Analysis of the impact of antimicrobial management and rational use of antibiotics

Abstract

Objective

The scientific antimicrobial management strategy (AMS) was used to standardise the clinical use of antibiotics and optimise the anti-infection treatment protocol.

Methods

By formulating antibiotic use indicators and policy interventions, carrying out prescription audits and drug analysis by pharmacists, and establishing an early warning mechanism for bacterial drug resistance, we formed a long-term and scientific antimicrobial management strategy.

Results

From 2012 to 2017, the clinical antibiotics use indicators appeared to trend downward. The rate of antibiotic use in outpatients, the rate of antibiotic use in hospitalised patients, and the antimicrobial use density decreased by 40.36%, 20.93%, and 10.71%, respectively, and the per capita drug cost of antibiotics in outpatients and inpatients decreased. The microbiological susceptibility test rate of antibiotics in hospitalised patients increased each year, and the resistance rate of the main detected bacteria did not significantly increase in the last 6 years. In the evaluation of rational drug use, the use of antibiotics has become more reasonable and standardised, and irrational drug use has been significantly reduced, but we still need to strengthen the optimisation of treatment prescription.

Conclusions

Scientific management can promote the rational use of antibiotics, reduce the expense of drug use and slow the development of drug resistance, but we need to further optimise the prescription of antibiotics to improve the level of drug treatment.

Introduction

Antibiotics have made many refractory infectious diseases treatable, but the abuse of antibiotics has also created a very challenging side-effect for humans—bacterial resistance. Bacterial resistance has become a major public health challenge in the field of global health.^{1 2} In China, the abuse of antibiotics has been particularly severe in the past decades, leading to possible bacterial drug resistance and adverse drug reactions.³ The results of the national bacterial resistance monitoring network (CARSS) of China’s Health Planning Commission in 2015 showed that bacterial resistance is very serious in China. For example, the resistance rate of Escherichia coli to third-generation cephalosporins is 59% (range 49.2–71.9%).⁴ To solve this problem, the Ministry of Public Health of China organised a special examination for the rational use of antibiotics and standardised the use of antibiotics at all levels of hospitals. Remarkable results have been achieved.^{5 6} At present, the focus is on how to establish a long-term scientific and specialised management mechanism for antibiotics, prevent rebound, optimise an anti-infection treatment scheme and improve the level of drug treatment. Our hospital is a tertiary hospital in China. Since 2012, we have taken many measures to reduce the irrational use of antibiotics and improve the level of drug treatment. Our experience is summarised for reference below.

Methods

Establishing a scientific management system for antibiotics

The scientific management of antibiotics needs to establish a complete long-term working mechanism. Our hospital formulated a scientific antimicrobial management strategy (AMS). The management system is the first stipulated step in the strategy, and its tasks include establishing the responsibilities of various departments, setting up the working group, defining the work mode, establishing the system of classification management, defining the rules of clinical application, etc. The coordination of the various departments is critical. The medical department is responsible for the daily supervision and management work, organising the training regarding rational drug use and coordinating other departments. The pharmacy department is responsible for the monitoring and evaluation of the clinical application of antibiotics, carrying out prescription audits and supplying antibiotics. The department of infectious diseases is responsible for the multidisciplinary diagnosis and treatment of difficult bacterial and fungal infectious diseases. The microbiological laboratory is responsible for strengthening clinical microbiological specimen monitoring and bacterial resistance monitoring. The infection management department is responsible for the establishment of standardised procedures for the control of nosocomial infectious diseases. The information department should make full use of information technology to support the management of the clinical application of antibiotics. All the above departments should cooperate with each other to jointly promote the management of antibiotics.

Setting and controlling the antimicrobial indicators scientifically

The antimicrobial clinical application indicators mainly include the rate of antibiotic use in outpatients, the rate of antibiotic use in hospitalised patients, the antimicrobial use density (AUD) and the microbiological susceptibility test rate. AUD=total antimicrobial consumption (cumulative defined daily dose)×100/(number of patients×average hospital day in the same period). The AUD can measure the extent and intensity of exposure to antibiotics in hospitalised patients. The control of antimicrobial indicators is an effective measure to prevent the clinical abuse of antibiotics. However, it should be set up and managed dynamically according to professional characteristics, distribution of disease and other factors. On the basis of referring to the average indicator of other hospitals in the same area, our hospital adopts the defined daily dose method to determine the control indicator of antibiotics in various departments.⁷ We collated the variety of antibiotics, the average course of treatment and the number of hospitalisations, and used defined daily dose to calculate the average AUD and drug utilisation index (DUI). The clinical pharmacist’s statistic is calculated for the above indicators every month, and the clinical departments that exceed the limit of the indicators will be assessed by the medical department. At the same time, indicator control is optimised according to the PDCA cycle method, as follows. A variety of measures will be taken to improve the departments’ clinical use of antibiotics, which repeatedly exceeded the standard (P). The measures are carried out by the pharmacy department and the medical department (D). In the process of execution, we should compare the results and the goals to be achieved, analyse the progress and correct the deviations (C). We regularly summarise successful experiences and move to the next PDCA loop to solve new problems (A). The concrete measures are shown in figure 1.

Figure 1.

The continuous and effective control process of antimicrobial indicators.

An objective and comprehensive prescription review to improve the medication level

Clinical pharmacists extract outpatient and inpatient cases monthly for prescription evaluation using rational drug information software. The evaluation items include the indications, usage and dosage, course of treatment, drug combination, etc. The evaluation basis is objective, comprehensive and strict according to the Guidelines for Clinical Application of Antimicrobials (2015 edition) and the drug instructions. For use beyond the manual, we should refer to the guidelines for infectious diseases and the evidence grading system of the Oxford Centre for Evidence-based Medicine.^{8 9} This will encourage the occurrence of irrational use of drugs to be modified, and the doctors with irrational drug prescription patterns will be trained in rational prescription of drugs.

Establishing an early bacterial resistance warning mechanism to delay bacterial resistance

The clinical pharmacists integrate the antimicrobial susceptibility data from all patients every month. The drug resistance of the main pathogens is collected, classified and screened for early warning and analysis. We suggest that antibiotics should be selected with reference to the results of drug sensitivity tests for those antibiotics with a rate of >50% of the main target bacteria. For the main target bacteria, a drug resistance rate of >75% will trigger a discussion by the pharmaceutical administration and pharmacy committee about whether to suspend the application or replace some of the antibiotics. At the same time, the clinical pharmacists will have carried out a special analysis on the drug-resistant bacteria in the key department and checked whether the case examination was adjusted in a timely way, according to the results of the drug sensitivity test.

Results

Clinical antibiotic use indicators increasingly improved

Through indicator control, rational use and review of drug analysis, as well as the promotion of the long-term mechanism of AMS, the clinical usage indicators of antibiotics showed a downward trend from 2012 to 2017: the utilisation rate of antibiotics in inpatients and outpatients and the intensity of use in outpatients decreased by 40.36%, 20.93% and 10.71%, respectively (figure 2). Single factor analysis of variance was performed by SPSS 21.0 software. In addition to moxifloxacin, the AUD of the top 10 antibiotics was reduced, as shown in tables 1 and 2.

Figure 2.

Trend map of antibiotics in our hospital from 2012 to 2017. DDDs, defined daily doses. 

Table 1.

Changes in the antimicrobial use density from 2012 to 2017—1

Year	Piperacillin tazobactam	Cefoperazone and sulbactam	Ceftazidime	Cefuroxime	Levofloxacin
2012	3.07±0.17	6.92±0.18	3.78±0.09	3.61±0.27	2.51±0.18
2013	3.01±0.18	6.42±0.77	2.90±0.48	2.25±0.62	1.89±0.28
2014	2.09±0.12	6.95±0.08	3.02±0.90	1.89±0.20	1.83±0.95
2015	2.93±0.09	6.53±0.78	1.23±0.46	1.84±0.13	1.53±0.12
2016	2.12±0.08	5.37±0.64	2.54±0.31	1.34±0.23	1.53±0.12
2017	2.25±0.07	5.46±0.75	3.67±0.33	1.33±0.74	0.74±0.34
F value	168.267	588.083	479.426	88.922	91.444
P value	0.000	0.000	0.000	0.000	0.000

Table 2.

Changes in the antimicrobial use density from 2012 to 2017—2

Year	Moxifloxacin	Ceftriaxone	Azithromycin	Meropenem	Aminosine
2012	0.16±0.49	1.68±0.25	2.67±0.19	0.66±0.92	1.39±0.12
2013	0.35±0.67	1.52±0.16	2.06±0.12	0.54±0.45	1.18±0.07
2014	1.00±0.23	1.11±0.17	1.44±0.24	0.48±0.52	0.93±0.12
2015	1.73±0.14	0.65±0.19	1.58±0.11	0.51±0.60	0.91±0.12
2016	1.91±0.84	0.91±0.92	1.56±0.12	0.40±0.06	0.75±0.06
2017	2.37±0.84	0.61±0.14	1.43±0.11	0.41±0.05	0.65±0.07
F value	613.269	77.517	114.595	27.009	99.377
P value	0.000	0.000	0.000	0.000	0.000

Per capita drug costs of antibiotics in patients are decreasing

Through scientific antimicrobial management, from 2012 to 2017 the per capita drug cost of antibiotics in outpatients and hospitalised patients was significantly reduced (table 3).

Table 3.

Per capita drug cost of antibiotics for patients from 2012 to 2017

Year	Per capita drug cost of antibiotics for outpatients (yuan)	Per capita drug cost of antibiotics for hospitalised patients (yuan)
2012	42.42±12.92	848.42±15.29
2013	38.25±1.91	756.92±34.43
2014	35.21±5.06	749.67±26.40
2015	37.92±4.50	741.50±21.67
2016	36.51±2.43	658.75±23.55
2017	33.06±1.72	619.08±14.10
F value	3.224	140.766
P value	0.012	0.000

Cases of irrational use of drugs were significantly reduced

Through drug reviews and clinical pharmacist interventions, we have constantly standardised the clinical application of antibiotics. Clinical pharmacists communicate with doctors about common problems in real time and organise the training supporting rational use of antibiotics. After a few years of effort, the irrational use was significantly reduced (table 4).

Table 4.

Statistics of cases of irrational use of drugs from 2012 to 2017

Year	Useless drug indication	Drug selection error	Error of usage and dosage	Medication course error	No aetiology detection or no select drug according to sensitivity results	Total
2012	94	39	89	53	150	425
2013	58	28	75	38	78	277
2014	59	25	69	31	52	236
2015	31	29	51	30	39	180
2016	30	25	47	24	29	155
2017	28	26	38	21	20	133

Units=number of cases.

Sampling number: 250 outpatient prescriptions and 300 hospitalised cases were selected each month, for a total of 6600 cases a year.

Changes in bacterial resistance

The top five bacteria in our laboratory were Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, faecal cocci and Staphylococcus aureus. In the last 5 years, the resistance rate of the pathogenic bacteria to common antibiotics was decreased or flat, and the rate of drug resistance was not increased (online supplementary figure 1-5).

Discussion

With the continuous focus on special corrective activities for the clinical application of antibiotics, the clinical usage of antibacterial drugs has been increasingly standardised in the whole country, and the abuse of antibacterial drugs has been gradually corrected.¹⁰ Our hospital makes effective use of approaches such as indicator control, prescription review and hierarchical management. For overall management and monitoring, the close cooperation between medical administrative departments and pharmaceutical departments is a guarantee for effective management. In addition, for the frequently occurring irrational drug use, we thoroughly analysed and warning in the hospital. Continuous induction can improve the level of antimicrobial therapy. We summarised the common problems as follows for reference.

Recommending the most suitable antibiotics for clinical selection

We should select the first-line recommended drugs according to the location of infection and the type of pathogenic bacteria and choose other alternative treatments only when the first treatment drug is ineffective or cannot be selected due to factors such as patient allergy.

Irrational drug use case: In 2015, our hospital used ciprofloxacin in outpatients for upper respiratory tract infections and community-acquired pneumonia (young adults). The common pathogenic bacteria of the upper respiratory tract infection in young adults without underlying diseases and in patients with community-acquired pneumonia were Streptococcus pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, Moraxella species, etc. Ciprofloxacin has broad-spectrum antibacterial activity but does not belong to the respiratory quinolone antibiotic family. Its antibacterial effect on Gram-positive (G+) bacteria was significantly lower than that of levofloxacin and other respiratory quinolones. Ciprofloxacin has a higher activity against aerobic Gram-negative (G−) bacteria, so it is generally recommended for lower respiratory tract infections caused by P. aeruginosa or G− bacteria, but it is not recommended for upper respiratory tract infections or general community-acquired pneumonia (CAP). In the CAP guidelines of China, the UK and the USA, the choice of antibiotics recommended for the initial treatment of CAP for young adults and patients without basic diseases are penicillins, macrolides, first- or second-generation cephalosporins and respiratory quinolones.^{11 12}

Determining the standard usage and dosage of antibiotics

There are many versions of the domestic individual drug instructions for some antibiotics, and the contents of the usage and dosage of the items are very different.

Irrational drug use case: The daily dose for cefatrizine ranged from 1 g to 4 g in clinical treatment, and there was a problem of excessive dosage. According to relevant guidelines, we recommend a dosage for adults of 0.5 to 2 g once daily in 2–4 doses; adults with septicaemia can increase to 4 g per day. Clindamycin phosphate and flucloxacillin are time-dependent antibiotics; the drugs are usually given once per day, which does not conform to the pharmacokinetic characteristics of the drugs. They should be administered several times a day. Levofloxacin is a concentration-dependent antibiotic and should be given once per day. However, we should be alert to the adverse drug reactions of levofloxacin, including tendon injury and effects on the nervous system, mental health and heart. The US Food and Drug Administration recently issued several drug alerts on the serious adverse effects of fluoroquinolones. The incidence of adverse reactions is related to dosage. If we consider the risk to mental health or adverse reactions of patients, we can divide the dose into twice per day.^{13 14}

Avoiding the incorrect prophylactic use of antibiotics

For preventive use of drugs, guidelines should be strictly followed and antibiotics should not be administered when there is no indication for prophylactic use.

Irrational drug use case: An elderly patient was diagnosed with benign prostatic hyperplasia and urinary retention. The patient had no fever, the white blood cell count was normal, and the pathogenic bacteria was not checked in urine culture. However, the doctor gave her piperacillin sodium and tazobactam sodium, 3 g intravenous drip twice daily for the prevention of infection.

Problem: This case lacked an indication for prophylaxis. We should not blindly choose broad-spectrum antibiotics to prevent multiple bacterial infections in the prophylactic use of antibiotics for non-operative patients.^{8 15} Inappropriate cases of antibacterial use in preterm infants was also common. Preterm infants are susceptible to bacterial infection because of their immunological characteristics, such as poor skin and mucosal barrier function, less gastric acid, dysfunction of the blood–brain barrier, and incomplete lymph node development. Infection can cause serious complications. Therefore, the prevention of infection is necessary in some cases. However, the random prophylactic application of antibiotics can lead to double infection of fungi, such as mould, so it is necessary to be clear about the indication for the use of the antibiotic. By retrieving evidence-based information, we suggest the following indications: (1) a pregnant woman with a systemic infection or local bacteria and mycoplasma infection in the reproductive tract; (2) a history of premature rupture of the membranes, with a time period from the premature rupture of >12 hours; (3) preterm infants with a history of inhalation of amniotic fluid; and (4) preterm infants with tracheal intubation, mechanical ventilation and sputum aspiration after birth.^{16 17}

Standardising the combination of antibiotics and avoiding harmful drug interactions

For mild infections, no combination of drugs is recommended. For severe infections, to cover common pathogenic bacteria, a combination of antibiotics is often needed. However, the combination should carefully consider the antimicrobial spectrum and drug characteristics, should strictly follow the guidelines recommended for the choice of the best treatment drugs, and cannot be randomly combined.

Irrational drug use cases: Piperacillin tazobactam sodium or meropenem combined with ornidazole. Piperacillin tazobactam and meropenem target anaerobic bacteria and can be unnecessarily combined with ornidazole.¹⁸ We should also pay attention to the interaction between antibiotics and other drugs to avoid adverse events. For example, the combination of moxifloxacin and amiodarone may cause adverse cardiac reactions and prolong the QT interval. These drugs must be closely monitored when combined.¹⁹

Standardising the clinical application of the antiseptic drug susceptibility test

Pathogen monitoring and drug sensitivity results can guide the clinical application of antibiotics. The treatment plan for an infection should be adjusted according to the results of drug sensitivity, especially when the effect of treatment is not ideal.

Irrational drug use cases: A patient with chronic urinary tract infection was given piperacillin as a first-line medication. The condition did not obviously improve 7 days after treatment, and the urine culture showed piperacillin-intermediate E. coli. The drug with intermediate effect should be increased to achieve a therapeutic dose or directly replaced by a more effective drug.

On the whole, the use of antibacterial drugs in our hospital is becoming more and more reasonable, but there is still the problem of the behaviour of individual physicians. Hospital clinicians continue to strengthen the ‘Guiding principles of clinical application of antibacterials’ training, with emphasis on the clinical need to pay attention to bacterial culture problems, preventive medication indications, perioperative medication timing and the combination operation period; attention should also paid to optimising the treatment plan and improving the standard of treatment. The outpatient population is numerous and mobile, with differences in the severity of disease; compliance with the results of laboratory examination is not high, especially some patients consider antibacterial drugs to act as anti-inflammatory medications to rapidly improve the symptoms and request antimicrobial drugs and other treatments in the clinic. Hospitalised patients are more likely to agree to a standard treatment with limited or no antimicrobials. As a first line of defence in the rational use of antimicrobial drugs, we need to pay special attention to correct this.

In addition to the basic elements that support the rational use of drugs in a manner that is safe, effective and economic, some doctors prescribing medications on the antibacterial spectrum need to be aware of pharmacokinetics, adverse reactions and drug resistance of pathogenic bacteria and the changes in the new anti-infection learning guide to enhance their understanding, especially if the medication is not standardised, and a physician is not informed on the current relevant policies. Attention must be paid to antibacterial drug management and its performance, as the common residency guidelines bypass discussion of the use of antibacterial drugs. Therefore, with an emphasis on the future, medical institutions need to strengthen the public’s reasonable medication knowledge through publicity and training, so that the public is aware of the abuse of antibiotics and the harm that they can cause. Clinician behavior, especially for repeated medication errors by doctors, must also be addressed through administrative penalties but also by strengthened training that supports a fundamental understanding of the importance of the rational use of antimicrobial drugs. The pharmacy department should also continue to strengthen the management of the clinical application of antibacterial drugs. Clinical pharmacists should take full responsibility for the professional role of the pharmacy. Based on the improvement of the original work and the increased depth and coverage of antibacterial drugs in special comments, future clinical guidance should focus on the optimization strategy for the antibiotics treatments, especially the standardization of drug combination selections.²⁰

Research on the scientific management of antibiotics has been carried out in large general hospitals in China to a varying degree. However, there are different ways to carry out this research, such as AMS management relying on the multidisciplinary consultation mode, and the efficient management of antibiotics using the information system. From the perspective of the long-term mechanism of antimicrobial drug management, our study strengthens the management of the rational use of antimicrobial drugs in the areas of index control and rational drug use evaluation, and emphasises the use of evidence-based medical evidence to guide rational drug use. Our study is practical and can be used for reference by other hospitals.

Conclusion

The purpose of this study is to promote rational drug use, and avoid the overuse of antibiotics and their incorrect usage and dosage.²¹ Following a reasonable and scientific management plan and taking proper control of antibacterial agents can effectively promote rational drug use and delay the development of bacterial resistance. The effectiveness of the work depends on the cooperation of all departments in the hospital. The hospital, the medical department and the pharmacy department can share information and work together to better promote the rational use of drugs.

Next, we will use information technology to carry out more reasonable indicator control, conduct in-depth clinical training of clinical pharmacists for rational drug use, and participate in hospital rounds and consultations, in order to better ensure the best anti-infective treatment plan for our patients .

What this paper adds.

What is already known on this subject

• At the 71st United Nations General Assembly, the issue of bacterial resistance around the world was discussed, becoming the fourth health issue to be discussed in the history of the organisation. The irrational use of antibiotics leads to the rapid development of bacterial resistance, especially in China and certain other countries. Thus, how to use antibiotics scientifically and rationally has become a common concern in the entire country.

What this study adds

• Since 2011, China has carried out ‘special administration activities for clinical application of antibacterial drugs’, and various hospitals have taken measures to reduce the abuse of antibiotics. In our hospital, the rational use of antibiotics was promoted by formulating antibiotic use indicators and policy interventions, having pharmacists carry out prescription audits and drug analysis, and establishing an early warning mechanism.