Burden of enteral supplement interactions with common antimicrobial agents: a single-centre observational analysis

Abstract

Introduction

Oral antimicrobials, including ciprofloxacin, levofloxacin and doxycycline, are susceptible to binding with enteral therapies such as calcium and iron therapies. Administered together, the bioavailability of these antimicrobials is expected to be reduced.

Methods

A retrospective case series of patients receiving oral antimicrobials (ciprofloxacin, levofloxacin and doxycycline) was analysed at a single-centre NHS acute hospital (April 2016–September 2019). Patient demographics, including concurrent enteral therapies, were recorded using medical records. Clinically important interactions were defined as doses administered within 2 hours of antimicrobial therapy.

Results

A total of 4067 prescriptions for the study antimicrobials (ciprofloxacin, n=1905; levofloxacin, n=538; and doxycycline, n=1624) were prescribed for 3584 patients. 1918/3583 (53.5%) of the patients were female, and the median age was 67 years (range 0.5–105.0 years). 810/4067 (19.3%) prescriptions reviewed had an interacting enteral therapy (calcium or iron salt) administered within 2 hours of the study medication.

Conclusion

The concomitant administration of enteral calcium and iron with oral antimicrobials is common within the acute care hospital setting. Approximately one in five patients has a clinically important interaction which may impair oral bioavailability and limit treatment efficacy. As antimicrobial stewardship teams strive for increased intravenous-to-oral de-escalation, it is important that optimum dosing administration is followed to optimise patient outcomes.

Introduction

Antimicrobials are among the most commonly prescribed drugs in the hospital setting, and many have properties that predispose them to significant drug–drug and drug–food interactions. Polypharmacy is more prevalent due to ageing population and increasing rate of comorbidities. Interactions involving antimicrobials with other medications (eg, cytochrome P450 enzyme inducer or inhibitors) or comorbidities (eg, quinolones and epilepsy or aminoglycosides in myasthenia gravis) are well described, and prescribers and pharmacists are experienced in managing these interactions through dose adjustments or avoidance. Experiences with less obvious interactions such as enteral drug–drug or drug–food interaction are less understood and are poorly studied in the acute care hospital setting.

The absorption of oral or enterally administered antimicrobials can be significantly impaired by concurrently administered mediation, food or supplements. The fluoroquinolones ciprofloxacin and levofloxacin are prone to significant enteral interactions. At low pH, the fluoroquinolones bind or chelate with oral divalent or trivalent cation-containing compounds, including aluminium, calcium, zinc, iron salts and sucralfate. This results in significantly reduced systemic absorption from the gastrointestinal tract and consequently risks subtherapeutic serum levels and potential treatment failure. Relative ciprofloxacin bioavailability can be reduced by more than 40% and 85% when taken with calcium and aluminium-based therapies, respectively.^1–4 Levofloxacin is likely more stable in the presence of calcium but is still expected to have reduced bioavailability of 20% or more.^{5 6} Iron-based therapies are demonstrated to reduce ciprofloxacin bioavailability by greater than 50% in human studies.^7–9 Tetracyclines and their derivative, doxycycline, are also susceptible to enteral metal ion interactions, and reduced bioavailability has been demonstrated with concomitant administration.^10–12

National formularies and manufacturers recommend avoiding taking levofloxacin, ciprofloxacin and doxycycline for 2 hours before or after taking enteral aluminium, calcium or iron salts. Patients are provided such instruction on hospital discharge or in primary care through direct counselling from healthcare profession or via patient information leaflets (PILs). Within the acute care hospital setting, such instruction is not offered, and instead, nursing staff are responsible for the administration of prescribed therapies. Concurrently prescribed antimicrobials with interacting enteral supplements are likely to be commonly encountered in the hospital setting, and the burden of this interaction is unclear. Antimicrobial stewardship strategies promote the early de-escalation of intravenous to oral therapies to reduce costs and indirect treatment complications, but the consequence of these enteral interactions on treatment outcomes is poorly understood.^{13 14} The efficacy of early intravenous to PO switch may be compromised if drug–drug or drug–food interactions exist.

We undertook a retrospective observational study in a large central London teaching hospital to identify the burden of clinically important drug–drug interactions that impair oral bioavailability of commonly used antimicrobials (ciprofloxacin, levofloxacin and doxycycline).

Methods

A retrospective case series of patients administered enteral antimicrobials (ciprofloxacin, levofloxacin and doxycycline) was analysed from a single-centre NHS acute care hospital, Chelsea and Westminster (London, UK).

Patients who received enteral (via oral or a nasogastric/percutaneously inserted feeding tubes) ciprofloxacin, levofloxacin and doxycycline as inpatients between April 2016 and September 2019 were included. Electronic prescribing records (Lastword) were used to identify patients with one or more administered doses of the study antimicrobials. Patients receiving enteral antimicrobials on the critical care wards were excluded due to the absence of electronic prescribing records within this specialty. Where patients received more than one course of an antimicrobial, only the first record was analysed. Patient demographics and concomitant medication, including concurrent administered calcium-based and iron salt therapies, were recorded. The time for each dose prescribed of study antimicrobials and calcium/iron therapies were recorded.

The data were analysed to see the frequency of concurrently administered study antimicrobials with enterally administered calcium and iron therapies. Calcium therapies containing >10 mmol/dose of Ca²⁺ and iron supplements containing >100mg/dose of iron salt were included. Dosing administrations of calcium/iron within 2 hours (before or after) of the study antimicrobial were defined as clinically important within this study.

All data were anonymised and analysed on Excel V.2017. Descriptive statistics were derived using GraphPad V.8 (2018). Data were anonymised at point of collection.

Results

A total of 4067 prescriptions for the study antimicrobials (ciprofloxacin, n=1905; levofloxacin, n=538; and doxycycline, n=1624) were prescribed for 3584 patients. Of the 3583 patients, 1918 (53.5%) were female and the median age was 67 year (range 0.5–105.0 years). Details of antimicrobial dosing and frequency are presented in table 1.

Table 1.

Patient demographics and the antimicrobial treatments prescribed within this study population

	Ciprofloxacin	Levofloxacin	Doxycycline	Total
Number of prescriptions	1905	538	1624	4067
Age, median (years)	65	76	69	69
Range (years)	0.5–105	21–101	10–105	0.5–105
Sex (female)	927 (48.6%)	321 (59.7%)	942 (58%)	2190 (53.8%)
Daily dose, median (range)	1000 mg (250–1500 mg)	500 mg (250–1000 mg)	200 mg (50–400 mg)	–
Dosing frequency
Once a day  Two times per day	40 (2.1%) 1865 (97.9%)	322 (61%) 206 (39%)	1247 (76.8%) 377 (23.2%)	–

A calcium supplement was prescribed concurrently with 289/1906 (15.1%), 103/538 (19.1%) and 262/1624 (16.1%) of the patients receiving ciprofloxacin, levofloxacin and doxycycline, respectively. Iron-based enteral treatments were prescribed concurrently with 162/1906 (8.5%), 44/538 (8.2%) and 117/1624 (7.2%).

Administration timings for the antimicrobials were uniformly prescribed for administration at 08:00 (3874/6460), 18:00 (2262/6460) and 20:00 (168/6460) in 97.6% of all doses reflecting the default timings on the electronic system (figure 1).

Figure 1.

Administration times for antimicrobials (above X-axis) and supplements (below X-axis) in a London teachinghospital, April 2016–September 2019.

Clinically important enteral interactions, defined as receiving one or more doses each day within 2 hours of preantimicrobial or postantimicrobial dose, were calculated for all patients prescribed concurrent enteral iron or calcium supplementation (table 2). Of these interacting prescriptions, a calcium and/or iron supplement was administered within 2 hours of study antimicrobial in 379/397 (95.4%), 123/126 (97.6%) and 308/341 (90.3%) of ciprofloxacin, levofloxacin and doxycycline prescriptions, respectively. Of the 4067 prescriptions reviewed, 810 (19.3%) had an interacting therapy administered within 2 hours of the study medication (table 2).

Table 2.

Burden of drug–drug interactions with common antimicroibals

	Ciprofloxacin	Levofloxacin	Doxycycline	Total
Calcium supplements
Concurrent prescription with antimicrobial	289/1905 (15.1%)	103/538 (19.1%)	262/1624 (16.1%)	654/4067 (16.1%)
Administration within 2 hours of antimicrobial	275/289 (95.2%)	100/103 (97.1%)	233/262 (88.9%)	608/654 (93%)
Administration at same time of antimicrobial	264/289 (91.4%)	99/103 (96.1%)	226/262 (86.3%)	589/654 (90.1%)
Iron supplements
Concurrent prescription with antimicrobial	162/1905 (8.5%)	44/538 (8.2%)	117/1624 (7.2%)	323/4067 (7.9%)
Administration within 2 hours of antimicrobial	155/162 (95.7%)	42/44 (95.5%)	112/117 (95.7%)	309/323 (95.7%)
Administration at same time of antimicrobial	150/162 (92.6%)	42/44 (95.5%)	107/117 (91.5%)	299/323 (92.6%)
Calcium or iron supplements
Concurrent prescription with antimicrobial	397/1905 (20.9%)	126/538 (23.4%)	341/1624 (21%)	864/4067 (21.2%)
Administration within 2 hours of antimicrobial	379/397 (95.4%)	123/126 (97.6%)	308/341 (90.3%)	810/864 (93.8%)
Administration at same time of antimicrobial	364/397 (91.7%)	122/126 (96.8%)	299/341 (87.7%)	785/864 (90.1%)

Discussion

In this retrospective analysis of hospitalised patients receiving oral antimicrobial (ciprofloxacin, levofloxacin and doxycycline), clinically important enteral interactions were evident in one in five prescriptions. Iron and calcium-based therapies were frequently administered concomitantly with antimicrobial therapy typically at the same time of an antimicrobial dose.

The interactions of therapeutic-dosed iron and calcium salts administered within 2 hours of the study antimicrobials have been well described in the literature. These enteral interactions, a result of binding and chelating of the cation salts with the active component of ciprofloxacin, levofloxacin and doxycycline, reduce antimicrobial drug absorption from the gastrointestinal tract and reduce bioavailability. This can contribute to subtherapeutic antimicrobial dosing and consequentially potential treatment failure.

In the outpatient or primary care setting, patients and carers will receive counselling on receipt of a new medication detailing the optimum timing of administration and common concomitant therapies that should be avoided while on antimicrobials. Patients are counselled on when to take medication in relation to food and on other dietary products that may impair absorption.¹⁵ Additionally, PILs detailing optimum administration conditions are provided with each new medication dispensed. In the acute care hospital setting, the responsibility of dosing administration and timing related to concomitant therapies and nutrition are the responsibility of the healthcare professionals. Patients receive minimal information on the nature of therapy and often lack knowledge on even the name of therapy received due to the paternalistic nature of prescribing in the acute setting. It is thus the responsibility of the prescriber, the staff administering treatment and the pharmacist to decide the optimum administration schedules during admission. This may be challenging due to increasing phenomenon of polypharmacy, the numerous changes of medications encountered on a new hospital admission and the limitations of current prescribing systems.

Electronic prescribing has helped revolutionise the capabilities of antimicrobial stewardship, improving surveillance and feedback on antimicrobial prescribing practices within a hospital.^{14 16} These systems, however, introduce new restrictions for prescribers and pharmacy teams. Standardised administration timings become default for medication (eg, 08:00 for once per day administrations and 08:00 and 18:00 for two times per day administrations). This reduces variance for the administering healthcare professional but results in overlap in enterally interacting therapies as demonstrated within this study. With traditional paper drug charts, interacting therapies can be easily omitted for the duration of an antimicrobial therapy by the prescriber or pharmacist (annotating the paper chart).¹⁷ On electronic prescribing charts, temporarily postposing or holding doses is more complicated and is not permissible by all professionals. In this study site, the pharmacy team requires verbal or written consent from the prescriber to hold administrations on the electronic prescribing system. This barrier limits the intervention and high rates of interacting therapies are evident. As healthcare systems migrate to electronic prescribing systems, we must be cognisant of these potential drug–drug interactions and seek to find ways to alert prescribers of any clinically important interactions or allow for automated time lapses between therapy administrations.

An intravenous-to-oral switch, or de-escalation, is a core component of the antimicrobial stewardship strategy. This can lead to reductions in catheter-related complications, hospital length of stay and unnecessary use of broad-spectrum antimicrobials. Antimicrobial teams are increasingly dependent on oral antimicrobials such as ciprofloxacin, levofloxacin and doxycycline for invasive bacterial infections and assume adequate bioavailability if the patient is eating and drinking. However, we must be diligent and identify potential enteral interactions that impair absorption and may lead to subtherapeutic serum levels and consequential treatment failure.

Limitations

This study is completed at a single study site using a single Electronic Prescribing and Medicines Administration (EPMA) system and thus limits it applicability to other settings. Other prescribing systems may provide more intuitive interaction checkers and may enable prescribers to resolve potential interactions when used.

This study demonstrates a high burden of interacting therapies with commonly used antimicrobials in an acute teaching hospital. Administration of iron and calcium therapies within 2 hours of ciprofloxacin, levofloxacin and/or doxycycline can significantly reduce drug bioavailability and result in subtherapeutic serum levels. Without careful identification of these interactions and mitigation of this risk, the antimicrobial stewardship strategies promoting early intravenous-to-oral switches may be undermined and may impair patient outcomes.

What this paper adds.

What is already known on this subject

• Oral antimicrobials can interact with foods and other medications, which can affect absorption.

• Ciprofloxacin, levofloxacin and doxycycline are known to interact with oral irons and cations, which can reduce bioavailability.

• Pharmacists play an important role in counselling patients on optimal administration timing.

What this study adds

• Concomitant administration of oral ciprofloxacin, levofloxacin and doxycycline with iron and calcium supplementation is commonly encountered in the hospital.

• Electronic prescribing systems may contribute to a high burden of drug–drug interactions due to the standardised administration timings.

Data availability statement

Data are available upon reasonable request. Data are available upon request to the author.

Ethics statements

Patient consent for publication

Not required.

Ethics approval

Ethical consent was not required for this retrospective analysis following review by the Trust clinical governance team, and it was completed as a service evaluation project.