Managing antibiotic shortages: lessons from EAHP and ECDC surveys

Abstract

Aims and objective

To compare antibiotic shortages in Europe between 2013 and 2020 and the views of hospital pharmacists on overcoming shortages via antimicrobial stewardship.

Methods

A series of European Association of Hospital Pharmacists (EAHP) surveys on medicine shortages, including a survey on the future crisis preparedness of hospital pharmacies, conducted between 2013 and 2020 were compared for the type of antibiotic shortages and respective mitigation strategy. These were analysed taking into account hospital pharmacists’ views on antibiotics provided in the European Centre for Disease Prevention and Control (ECDC) survey on healthcare professionals’ knowledge, attitudes and behaviours about antibiotics, antibiotic use and antibiotic resistance from 2018.

Results

Since 2013 there has frequently been a shortage of antibiotics in European hospitals. In 2014, 67% (347/521) of hospital pharmacists experienced shortages of antimicrobials compared with 77% (1032/1348) in 2018, 63% (1158/1837) in 2019 and 37% (539/1466) in 2020. More than 80% of hospital pharmacists managed antibiotic shortages through substitution in 2014 (284/336) and 2018 (786/946), while this percentage was 40% (63/158) and 42% (620/1466) in 2019 and 2020, respectively. Although 72% (870/1204) of hospital pharmacists received information on how to avoid inappropriate antibiotic prescribing, dispensing and administration, only 37% (450/1204) changed their views and 28% (338/1204) changed their practice in steering antimicrobial treatment.

Conclusion

Antibiotic shortages affect proper antimicrobial stewardship because of limited appropriate alternatives, taking into account patients’ clinical condition and type of infection. While substitution remains a leading mitigating tool for antibiotic shortages, it carries numerous risks and the potential for antimicrobial resistance and suboptimal health outcomes.

Introduction

Surveys conducted by the European Association of Hospital Pharmacists (EAHP) and the American Society of Health-System Pharmacists (ASHP) showed that antibiotics are among the drugs most affected by shortages.^{1 2} Shortages of antimicrobials in the USA increased from 2001 to 2013 with 148 reported shortages of antibiotics; piperacillin/tazobactam was affected by a shortage for almost 5 years.³ The percentage of hospital pharmacists reporting shortages of antibiotics in Europe increased from 57% (237/418) to 77% (1032/1348) between 2014 and 2018.¹ These shortages bring additional risks to the management of antimicrobial therapy because of the complexity of selecting an appropriate antibiotic in an era of bacterial resistance as reported by the WHO Global Report and the lack of newly developed antibiotics.^4–6

The COVID-19 pandemic proved to be another challenge for the proper use of antibiotics, with almost 74% of patients admitted to hospital being prescribed an antibiotic.⁷ Prescribed antimicrobial treatment usually involves empirically-based broad-spectrum antibiotics. However, this high percentage does not correspond with the rate of 14% co-infected COVID-19 patients in the intensive care unit, indicating that antimicrobial treatment was not fully justified.⁸

Challenges in the use of antimicrobial treatment during a shortage are related to potential consequences for a patient in terms of treatment delay and overuse of broad-spectrum antibiotics. This may cause suboptimal therapy leading to inferior treatment efficacy and potential increased toxicity due to the adverse events profile of the alternative.⁴ When using alternatives, healthcare professionals are not always aware of their administration patterns and particularities with regard to dosing and adverse events profile, which may lead to medication errors.⁹ Therefore, a higher incidence of medication errors occurs in emergency departments where the time constraints do not allow healthcare professionals to evaluate all aspects of the application patterns of alternative treatments.¹⁰

In view of the rising trend in antimicrobial shortages and the consequences for patient treatment and the rational use of antibiotics, a thorough analysis of all EAHP surveys on shortages from 2013 was carried out, together with the European Centre for Disease Prevention and Control (ECDC) survey on healthcare professionals’ knowledge, attitudes and behaviours about antibiotics, antibiotic use and antibiotic resistance, which also included hospital pharmacists’ views, in order to elucidate the challenges and risks in conducting antimicrobial stewardship and optimising health outcomes.

Methods

We compared the results from four EAHP surveys on shortages conducted between 2013 and 2019, including a survey of the future crisis preparedness of hospital pharmacies from 2020. The survey results were evaluated for the type of antibiotic shortages and mitigation strategies carried out by hospital pharmacists. In addition, we used selected data provided by the ECDC based on the survey of healthcare workers’ knowledge, attitudes and behaviours about antibiotics, antibiotic use and antibiotic resistance carried out in 2018, where hospital pharmacists together with other healthcare professionals provided feedback on this topic.¹¹

No ethical approval was sought for the EAHP surveys as the information obtained was practice-based. Moreover, the healthcare professionals freely participated in all surveys and no patients were involved.

Results

Antibiotic shortages across Europe

The first EAHP survey covered the prevalence of shortages, with 63% (214/339) of hospital pharmacists reporting daily and weekly shortages, frequently affecting antibiotics.¹² In 2014, experiencing shortages on a weekly/daily basis increased to 67% (347/521), while 57% (237/418) of hospital pharmacists from 23 countries reported antimicrobial shortages to be the most frequent (table 1).¹³ Moreover, the EAHP survey of 2014 elucidated the growing problem of steering antimicrobial treatments during shortages. It showed that antibiotics mostly affected by shortages are broad-spectrum antibiotics such as oral amoxicillin in Lithuania, the Netherlands and Italy; amoxicillin/clavulanic acid in Switzerland, Austria, Portugal, Belgium and Spain; gentamicin in Switzerland, Greece and Hungary; linezolid in Italy, Germany, Spain and Portugal; meropenem in Spain, Austria, Denmark and Belgium; and teicoplanin in the UK (figure 1).¹³

Table 1.

Antimicrobial shortages and use of substitutions as a mitigation strategy based on European Association of Hospital Pharmacists (EAHP) surveys between 2013 and 2020

Year*	Hospital pharmacists experiencing antibiotic shortages, % (n/N)	Substitution/seeking for an alternative, % (n/N)	Negative impact of shortages, % (n/N)	Overall number of survey responses from hospital pharmacists and countries represented
2013	Frequently occurring, no percentage provided	N/A	51% (112/221)	346 from 29 European countries†
2014	57% (237/418)	85% (284/336)	47% (173/369)	607 from 35 European countries‡
2018	77% (1032/1348)	83% (786/946)	47% (456/969)	1666 from 38 European countries§
2019	63% (1158/1837)	40% (63/158)¶	63% (1153/1837)	2136 from 39 European countries**
2020	37% (539/1466)	42% (620/1466)	59% (858/1460)	1664 from 36 European countries††

*Year when EAHP conducted the survey.

†Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Estonia, Finland, France Germany, Greece, Hungary, Ireland, Italy, Lithuania, the Netherlands, North Macedonia, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Switzerland, Turkey, UK.

‡Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Malta, the Netherlands, North Macedonia, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Switzerland, Turkey, UK.

§Albania, Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Montenegro, the Netherlands, North Macedonia, Norway, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, UK.

¶Reported by patients who participated in the 2019 survey.

**Albania, Andorra, Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Lithuania, Luxembourg, Malta, Montenegro, the Netherlands, North Macedonia, Norway, Poland, Portugal, Romania, Russia, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, UK.

††Austria, Belgium, Bosnia and Herzegovina, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Montenegro, the Netherlands, North Macedonia, Norway, Poland, Portugal, Romania, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, UK.

Figure 1.

Groups of antibiotics affected by shortages in Europe between 2013 and 2020.

In 2018 the EAHP repeated the survey and found devastating effects of antibiotic shortages, where broad-spectrum antibiotics instead of first-line (narrower spectrum) antibiotics were prescribed and reportedly led to a higher risk of antimicrobial resistance.¹ With 77% (1032/1348) of hospital pharmacists reporting antimicrobial shortages in 2018, they represented the medicines affected most frequently by shortages, with piperacillin/tazobactam not being available in 18 European countries.¹ Cephalosporins most frequently affected by shortages in 20 countries in 2018 were ceftazidime, cefuroxime, cefotaxime and ceftriaxone (figure 1). In comparison with medicine shortages in 2018, antimicrobials remained the medicines most frequently in short supply in 2019 accounting for 63% (1158/1837) of all reported shortages (table 1).

Apart from cephalosporins and piperacillin/tazobactam, hospital pharmacists reported additional antimicrobial shortages in 2018, such as tobramycin and aztreonam (Hungary), gentamicin (Czech Republic, Switzerland), trimethoprim/sulfamethoxazole (UK), cefamandol, ticarcillin (France) and cefepime (Switzerland) lasting from a few months up to 5 years (figure 1).¹

Delay in initiating antimicrobial treatment and transfer of patients to another facility where a medicine is available was reported in Spain, Greece and Serbia.¹ In 2014, 67% (347/521) of hospital pharmacists reported weekly and monthly problems with shortages and, in 2018, 75% (1242/1666) of hospital pharmacists experienced shortages at least weekly, having difficulties in providing the best care to patients.¹

Substitution of antimicrobial treatment

More than 80% of hospital pharmacists managed antibiotic shortages through substitution in 2014 (85%; 284/336) and 2018 (83%; 786/946) while, in 2019 and 2020, this percentage was 40% (63/158) reported by patients and 42% (620/1466) reported by hospital pharmacists (table 1). The majority of hospital pharmacists (83%; 786/946) reported informing a prescriber of shortages and proposing a substitute to mitigate shortages.¹ In the case of generic substitution, it is not always necessary to inform the prescriber. However, when there is a difference in medicine formulation, bioavailability, excipients and cost, the prescriber is usually contacted (Germany).¹ The EAHP survey conducted in 2020 during the COVID-19 pandemic showed that hospital pharmacists continued to experience shortages of antibiotics (37%; 539/1466), while the majority of survey respondents confirmed that substitution was the most frequently used means to overcome a shortage (42%; 620/1466) (table 1).¹⁴

Despite mitigation and substitution, more than 40% of hospital pharmacists in 2014 (47%; 173/369) and 2018 (47%; 456/969) and more than 50% in 2013 (51%; 112/221), 2019 (63%; 1153/1837) and 2020 (59%; 858/1460) believed that medicine shortages, including antibiotic shortages, negatively impacted patient care (table 1).^{12 14 15} In 2018, 58% (555/946) of hospital pharmacists witnessed consequences of shortages resulting in delayed care, 31% (297/946) cancellation of care, 25% (241/946) medication errors, 25% (239/946) suboptimal care, 20% (192/946) increased length of hospital stay and 5% (43/946) readmissions due to treatment failure.¹ In 2019, 42% (771/1837) of hospital pharmacists observed delay in care, 27% (448/1837) cancellation of care, 28% (512/1837) suboptimal treatment and 18% (326/1837) increased length of stay.¹⁵

Hospital pharmacists’ views on antimicrobial treatment

In 2018, hospital pharmacists participated in the ECDC survey of healthcare workers’ knowledge, attitudes and behaviours about antibiotics, antibiotic use and antibiotic resistance, the detailed results of which were shared with EAHP. Eighty-one percent (n=974/1204) of respondents strongly agreed that access to guidelines was needed for managing infections and 78% (n=940/1204) strongly agreed that access was needed to the materials to give advice on prudent antibiotic use and antibiotic resistance (table 2).¹⁶ Sixty percent (n=727/1204) of hospital pharmacists confirmed that they lived in a country with a national action plan on antimicrobial resistance. The survey showed that 84% (1008/1204) of hospital pharmacists were aware that there is a connection between prescribing/dispensing/administration of antibiotics and antibiotic resistance (table 2).¹⁶

Table 2.

Hospital pharmacists’ views on conducting antimicrobial treatment

Question topic	No of hospital pharmacists responding Yes/Strongly agree
Having access to guidelines needed for managing infections	81% (974/1204)
Having access to the materials needed to give advice on prudent antibiotic use and antibiotic resistance	78% (940/1204)
Living in a country where a national action plan on antimicrobial resistance exists	60% (727/1204)
Aware that there is a connection between prescribing/dispensing/administration of antibiotics and antibiotic resistance	84% (1008/1204)
Agree that in their current role are contributing to/leading antimicrobial stewardship programmes or tackling antimicrobial resistance	67% (809/1204)
Have sufficient knowledge about how to use antimicrobials properly	37% (443/1204)
Received information about avoiding unnecessary prescribing or administering or dispensing of antibiotics	72% (870/1204)
Changed views about avoiding unnecessary prescribing or administering or dispensing of antibiotics	37% (450/1204)
Changed practice on prescribing or administering or dispensing of antibiotics	28% (338/1204)

Hospital pharmacists strongly agreed to contributing to/leading antimicrobial stewardship programmes or tackling antimicrobial resistance (AMR) (67%; 809/1204) (table 2),¹⁶ 37% (443/1204) knew how to use antimicrobials properly for their current practice and 72% (870/1204) received information on how to avoid inappropriate antibiotic prescribing, dispensing and administration, leading to <40% of hospital pharmacists changing their views (37%; 450/1204) and <30% adjusting their current practice in managing antimicrobial therapy (28%; 338/1204) (table 2).¹⁶

Discussion

Antimicrobial shortages have been increasing in Europe since the beginning of this century, as confirmed by several EAHP-led surveys.^{1 12–15} Since 2013, more than 50% of hospital pharmacists across Europe reported antibiotic shortages (2014: 57% (237/418), 2018: 77% (1032/1348), 2019: 63% (1158/1837)).^{1 13 15} This percentage reduced in 2020 to 37% (539/1466), not because the shortage situation improved but due to the fact that hospital pharmacists who participated in the survey worked in hospitals treating only COVID-19 patients and also in hospitals providing regular but limited services to non-COVID patients, which might have affected the seriousness of antibiotic shortages.¹⁴

EAHP has been constantly working on increasing the awareness of healthcare professionals to the importance of conducting antimicrobial stewardship (AS) across European healthcare settings.¹⁷ Multidisciplinary collaboration within AS teams, bringing together hospital pharmacists, microbiologists and infectious disease specialists, is essential throughout the process of selection of appropriate antimicrobial treatment, its route of administration, dosage regimen and duration.¹⁷ However, frequent antibiotic shortages prevent carrying out a proper AS and challenge healthcare professionals in finding the most suitable treatment for a patient.^{3 18}

EAHP surveys from 2014 and 2018 showed rising antibiotic shortages belong to a broad spectrum group of antibiotics, such as meropenem, piperacillin/tazobactam and teicoplanin, which resulted in the introduction of alternatives associated with a higher incidence of Clostridium difficile infections and less optimal health outcomes due to alternative treatments.¹³ Depending on the choice of substitutes and the adequacy of their spectrum of activity, antimicrobial shortages impact patient outcomes and affect AMR, resulting in detrimental side effects and more expensive treatment.^19–21

The majority of hospital pharmacists overcame shortages via substitution. Although the EAHP surveys do not reveal how the substitution is carried out, hospital pharmacists’ answers to open-ended questions showed that antimicrobial substitution depends mostly on the available alternatives.^{1 13 15} Research conducted in six European hospitals confirmed the challenges hospital pharmacists are facing when substituting antibiotics.²² To conduct AS properly, it is of utmost importance for healthcare professionals to have access to information on alternatives, the antibiotic spectrum of activity and patient clinical status, which is not always the case.²² Among hospital pharmacists who have access to shortage reporting systems on a national basis, 56% (371/663) consider these systems to be effective, while many believe that they do not have timely access to information or that the information they receive is outdated.¹ The unpredictable nature of shortages and lack of information provided to healthcare professionals undermine efforts to plan an effective mitigating strategy aimed at providing medicine to patients.²¹ Moreover, the information needed for substitution should be promptly fed into hospital information technology (IT) systems.²² The availability of alternatives, dosage and reconstitution requirements of alternatives and an effectiveness assessment compared with the initial treatment are not always thoroughly assessed due to insufficient data provided to healthcare professionals either by the industry and supply chain personnel or by the authorities.²²

Hospital pharmacists reported in the EAHP surveys that shortages affected patient care in multiple ways including suboptimal care, increased medication errors, increased length of stay and frequent hospital readmission due to suboptimal management of shortages. Substitution bears numerous challenges for a patient including potential allergies to a new treatment, delay in the onset of activity of the substitute and possible drug–drug interactions, which should be assessed by a review of the patient's medical records and clinical status assessment.²² Routine clinical practice conducted by healthcare professionals sometimes does not take into account a rapid change in antimicrobial treatment when a shortage occurs, when information on shortages and the possibilities for its mitigation are not well transmitted among healthcare professionals.^{22 23 24}

A study carried out in Belgium confirmed that hospital pharmacists spend at least 5 hours per week substituting medicines affected by a shortage. This is of particular importance when it comes to antibiotic shortages. AS also has to be carried out throughout a substitution via complete patient medical record validation, providing further information on alternative antibiotics in the hospital prescribing/ordering and dispensing IT systems.⁴ However, lack of time and a high workload while managing shortages accompanied by regular task interruption prevents substitutions by hospital pharmacists being carried out properly.²² Moreover, inappropriate interprofessional communication, essential for multidisciplinary-led AS, leads to misunderstandings and delays in the transfer of information on alternative antibiotics. Electronic prescribing, essential for proper handling and dissemination of information on antibiotic substitution, is lacking.²² The absence of electronic prescribing in the healthcare setting impedes shortage mitigation and also increases medicine errors in healthcare settings, repeatedly reported in the EAHP surveys.²⁵

If electronic prescribing systems are not used properly, and if the information on a substitute is not provided, some healthcare professionals might not be made aware of actual antimicrobial shortages, which affects the prescribing practice and also increases the time needed to overcome the shortage.²² Substituting an antibiotic due to a shortage necessitates thorough monitoring of a patient, which often fails due to inappropriate hospital IT systems, lack of communication and internal procedures needed to assess the effectiveness of the alternative treatment compared with the initial treatment.²²

While shortages affect the way AS is conducted in a healthcare setting, stewardship itself may assist in managing shortages as well. A shortage of piperacilin/tazobactam, frequently reported in the EAHP surveys, made healthcare professionals aware of the need to preserve antibiotics throughout a shortage. Hospital pharmacists had to intervene through substitution to assure the continuity of treatment. Changing guidelines for antibiotic prescription and carrying out prospective prescription audits of prescribing patterns effectively reduces the unnecessary use of antibiotics and prevents stock running out.²⁶ However, effective conservation of an antibiotic affected by a shortage often leads to increased utilisation rates of alternatives, which may, in turn, cause other shortages and affect antimicrobial resistance patterns.²⁶ A study exploring modalities of managing piperacillin/tazobactam shortages between 2014 and 2018 showed that physicians substituted this antibiotic based on their preferences rather than the guidance provided by the AS team, since awaiting for pre-approval of treatment is frustrating for healthcare professionals.^{27 28}

Providing less effective substitutes may lead to AMR since bacteria are able to develop resistance patterns and adapt to the antibiotics used as alternatives. Moreover, the long-term effects of AS performed to mitigate antibiotic shortages may occur long after the substitution took place, subtly affecting bacterial susceptibility to antibiotics, which only underlines the importance of post-substitution monitoring for detecting the effects of AS and providing the foundation for corrective action.^{23 24}

The ECDC survey showed that a high percentage of hospital pharmacists are aware of the importance of AS but, because of the many obstacles in everyday practice, fewer hospital pharmacists change their treatment patterns and avoid unnecessary prescriptions, which may particularly affect treatment of multidrug-resistant microorganisms.^{3 11} This should be considered as a signal for a more inclusive approach, which will provide pharmacists with an opportunity to actively engage in changing and adapting antimicrobial prescribing practices to successfully overcome antibiotic shortages through AS.

Conclusion

Antibiotic shortages affect AS by limiting available alternatives appropriate for a patient and his/her clinical condition. As members of the AS team, hospital pharmacists have an important role in steering the process of selection of the most suitable alternatives. They possess the knowledge and skills needed to assess alternative antimicrobial treatment, its prescribing, dispensing and administration patterns and patient safety implications. Management of shortages limits hospital pharmacists’ time, which is needed to carefully carry out substitution taking into account the available treatment options. Moreover, lack of information on alternative antimicrobials, which is not harmonised and fed into hospital information systems, places an additional burden on successful implementation of AS during shortages. While AS has been affected by ongoing shortages, it may also serve as a shortage mitigation tool via restrictions in antibiotic dispensing and an audit of current antimicrobial treatments. Management of antibiotic shortages and AS are interlinked as they influence each other in ways that can ameliorate or worsen patient care.

What this paper adds.

What is already known on this subject

• Medicine shortages in Europe have been on the rise since the beginning of the 2000s.

• The management of antibiotic shortages has numerous challenges due to antimicrobial resistance and the lack of alternatives.

• Hospital pharmacists are aware of the negative impact of shortages on patients' health outcomes.

What this study adds

• A unique comparison of shortages in Europe between 2013 and 2020 shows that antibiotics are among the medicines most affected by shortages.

• Antibiotic substitution remains a leading shortage mitigation tool despite the challenges faced by hospital pharmacists.

• A starting point for getting hospital pharmacists more involved in multidisciplinary-led antibiotic substitution to change prescription patterns and optimise health outcomes.

Data availability statement

Data are available upon reasonable request.

Ethics statements

Patient consent for publication

Not applicable.

Ethics approval

This study does not involve human participants.