19 Pandemic. Emerg Infect Dis. 2022;28(11):1-8.
• Versporten A, Zarb P, Caniaux I, Gros MF, Drapier N, Miller M, et al. Global-PPS network. Antimicrobial consumption and resistance in adult hospital inpatients in 53 countries: results of an internet-based global point prevalence survey. Lancet Glob Health. 2018;(6):e619-e629.
• WHO. The WHO AWaRE (Access, Watch, Reserve) antibiotic book. Geneva: World Health Organization; 2022.
• Wushouer H, Zhou Y, Zhang W, Hu L, Du K, Yang Y, et al. Inpatient antibacterial use trends and patterns, China, 2013-2021. Bull World Health Organ. 2023;101(4):248-261B.

Edited by

• Associated Editor:
  Silvya Stuchi Maria-Engler

Publication Dates

• Publication in this collection
  20 Jan 2025
• Date of issue
  2025

History

• Received
  20 Feb 2024
• Accepted
  22 Apr 2024