Abstract
Older patients are at high risk of infections, which often present atypically and are associated with high morbidity and mortality. Antimicrobial treatment in older individuals with infectious diseases represents a clinical challenge, causing an increasing burden on worldwide healthcare systems; immunosenescence and the coexistence of multiple comorbidities determine complex polypharmacy regimens with an increase in drug–drug interactions and spread of multidrug-resistance infections. Aging-induced pharmacokinetic and pharmacodynamic changes can additionally increase the risk of inappropriate drug dosing, with underexposure that is associated with antimicrobial resistance and overexposure that may lead to adverse effects and poor adherence because of low tolerability. These issues need to be considered when starting antimicrobial prescriptions. National and international efforts have been made towards the implementation of antimicrobial stewardship (AMS) interventions to help clinicians improve the appropriateness and safety of antimicrobial prescriptions in both acute and long-term care settings. AMS programs were shown to decrease consumption of antimicrobials and to improve safety in hospitalized patients and older nursing home residents. With the abundance of antimicrobial prescriptions and the recent emergence of multidrug resistant pathogens, an in-depth review of antimicrobial prescriptions in geriatric clinical practice is needed. This review will discuss the special considerations for older individuals needing antimicrobials, including risk factors that shape risk profiles in geriatric populations as well as an evidence-based description of antimicrobial-induced adverse events in this patient population. It will highlight agents of concern for this age group and discuss interventions to mitigate the effects of inappropriate antimicrobial prescribing.
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Older patients are at high risk of infections and adverse events due to antimicrobial medications. |
Inappropriate antimicrobial use contributes to complications, mainly due to drug underexposure that leads to antimicrobial resistance, and drug overexposure that leads to adverse effects and poor adherence because of low drug tolerability. |
Antimicrobial stewardship interventions addressing adherence to guidelines, dosage adjustment in liver and kidney dysfunction, as well as formulary adaptations and therapeutic drug monitoring can be lifesaving and improve the safety and effectiveness of antimicrobial treatments. |
1 Introduction
Infections are common in older and frail patients and are associated with a significantly higher risk of morbidity, mortality, and health care costs [1]. A diagnosis of infection in the elderly may be challenging because classic symptoms may lack or mimic those of a comorbid condition [2, 3]. Community-acquired pneumonia, for example, may present with confusion only and this will delay the diagnosis, especially in patients with underlying cognitive impairment or dementia. On the other hand, elderly patients may have fever without apparent infections, thus making a very difficult decision on how and when to start antibiotics [3, 4]. However, the choice of the class of antimicrobial agents in older patients is often a challenging issue. Indeed, the type of antibiotic should consider factors related to patient, culprit pathogen (if and whenever possible), pharmacokinetic (PK) and pharmacodynamic (PD) properties, and the presence of polypharmacy, which may significantly increase the risk of developing adverse drug reactions and interactions.
The aim of this review was to describe the PK and PD aspects that may affect the safety of antimicrobials in older patients, as well as their impact on polypharmacy and drug interactions involving antimicrobial agents. Potentially useful interventions for reducing the risk of drug interactions when prescribing antimicrobials to older patients are also reviewed.
1.1 Search Strategy
Identification of relevant articles to 1 September 2022 was performed on standard databases (MEDLINE and Cochrane Library) by combining the following keywords: ‘Antimicrobial*’; ‘older or elder* or over 65 or aging’; ‘drug-related or medication-induced’. Search results were limited to studies written in the English language from 1990 to 2022. For the key studies, we reviewed the bibliographies and citations and performed an author search to identify any additional studies. Two independent reviewers (LS and AC) identified and summarized the study characteristics (design, sample size, demographics, and clinical data), thereby selecting studies deemed relevant for the aim of this review. 5291 articles were originally included; studies were initially screened based on title and abstract and 4890 articles were excluded. The full-text of the remaining 401 articles was screened and 213 were not found to fulfil the aim of the present review and were finally excluded, resulting in the inclusion of 188 articles.
2 Age-Related Changes in Pharmacokinetics/Pharmacodynamics and their Impact on Safety and Tolerability of Antimicrobial Agents
PK processes (absorption, distribution, metabolism, and excretion) undergo relevant modifications during aging (Table 1). The loss of functional capacity of several organs and reduced homeostasis plays a key role in the pathophysiology of these age-related changes. However, changes in PK may also result from the coadministration of selected drugs, as is the case for several antimicrobial agents. In this section, we summarize the most relevant modifications in PK occurring during aging, and PK interactions involving antimicrobial agents relevant to older patients. We will also review the peculiar PD processes involving antimicrobial agents and the impact of PK alterations on PD.
2.1 Absorption
Aging is characterized by a reduction in esophageal peristalsis, which contributes to the observed increase in the prevalence of reflux disease in advanced age [5]. The resulting increase in exposure of the esophageal mucosa to acid secretions [6] may lead to an increased risk of esophageal lesions caused by drugs [7]. Aging is also characterized by a reduction of gastric acid secretion [8], although such a reduction was not confirmed in subjects without Helicobacter pylori infection or gastric mucosal atrophy [9, 10]. In addition, no significant change in terms of atrophy or intestinal metaplasia was detected during long-term therapy with proton pump inhibitors [11], a very common and often inappropriate practice among older patients [12]. However, an increase in gastric pH, especially due to proton pump inhibitors or calcium carbonate use, can alter both the solubility and chemical stability of β-lactams, macrolides azoles, and atazanavir, thus reducing bioavailability [13]. Conversely, acidic drugs such as raltegravir have shown to become more available in less acidic environments, with potential increased bioavailability and toxicity [14]. Gastric emptying and peristalsis are also slowed during aging [15, 16], and splanchnic blood flow and bowel surface are reduced [17]; all these factors can contribute to decrease the bioavailability of amoxicillin and clavulanic acid when assumed after the meal [18]. The proper use of these agents in elders with altered gastrointestinal mobility needs to be addressed. Reduced active transport function may also lead to a significantly lower bioavailability of selected drugs [19, 20]. Drug interactions causing an inhibition of intestinal P-glycoprotein (P-gp) may affect either absorption or presystemic metabolism. For example, inhibition of P-gp by clarithromycin or levofloxacin may increase the serum concentration of sulfonylureas, such as glipizide, leading to refractory hypoglycemia [21,22,23]. Similarly, inhibition of intestinal P-gp by clarithromycin and erythromycin may increase digoxin concentration and toxicity [24]. Finally, specific antifungal agents, such as itraconazole and caspofungin can also inhibit P-gp [25].
2.2 Distribution
Several changes in physiology occur in body composition with aging and may significantly impact drug distribution (Table 1). Aging is associated with an increase in body fat mass by approximately 20–40% and a decrease in total body water and lean body mass by approximately 10–15% [26]. These changes result in a significant increase of the volume of distribution (Vd) for lipophilic drugs, such as macrolides, fluoroquinolones, rifampin, and tetracyclines, with consequent prolongation of their half-life [27]. Similarly, aging is associated with a significant reduction of the Vd for water-soluble drugs, including β-lactams, glycopeptides, aminoglycosides, and azoles, with a consequent more rapid increase in plasma concentrations [28] and the need to start with lower doses [29].
Aging-induced modifications of plasma protein binding have shown to be less relevant for drug therapy, as compensatory mechanisms of drug redistribution generally lead to stable steady-state unbound drug concentrations [25, 30]. Indeed, changes in protein binding may influence the area under the curve of the unbound fraction (fu AUC) for few drugs highly extracted by the liver, extensively protein bound, and administered intravenously [31], such as haloperidol [32] and theophylline [33]. However, several diseases frequently observed in older patients may lead to more pronounced changes in protein binding capacity that cannot be ascribed to the aging process [31]. Furthermore, some antimicrobial medications may undergo protein binding drug interactions that increase the risk of drug toxicity. In this regard, cotrimoxazole may displace methotrexate and sulphonylureas from plasma protein binding sites, thus rising their concentrations and leading to increased risk of hypoglycemia and severe bone marrow depression [25], respectively.
Blood–brain barrier permeability undergoes significant modifications during aging, which may alter drug PK in the central nervous system (CNS). P-gp function declines during aging, which may cause an increased influx of toxic substances in the CNS, and a consequent increased risk of developing neurodegenerative diseases [34], as well as excessive cerebral levels of drugs and xenobiotics [35]. Until now, antibiotics seem to have a less prominent inhibitory effect on the blood–brain barrier P-gp activity: the rate of transfer of verapamil from plasma to brain was unaffected by the coadministration of clarithromycin, suggesting that a clinical dose of clarithromycin does not affect P-gp activity at the blood–brain barrier [36].
2.3 Metabolism
Relevant changes in metabolism occur during aging (Table 1). A 20–30% reduction in liver volume is observed with aging [37] and hepatic blood flow is reduced by approximately 20–50% [38, 39]. These anatomical and functional changes lead to reduced hepatic first-pass effect, with relevant consequences for specific drugs [20, 40]. For example, drugs undergoing extensive first-pass metabolism may have their bioavailability increased [41, 42], while drugs that need to be activated in the liver may have their bioavailability reduced [43]. In older patients, a reduction up to 40% of the hepatic clearance of drugs undergoing flow-limited metabolism has been observed [39, 44]. Cytochrome P450 (CYP)-mediated phase I oxidization, reduction, and hydrolysis reactions are impaired to a greater extent with respect to phase II conjugation reactions, mainly due to the reduced hepatic blood flow and overall liver size [39, 44]. The effects of aging on CYP activities are still to be elucidated [45,46,47]. The aging process per se does not affect most CYP enzymatic activities and enzyme affinity for their substrates. Rather, the age-related reduced phase I hepatic clearance is largely to be ascribed to the above morphological and circulatory changes [37, 48]. Nevertheless, an age-related reduction by approximately 20% has been observed in the metabolism of CYP2D6 substrates [49, 50]. Such a finding was not confirmed for CYP3A subfamily substrates [51,52,53], and former evidence suggests that aging per se has no relevant impact on the activation of some important CYPs, including CYP3A4, CYP2D6 and CYP1A2 [54, 55].
Multiple antimicrobial medications, including fluoroquinolones, macrolides and antifungal azoles, undergo first-pass hepatic metabolism; after phase I oxidation and phase II conjugation processes, these drugs are transformed into hydrosoluble compounds that can be renally excreted [13, 56]. Among macrolides, erythromycin, clarithromycin, and telithromycin, but not azithromycin, are able to inhibit both intestinal and hepatic CYP3A4 [25, 57, 58]. Coadministration of these antimicrobials and other selected CYP3A4 substrates, including dihydropyridine calcium channel blockers, simvastatin, atorvastatin, lovastatin, cyclosporine, midazolam, and tacrolimus, may be harmful because of drug–drug interactions and increased risk of adverse effects. Careful evaluation of drug regimens is thus needed in order to limit the risk of confusion, sedation and falls from benzodiazepines [59, 60], hypoglycemia from sulfonylureas [61], rhabdomyolysis from statins [62], severe hypotension from calcium channel blockers [63], nephrotoxicity from immunosuppressive medications [25], and toxicity of phenytoin and theophylline [25, 57, 58, 64]. Furthermore, erythromycin, and to a smaller extent clarithromycin, and telithromycin may increase the risk of bleeding in older patients taking warfarin [25, 57, 58]. Additionally, macrolide-induced CYP3A4 inhibition may increase serum concentrations of cholinesterase inhibitors such as donepezil, thus enhancing vagal signaling and favoring dysregulation of sinus node cardiac conduction, with subsequent risk of sinus bradycardia, bradyarrhythmias, and neurocardiogenic syncope [65, 66]. Despite the fact that recent evidence did not show an increased risk of cardiac events in older patients taking donepezil or clarithromycin, the use of antimicrobial medications other than clarithromycin in this population should be preferred whenever possible [67]. Finally, prolongation of the QTc interval potentially leading to torsade de pointes and death may be caused by antimicrobial-induced CYP3A4 inhibition, with increased levels of some antiarrhythmics, tricyclic antidepressants, and antipsychotic agents [25, 68]. Of note, several antimicrobial medications have been associated with risk of QT prolongation: azoles, erythromycin, clarithromycin, chloroquine, moxifloxacin and to a lesser extent ciprofloxacin and levofloxacin. Among macrolides, azithromycin does not inhibit CYP3A4 and was originally considered of low cardiotoxic potential; however, recent evidence showed a small increase in the risk of cardiac death among older patients with pneumonia [69], while discordant results in other settings need further investigation [70, 71]. To date, the macrolide/ketolide solithromycin has shown no effects on cardiac repolarization and is considered well tolerated in patients with QT risk when a macrolide is indicated [68, 72].
Inhibition of CYP3A4 and CYP1A2 enzymes by ciprofloxacin, levofloxacin, and moxifloxacin may increase the toxicity of several drugs commonly used in the geriatric setting, such as benzodiazepines, fentanyl, carbamazepine, simvastatin, lovastatin, atorvastatin, theophylline, haloperidol, and warfarin [60, 73].
Conversely, rifampin induces CYP2C9, CYP2C19, and CYP3A4 enzymes, thereby decreasing the bioavailability of several drugs, including warfarin, phenytoin, valproic acid, caspofungin, azoles, digoxin, amiodarone, simvastatin, atorvastatin, lovastatin, β-blockers, and sulfonylureas [25, 73].
2.4 Excretion
Renal excretion of drugs undergoes relevant modifications during aging (Table 1). However, deterioration of kidney function with advancing age can be exacerbated by polypharmacy and multimorbidity, which are highly prevalent in older populations and are known to affect renal function independently of aging [74].
In general terms, a loss of renal mass up to 20–25% [75] and a decrease of kidney length by 15% characterizes kidney aging [76]. Histological changes in the aging human kidney include increased interstitial fibrosis, tubular atrophy, arteriosclerosis, and glomerulosclerosis [77,78,79]. Such morphological changes result in relevant functional modifications affecting the PK of either water-soluble drugs or water-soluble metabolites of lipophilic drugs, with a consequent increased risk of ADRs [80]. Indeed, the age-related reduction in the clearance of inulin ranges between 13% and 46% [74, 77, 81,82,83]. Aging is also associated with important tubule-interstitial changes, including tubular diverticula, atrophy and fat degeneration, reduced sodium reabsorption, reduced potassium secretion, interstitial fibrosis, and medullar hypotonicity [84].
Many antimicrobial agents can undergo drug–drug interactions with renally excreted drugs. For instance, digoxin, methotrexate, and amantadine may affect renal tubular secretion of cotrimoxazole and increase its serum concentration and toxicity [25]. Similarly, ciprofloxacin can decrease tubular secretion and renal excretion of methotrexate, potentially leading to severe hepatic, renal, bone marrow, and dermatological adverse effects [25, 85]. Furthermore, use of probenecid, methotrexate, aspirin, and indomethacin can decrease tubular secretion of β-lactams, thus increasing their serum concentration. More specifically, probenecid was shown to double the AUCs of amoxicillin, ampicillin, ticarcillin and nafcillin, and increase the AUC of meropenem by 55% [25]. In this regard, administration of probenecid to boost β-lactam concentrations should be avoided in older patients as well as individuals with renal impairment or a history of seizure, as it may enhance the risk of antibiotic-induced convulsions [25, 86].
2.5 Pharmacokinetics/Pharmacodynamics
Several PD changes occur with aging [87]. In this context, PD processes involve the multiple relationships between antimicrobial serum concentration and binding capacity to microbial antigens, which in turn lead to cell growth inhibition or death, as measured by minimum inhibitory concentration (MIC) [88, 89]. Antimicrobial drugs can have either a concentration-dependent (e.g. aminoglycosides, metronidazole, fluoroquinolones, daptomycin, and tetracyclines) or time-dependent killing activity (e.g. β-lactams, clindamycin, and vancomycin). While PD activity of concentration-dependent antibiotics mainly depends on the maximum plasma concentration reached, the killing activity of time-dependent antibiotics depends on the amount of time during which the plasma concentration exceeds the MIC for the organism [88,89,90]. In particular, optimization of antibiotic treatment in patients with decreased renal function should take into consideration the type of bacterial killing. Indeed, the risk of overdosing of concentration-dependent antibiotics can be addressed by increasing the dosing intervals (e.g. changing from 6 to 8 h or 12 to 24 h) and maintaining the same dose, thereby maximizing the peak serum dose [91]. Conversely, reducing the dose of time-dependent antibiotics in older patients with impaired renal function may be performed by decreasing the dose and continuing with the same dose interval [91].
Given the tight interconnections between PK and PD, the two processes need to be considered when evaluating doses and times of antimicrobial administration.
Indeed, the PK/PD ratio is used to estimate the antimicrobial effectiveness by correlating free drug (ƒ) exposure (area under the plasma concentration-time curve over 24 h of dosing [ƒAUC24]) to measures of drug potency (MIC). Other PK/PD parameters used in clinical practice are represented by ƒCmax/MIC, the ƒAUC24/MIC (i.e. the area under the inhibitory plasma concentration-time curve [AUIC]), and the time above the MIC (T/MIC) [88]. In this regard, several studies have yet shown the benefits of an integrated approach combining PK and PD parameters in patients with infectious diseases. For instance, Preston et al. showed that among hospitalized patients with respiratory, skin, or complicated urinary tract infections, high ƒAUC24/MIC values were associated with lower rates of clinical failure and low prevalence of adverse effects [92]. PK/PD parameters may also be used to monitor antimicrobial concentrations and clinical course of infections, thus assisting the clinician to intercept early antimicrobial resistance and the development of harmful adverse effects [93]. Furthermore, PK/PD modeling was adopted to tailor the dosing regimen of gentamycin to decreased renal function in patients with end-stage renal disease (ESRD) [94]. In other studies, PK/PD modeling was used to test the susceptibility of emerging strains of multidrug-resistant bacteria to traditional antibiotics, such as β-lactams and carbapenems [95, 96]. Integration of PK and PD can then be necessary to tailor antimicrobial treatments that may help achieve therapeutic goals, prevent selection of drug-resistant bacteria, and minimize toxic effects in the geriatric population [89, 93, 96].
3 Clinical Profile of Older Patients at Risk of Adverse Events and their Consequences
Older individuals are particularly prone to develop adverse drug events (ADEs) related to antimicrobial medications [60, 73]. Polypharmacy, comorbidities impacting renal and liver functioning, and reduced adherence to therapy due to cognitive and functional barriers (e.g. dysphagia), as well as age-related changes in PK and PD, contribute significantly to the higher incidence of antimicrobial ADEs in older patients [60, 73]. In this section, we describe the most important conditions whose early diagnosis and constant monitoring may intercept those segments of the elderly population at major risk of antimicrobial-associated ADEs.
3.1 Chronic Kidney Disease
Antimicrobial prescription in chronic kidney disease (CKD) represents a twofold clinical challenge, as inappropriately low or high doses are both deleterious. Underdosing is indeed associated with therapeutic failure and increased antimicrobial resistance, which is more common in CKD [97, 98]. Conversely, overdosing may lead to toxicity and ADEs [99]. Inadequate estimation of renal function in older patients is one of the factors that complicate antimicrobial appropriateness [100]. Indeed, decreased serum creatinine levels secondary to muscle wasting, sarcopenia, and protein catabolism may lead to overestimation of estimated glomerular filtration rate (eGFR) calculated by creatinine-based Modification of Diet in Renal Disease (MDRD), Cockgroft–Gault, and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations [101], which are generally reported in product labels. Direct measurement of creatinine clearance or measured GFR (mGFR) should then be used to avoid overdosing of hydrophilic medications [102], especially in patients with mild–moderate CKD. Alternatively, recent guidelines have advocated the incorporation of innovative biomarkers such as serum cystatin C to improve the estimation of GFR among older patients in the ‘creatinine-blind range’ [103]. In these individuals with an eGFR between 45 and 70 mL/min/1.73 m2 and urine albumin/creatinine < 30 mg/g, GFR estimation based on serum creatinine levels frequently leads to overestimation of renal function, potentially causing increased drug bioavailability and toxicity [103].
However, appropriate eGFR estimation is not always accompanied by correct antimicrobial dosing, despite the fact that dosage modifications of most renally cleared antimicrobials are implemented in most clinical guidelines. Indeed, non-adherence with dosing guidelines is common in patients with CKD, especially in critically ill patients in intensive care units where physicians often do not tailor antimicrobial dosing to eGFR in order to avoid underdosing and limit antimicrobial resistance, which is very common in these settings [104, 105]. Studies assessing the use of antibiotics at higher than recommended doses led to contrasting results, depending on the drug used and the dose reached. Indeed, a recent study evaluating the effects of overdosing of cephalosporins in advanced CKD did not find any association with increased adverse effects or treatment failure in older adults with eGFR <30 mL/min/1.73 m2 [106]. In contrast, older patients treated with higher doses of fluoroquinolones reported to have increased 14-day hospitalization rates due to altered mental status [107]. However, the definition of appropriate dosing of antimicrobial medications in CKD is likely contrasted by the limited number of studies specifically conducted in patients aged 65 years or older, which mainly evaluated dosage adjustment of levofloxacin and meropenem [73]. However, the use of dosages tailored to renal function does not always limit the risk of over- and underexposure to antimicrobial treatments, as revealed by a recent study conducted in older hospitalized patients treated with appropriate doses of levofloxacin [108]. In this context, implementation of therapeutic drug monitoring (TDM) in an acute care setting when dealing with older patients with CKD may be useful to approach antimicrobial dosage adjustment and prevent antimicrobial adverse effects and toxicity [109].
3.2 Liver Disease
Antimicrobial treatment in patients with liver diseases is a clinical challenge, as these patients are often characterized by a high risk of serious infections and a less favorable risk/benefit profile [110, 111]. Infections represent the most common and life-threatening complication of liver cirrhosis, with an overall incidence ranging from 25 to 40% in patients with decompensated cirrhosis [112]. The most frequent type of infections in patients with liver cirrhosis are represented by spontaneous bacterial peritonitis, followed by urinary tract infections, pneumonia, and soft tissue infections [113]. According to recent evidence, even mild impairment of liver function may increase the susceptibility to infections. Indeed, patients with non-alcoholic fatty liver disease, whose prevalence increases with advancing age, are more vulnerable to infections [114]. Treatment of patients with liver dysfunction is also challenging as many factors concur to impair antimicrobial metabolism. Liver dysfunction directly affects clearance of several antibiotics that undergo phase I metabolism, have a high protein binding, or are associated with a high prevalence of hepatotoxicity [115, 116]. In the presence of hypoalbuminemia related to impaired protein synthesis, highly bound antimicrobials undergo an increase in their free fraction with a high potential of adverse side effects and drug-related toxicity. Furthermore, their serum concentration tends to decrease more easily over time, thus potentially leading to antimicrobial resistance when facing bacterial infection from organisms with a high minimal inhibitory concentration (MIC) [117]. Prescription of ceftriaxone, vancomycin, ertapenem, and aztreonam, which are commonly used in acute care settings, should be carefully considered because of the high affinity with serum albumin [118]. Furthermore, most β-lactams that are not metabolized by the liver can undergo indirect fluctuations in their serum concentration related to increased Vd in patients with third-space retention and those with renal dysfunction, which is commonly associated with liver cirrhosis [115]. On the other hand, many lipophilic antibiotics, including fluoroquinolones, macrolides, tetracyclines, oxazolidinones, and metronidazole, are less affected by Vd but can shift from cells to plasma in patients with hypoalbuminemia [101]. Current evidence suggests antibiotics that can be safely prescribed in cirrhotic patients of all ages, with the Child–Pugh score guiding dosage [115, 119]; however, despite the fact that TDM would help achieve the optimal concentrations in this population, to date no study has been specifically conducted in patients older than 65 years of age.
3.3 Polypharmacy
The high prevalence of multimorbidity and polypharmacy among older adults contributes to the relatively high risk of interactions between antimicrobials and other drugs [60, 73]. Drug–drug interactions put the patients at risk of ADEs and negative health outcomes [60, 73] but are not easily predictable. As such, prescription of antimicrobials should always be preceded by a review of a patient’s medication list for sources of potential drug–drug interactions (Table 2) [120,121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142]. Some interactions are particularly bothersome and deserve special attention.
Prescription of trimethoprim and sulfamethoxazole inhibits resorption of potassium in the distal renal tubule, resulting in increased risk of hyperkalemia and hospitalization [143]; caution is needed when used along with angiotensin-converting enzyme inhibitors (ACEi) and potassium-sparing diuretics. Additionally, trimethoprim/sulfamethoxazole increases the toxicity of phenytoin [144] and sulfonylureas [145], leading to neurological symptoms (confusion, vomiting and coma) and increasing the risk of hypoglycemia, respectively. Another important interaction involves antibiotics able to suppress bacterial growth and production of vitamin K in the gastrointestinal tract, thereby potentiating the effect of warfarin. Indeed, prescription of warfarin with some medications, including quinolones, fluconazole, trimethoprim-sulfamethoxazole, and amoxicillin, may increase the international normalized ratio (INR) and the risk of bleeding [146]. Similarly, some antimicrobials interfere with the activity of the P-gp transporter and CYP3A4 enzyme, thus leading to potential interactions with direct oral anticoagulants (DOACs) [147, 148]. Rifampin is both a cytochrome inducer and a P-gp inducer. Indeed, its coadministration with DOACs will accelerate their metabolism, thus causing a reduction of bioavailability of anticoagulants, with subsequent increased thrombotic risk. Conversely, administration of DOACs with inhibitors of CYP or P-Gp will slow the metabolism of DOACs, thus increasing their serum concentration and, consequently, the risk of bleeding. Antimicrobial CYP inhibitors include itraconazole, fluconazole, ketoconazole, clarithromycin, and erythromycin, while antimicrobial P-gp transporter inhibitors include azithromycin, clarithromycin, erythromycin, itraconazole, and ketoconazole [147, 148].
3.4 Cognitive Impairment
Cognitive impairment represents a risk factor for poor antimicrobial medication adherence and development of several infectious diseases, including respiratory and urinary tract infections, skin and soft tissue infections, and sepsis [149, 150], which are both associated with increased mortality in this setting [151, 152].
The diagnosis of infections in patients with cognitive impairment of varying degree and severity still represents a clinical challenge because of several factors. First, a diagnosis of infection is often delayed as cognitive dysfunction affects patients’ ability to communicate their symptoms and physicians’ capacity to clinically monitor the course of the disease [149]. Furthermore, typical symptoms of infections such as fever, chills, and urinary complaints, are often lacking in patients with low cognitive reserve, while atypical symptoms often include neurological symptoms that may contribute to worsen cognitive function, as well as to delay diagnosis and appropriate management. In this regard, both urinary tract and respiratory tract infections often manifest with confusion, dizziness, memory complaints, and coma [153,154,155]. In outpatient settings, appropriate diagnosis is also complicated by difficulties in obtaining high-quality clinical specimens from patients unable to collect these samples because of poor cognitive function [149].
Even when infections are promptly recognized and diagnosed, their appropriate management can be difficult because of decreased adherence to therapeutic regimens and potential drug–drug and drug–disease interactions [156,157,158]. Memory impairments and forgetfulness may affect both timing and taking adherence, which have distinct impacts on clinical outcomes depending on the pharmacologic properties of the administered drugs [159]. Indeed, for time-dependent antibiotics, administering multiple doses over the course of the day is necessary to reach the clinical effectiveness, especially for short half-life molecules such as β-lactams. As a consequence, both timing and taking adherence are equally important. Conversely, for concentration-dependent antibiotics, taking adherence is more important than timing adherence, especially for long half-life antibiotics, as reaching the peak serum concentration is necessary to ensure clinical success [159]. In any case, simplification of complex drug regimens and communications between clinicians, patients, and caregivers may help increase adherence and improve clinical outcomes to antimicrobial regimens.
Another factor of concern is represented by the increased vulnerability of cognitively impaired individuals to the neurotoxic effects of antimicrobials [160]. Indeed, several antibiotics, including penicillins, levofloxacin, macrolides, metronidazole, and antimycobacterial agents, as well as antivirals and antimalarials, may cause cognitive adverse effects ranging from mild cognitive problems to encephalopathy and coma [149]. Many neurological disorders such as epilepsy and stroke can increase the permeability of the blood–brain barrier and further enhance β-lactam neurotoxicity [161]. Furthermore, prolonged administration of some antimicrobial medications, such as vancomycin, ampicillin, and streptozocin, may induce profound changes in the gut microbiota composition, altering the gut–brain axis involved in the pathogenesis of several neurodegenerative disorders [162,163,164,165]. A cumulative duration-dependent relationship between dementia incidence and days of antibiotic exposure recently emerged in a retrospective cohort study [166]. The association was significant after adjustment for several confounding factors potentially related to cognitive decline, including infectious diseases and dysphagia [166]. Furthermore, exposure to long-term antibiotic use during mid-life was recently associated with decline in cognitive performance [167]. In a study conducted among patients with Alzheimer’s disease, a 12-month treatment with doxycycline and rifampin compared with placebo caused a decline in cognitive function [168]. However, to date the evidence supporting these associations is still limited and needs further studies to be confirmed.
4 Adverse Events from Antimicrobial Agents among Older Patients
All classes of antimicrobials, such as antibiotics, antifungals, antimycobacterial agents, and antivirals, may cause adverse reactions that can involve one or more organ systems (Tables 3, 4). Older patients using antimicrobials have a higher risk of ADRs due to age-related changes in PK and PD, multimorbidity, and polypharmacy. Although the use of antimicrobials is widespread among older adults, high-quality data on ADRs in the older population are often lacking and only limited information is available on specific ADRs and their prevalence.
4.1 Adverse Drug Reactions to Antibiotics
4.1.1 Aminoglycosides
Aminoglycosides can potentially cause ototoxicity and nephrotoxicity [169, 170]. Older patients are more vulnerable and have a greater risk of toxicity with prolonged length of therapy (≥ 3 days) and concomitant use of ototoxic or nephrotoxic agents [101, 171]. Ototoxicity occurs as both vestibular (e.g., dizziness, ataxia, nystagmus) and cochlear (e.g., hearing loss) dysfunction in up to 15% and 2–25% of patients, respectively [172]. Nephrotoxicity is more common than ototoxicity, affecting between 10 and 30% of patients and presenting as acute tubular necrosis [171, 173]. Chinzowu et al. analyzed the absolute risk of acute kidney injury among older adults due to aminoglycoside exposure. Among 1853 patients across eight studies, 15.8% developed acute kidney injury after treatment with aminoglycosides. The absolute risk was 15.1% (95% confidence interval [CI] 12.8–17.3%) and was significantly higher than the average risk among younger patients (10.5%, 95% CI 10.1–10.8%) [174].
4.1.2 Tetracyclines
All tetracyclines such as doxycycline, minocycline, and tigecycline can potentially cause adverse reactions, including photosensitivity, cutaneous infections, esophagitis, and hepatotoxicity [175, 176], but the prevalence among older adults has not been specifically investigated.
4.1.3 Sulfonamides and Trimethoprim
Sulfonamides are among the most common drugs associated with nephrotoxicity, presenting as acute interstitial nephritis and crystal nephropathy [171, 173]. Other common toxicities induced by trimethoprim-sulfamethoxazole are gastrointestinal, hypersensitivity, and dermatologic reactions [172]. Although rare, the risk of neurotoxicity induced by sulfonamides is higher among older adults. Symptoms of neurotoxicity include delirium and psychosis, and more commonly, headache and drowsiness. The mechanisms are unknown but seem to be related to glutathione deficiency that is often present in geriatric patients [101, 169, 172].
4.1.4 Polymyxins
Polymyxins are frequently associated with nephrotoxicity and neurotoxicity. Colistin induces nephrotoxicity, and particular attention is required among older patients [101]. Among neurotoxic symptoms, headache, dizziness, and lower limb weakness are the most common [169].
4.1.5 Oxazolidinones
Thrombocytopenia is the major adverse effect after linezolid treatment. Duration of treatment and low baseline platelet count are associated with a higher risk of this ADR [101]. Symptoms of neurotoxicity have also been documented. Among these symptoms, headaches and peripheral neuropathy seem to be the most common but the incidence in older patients is unknown. The concomitant use of linezolid and agents that stimulate the CNS should be avoided due to the higher risk of neuropsychiatric events [172].
4.1.6 Macrolides
It is well-known that this class of drugs might cause gastrointestinal intolerance, hepatotoxicity, cardiotoxicity, and ototoxicity [172, 175, 176]. Ototoxicity presents as hearing decrements and tinnitus. For these reasons, macrolides should be avoided in older patients with baseline hearing problems [176]. Several studies reported a high risk of QT prolongation leading to cardiac arrhythmias, underlying that this ADR is limited to patients with higher-risk baseline such as pre-existing cardiovascular conditions and concomitant use of drugs, leading to arrhythmias [73, 176, 177]. However, other studies did not confirm the risk of arrhythmias [101]. Neurotoxicities such as delirium and psychosis are rare, but although the association is still not clear, neurotoxic events may occur more easily in older patients [172]. A recent systematic review by Chinzowu et al. highlighted an overall risk of acute kidney injury among older patients of 0.3% (95% CI 0.3–0.3%) [174].
4.1.7 Glycopeptides
Nephrotoxicity, ototoxicity, and, more rarely, red man syndrome (hypersensitivity reaction with signs of flushing and/or erythematous rash on the upper torso, neck, and face) are typically associated with glycopeptides [171]. Nephrotoxic events are the most feared of these adverse events because they occur with a high risk in older patients [101]. A recent meta-analysis by Hirai et al. highlighted that among 634 patients across eight studies treated with teicoplanin, the overall incidence was 11.0% (95% CI 8.0–13.0), with a higher risk in patients aged > 65 years [178]. Chinzowu et al. analyzed the risk of acute kidney injury among older adults in treatment with glycopeptides across eight studies (total of 23,431 participants), finding an overall absolute risk of 19.1% (95% CI 15.4–22.7%) [174]. The nephrotoxicity occurs as acute tubular necrosis but the mechanism of ADR is unknown [171, 173]. Ototoxicity occurs as hearing loss and/or tinnitus and is generally reversible [169, 175].
4.1.8 Lipopeptides
Common mild ADRs are constipation, nausea, and vomiting, while other less frequently reported but severe ADRs include myopathy and rhabdomyolysis, eosinophilic pneumonia, drug reaction with eosinophilia and systemic symptoms (DRESS), tubulointerstitial nephritis, peripheral neuropathy, and neutropenia [179]. Unfortunately, no data are available referring to the older population.
4.1.9 β-Lactams
β‑Lactam antibiotics are among the most prescribed drugs in both community and hospital settings [180]. These antibiotics are grouped together based on the β-lactam ring in their chemical structure, and subdivided into four families: penicillins, cephalosporins, carbapenems, and monobactams. Hypersensitive reactions are common and frequent ADRs associated with the use of penicillins, involving approximately 10% of the population, and with higher rates reported among older and hospitalized patients [180]. Patients who are allergic to penicillins may show cross-reactivity towards the other class. Nevertheless, the cross-reactivity seems to be overestimated [180, 181]. β-lactam antibiotics are commonly associated with nephrotoxicity (acute interstitial nephritis), especially in older patients [73, 171, 173]. Gastrointestinal reactions such as nausea, vomiting, and diarrhea are frequently associated with β-lactams, more often in older patients than in adults [182]. Penicillins (broad spectrum), cephalosporins (third/fourth-generation) and carbapenems may induce Clostridioides difficile diarrhea and colitis with a higher risk in patients ≥ 65 years of age [183]. Hepatotoxicity presenting as cholestasis and jaundice is commonly associated with the use of amoxicillin-clavulanic acid and flucloxacillin, with older age and longer duration of treatment as risk factors [181, 184]. Piperacillin/tazobactam may exacerbate heart failure, delivering a high sodium load [185]. Although rare, serious neurotoxicity related to β-lactam antibiotics are described in the literature [186,187,188], with a high risk in older patients using piperacillin/tazobactam, cephalosporins (particularly cefepime), and carbapenems [101, 172, 181]. Neurotoxic symptoms include seizures, encephalopathy, myoclonus, tremors, hyperexcitability, and hyperactivity [101, 172, 181, 186,187,188]. The ability of β-lactam antibiotics to induce neurotoxicity seems to be linked to the β-lactam ring [169, 186]. Although this adverse reaction may be difficult to recognize in critically ill patients, Payne et al. analyzed the neurotoxicity of cefepime (median age of 69 years), finding that 26% of patients experienced neurotoxicity despite appropriate dosing [188].
4.1.10 Fluoroquinolones
In general, fluoroquinolones are well tolerated; however, it is well-known that tendinopathy such as Achilles tendon rupture and Achilles tendinitis are correlated with their use [189]. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) regulatory authorities recommended special caution in older adults because these patients are at higher risk of tendon injury and it is suggested they avoid concomitant treatment with a fluoroquinolone and a corticosteroid [190, 191]. CNS effects such as dizziness, hallucinations, and seizures are not frequent but seem related to older age [172, 189], particularly in patients aged > 80 years [175]. Fluoroquinolones can rarely cause cardiotoxicity, inducing prolongation of the QT interval and increasing the risk of arrythmia [101, 189]. Furthermore, an increased risk of Clostridioides difficile infection is well-documented among older patients in treatment with fluoroquinolones [176, 183].
4.1.11 Nitrofurans
Common adverse reactions of nitrofurantoin include neurotoxicity, such as headache, dizziness, and drowsiness. The risk is higher in older adults [101, 172].
4.1.12 Nitroimidazole
Metronidazole can cause neurotoxicity and cardiotoxicity with prolonged use but the ADRs occur across all ages and are not specific for older adults [73, 172].
4.1.13 Lincosamide
The most well-known ADR of clindamycin is its disruptive effect on gut flora and the resultant diarrhea and colitis due to the overgrowth of Clostridium difficile [175, 183].
4.2 Adverse Drug Reactions to Antifungals
4.2.1 Echinocandins
Echinocandins are reportedly well tolerated [141]. The most common ADRs of echinocandins are mild and reversible, such as nausea, elevated hepatic enzymes, rash, and phlebitis [139,140,141]. Caution should be advised in older patients with liver dysfunction.
4.2.2 Triazoles
ADRs of triazoles include abdominal pain, nausea, vomiting, diarrhea, skin rash, and sometimes hepatotoxicity ranging from elevation of serum aminotransferases to fatal hepatic failure, especially in patients with pre-existing hepatic dysfunction [139,140,141]. Itraconazole and fluconazole can potentially cause cardiotoxicity for prolongation of the QT interval [73] and itraconazole can occasionally cause worse heart failure. Voriconazole can cause neurotoxicity, including visual and auditory hallucinations. The safety of voriconazole is similar in older patients compared with adults, but in clinical trials, voriconazole plasma concentrations were 80–90% higher in the former group [141].
4.2.3 Amphotericin B
Infusion-related reactions, hepatotoxicity, hematological effects, and nephrotoxicity are typically associated with the use of amphotericin B [141, 192]. Nephrotoxicity is the most feared of these because it can occur in most older patients, presenting with an increased creatinine level, hypokalemia, and/or hypomagnesemia [139,140,141, 192]. Although the lipid formulations have been shown to be substantially less toxic than conventional amphotericin B, particularly with respect to nephrotoxicity [193], concomitant use of other nephrotoxic drugs should be avoided [141, 192]. Furthermore, amphotericin B may cause heart failure but symptoms normalize with discontinuation of therapy [194].
4.2.4 Flucytosine
High plasma levels of flucytosine, maintained for a long time, cause reversible inhibition of the bone marrow and hepatic dysfunction. The concurrent use of flucytosine and nephrotoxic drugs should be avoided due to the risk of accumulation of flucytosine [141].
4.3 Adverse Drug Reactions to Antimycobacterial Agents
4.3.1 Isoniazid
It is well-known that isoniazid is hepatotoxic and the risk of hepatotoxicity increase with the age [175, 184, 195, 196]. Among antituberculosis drugs, isoniazid is the most hepatotoxic and patients aged ≥ 60 years are 3.5 times more likely to have liver injuries [184]. The risk increases with the association of rifampin [184]. Neurotoxic effects are common and include peripheral neuropathy [175], ataxia, restlessness, and insomnia [197].
4.3.2 Rifampin
Rifampin frequently causes red-orange discoloration of urine, tears, and sweat [175]. Nephrotoxicity is common in older adults [73] and the incidence varies from 1.8 to 16%, but the discontinuation of therapy leads to recovery in about 3 weeks [171]. As explained above, the combination of rifampin with isoniazid increases the risk of hepatotoxicity [184].
4.4 Adverse Drug Reactions to Antivirals
4.4.1 Nucleosides/Nucleotides Excluded Reverse Transcriptase Inhibitors
Acyclovir and ganciclovir are antiviral drugs used in the treatment of infections against herpes simplex virus and varicella zoster and against cytomegalovirus, respectively [198]. These drugs may be associated with nephrotoxicity by crystallization, precipitation, and obstruction of the renal tubule. In particular, the nephrotoxicity indication of acyclovir ranges from 12 to 48% [171]. Acyclovir is well tolerated but can cause gastrointestinal upset and headache [199]. Neurotoxicity (signs of confusion, hallucinations, and agitation) is a rarer ADR and occurs mainly in older patients or patients with renal dysfunction [200]. Given the high risk of neurological ADRs, older patients should be carefully monitored for these effects, which are generally reversible once treatment is discontinued [199]. The ADRs of ganciclovir are neutropenia, thrombocytopenia, mucositis, and hepatic dysfunction, and should be administered in older patients under close renal supervision to avoid toxicity [201]. Remdesivir and molnupiravir are antivirals for the treatment of coronovairus disease 2019 (COVID-19). The most commonly encountered ADRs with the use of remdesivir are nausea, vomiting, and transaminase elevations [202]. Molnupiravir can frequently cause headaches, diarrhea, and nausea [203]. Unfortunately, the prevalence of ADRs of remdesivir and molnupiravir in older patients is unknown.
4.4.2 Derivatives of Phosphonic Acid
Foscarnet is a direct-acting antiviral derived from phosphonic acid. When present, ADRs are severe and include nephrotoxicity due to renal tubule obstruction [171] and neurotoxicity. Therefore, foscarnet should be used with caution in older patients with impaired renal function [204].
4.4.3 Neuraminidase Inhibitors
Oseltamivir and zanamivir are neuraminidase inhibitors of influenza A and B viruses. Gastrointestinal disturbances can occur with oseltamivir. Zanamivir can cause cough, sore throat, and, in asthmatic patients, bronchospasm [205, 206].
4.4.4 Interferon-α
Interferon-α could be used in older patients for the treatment of hepatitis B and C. Common ADRs include fever, influenza-like symptoms, nausea, headache, depression, and alopecia that may be more severe in older adults [207, 208].
4.4.5 Nucleoside/Nucleotide Reverse Transcriptase Inhibitors
Although rarely reported, the risk of causing mitochondrial toxicity is a hallmark of this class of drugs. Toxicity is manifested by symptoms of myopathy, neuropathy, and lactic acidosis with fatty liver, particularly with lamivudine. Even at low doses, the use of adefovir-dipivoxil can cause nephrotoxicity. Tenofovir can cause renal and bone toxicity in HIV-infected patients. Particular caution should be exercised in older patients at risk of renal dysfunction and osteoporosis [209, 210].
4.4.6 Non-nucleoside Reverse Transcriptase Inhibitors
First-generation non-nucleoside reverse transcriptase inhibitors such as nevirapine and efavirenz have been associated with skin erythema and hepatotoxicity [211]. Efavirenz can cause neurotoxicity and cardiotoxicity, but unfortunately the prevalence among older adults has not been specifically investigated [212].
4.4.7 Protease Inhibitors
Typical ADRs of this class of drugs are the risk of hyperlipidemia, lipodystrophy, hyperglycemia, and insulin resistance, but limited information is available on their prevalence among older adults [213]. Nirmatrelvir is a protease inhibitor antiviral used in combination with ritonavir for the treatment of COVID-19. The most common ADRs reported with this treatment are dysgeusia, headache, and gastrointestinal disturbances, but no studies have been performed in older patients [214].
5 Interventions to Improve Safety and Tolerability
Appropriate use of antimicrobials in the elderly can be life-saving given the high prognostic impact of infections in this population. Inappropriate antimicrobial prescriptions in older patients are instead associated with increased risk of antimicrobial resistance, adverse side effects, morbidity, and mortality [215]. A barrier for the diagnosis and prevention of antimicrobial inappropriate prescriptions in clinical practice is currently represented by the lack of a gold-standard tool to evaluate antimicrobial inappropriateness. This is partly related to the different definitions of inappropriate antimicrobial treatment found in the literature and to the paucity of studies specifically conducted in elderly patients (Table 5) [216,217,218,219,220,221,222,223,224,225,226]. Some studies have defined inappropriateness based on clinical variables (presence of signs and/or symptoms of infection despite antimicrobial treatment [217, 219], while others have considered the appropriateness of diagnosis, dosage, route of administration, or duration of antimicrobial treatment [222, 224,225,226,227]. More objective methods to evaluate appropriateness are based on positivity of microbiological testing results but they are time-consuming and are not always available [218]. Finally, some studies used multiple criteria to evaluate appropriateness, based on clinical examination, laboratory evaluations, and adherence to guideline-based recommendations [220, 221, 223]. Recent studies comparing distinct criteria for inappropriate antimicrobial prescriptions have shown limited agreement among them [228, 229]. The proportion of inappropriate antimicrobial treatment varied widely across studies and care settings, as a likely result of heterogeneity of criteria used to evaluate appropriateness and inappropriateness of antimicrobial prescriptions; however, despite the fact that the definition of a gold-standard measure for inappropriate antimicrobial use has not yet been provided, inappropriate antimicrobial prescribing deserves to be addressed because it is associated with poor outcomes among older individuals [230]. In order to improve the appropriateness of antibiotic prescriptions in acute and long-term care settings, several antimicrobial stewardship (AMS) strategies have been implemented and taken into consideration (Table 6) [166, 230,231,232,233,234,235,236,237,238]. AMS is defined as the careful and responsible management of antimicrobial medications used to treat or prevent infections, in order to provide a prescription of the right drug, at the right time, at the correct dose, and for the appropriate duration [239]. The objectives of AMS include the containment of infectious diseases, appropriate antimicrobial use, and reduction of the emergence and spread of multidrug-resistant microorganisms. Despite these goals being universally recognized, standardized methods for their implementation and monitoring across different settings are still undefined. Distinct interventions are included in AMS programs; formulary modifications, including the choice of monotherapy targeting the more likely microorganism at the site of infection should be preferred over combination therapy whenever possible [240]. Combination therapy using narrow-spectrum antibiotics enhances the synergism of distinct antimicrobial compounds and is particularly active against Gram-negative bacteria [241]. Use of antibiotic resistance breakers, such as β-lactamase inhibitors, can be used to improve the efficacy of antimicrobials against multidrug resistance microorganisms. Another two AMS interventions used to contrast antimicrobial resistance are antimicrobial cycling and de-escalation; antimicrobial cycling consists of antimicrobial rotation aimed at decreasing the selective pressure on a particular drug in order to limit antimicrobial resistance [242], and antimicrobial de-escalation consists of antimicrobial switch from broad- to narrow-spectrum molecules, when laboratory findings of culture and sensitivity are available [243]; however, despite these opportunities, antimicrobial rotation and de-escalation are poorly studied in older patients. On the other hand, promotion of education and the importance of timely and appropriate microbiology sampling, as well as TDM with feedback, have been shown to be effective in decreasing antibiotic consumption and inappropriate use in long-term care settings [244, 245]. Dose optimization using PK and PD properties is also important. Several antibiotics need dosing modification according to renal and hepatic function to increase the benefits and limit the risk of toxicity and ADEs (Table 7) [121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138, 142, 246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268]; however, despite the importance of dosage adjustments in patients with renal and liver function impairment, these adjustments are rarely made and non-compliance with dosing guidelines is common [60]. In these cases, TDM-guided dosing is the most effective way to ensure optimal drug exposure for several antibiotics [269]. Despite the absence of studies specifically conducted in older patients, current literature has shown benefits of TDM in preventing hematologic toxicity of linezolid, nephrotoxicity of aminoglycosides and vancomycin, and neurotoxicity of β-lactams [269]. However, while there are many barriers to be overcome, AMS interventions have been shown to significantly improve different phases of the prescribing process and mitigate the effects of inappropriate antimicrobial prescribing in both long-term care and acute care older patients [226, 244, 270, 271]. There is then an urgent need to deliver effective and standardized AMS interventions and to find the best way to implement AMS programs in order to maintain their benefit over time.
6 Conclusions
Inappropriate prescription of antimicrobials to older patients represents a clinical challenge and a global issue that contributes to the spread of multidrug resistant microorganisms. Age-related changes in PK and PD processes increase the risk of drug underexposure that predisposes to the emergence of resistance, as well as of drug overexposure with potential adverse effects and drug discontinuation for poor tolerability. Multiple chronic diseases and polypharmacy complicate the choice of proper antimicrobial treatment and further increase the risk of adverse effects. Selected AMS interventions addressing adherence to guidelines, dosage adjustment in liver and kidney dysfunction, as well as formulary adaptations and TDM can be life-saving and can improve the safety and effectiveness of antimicrobial treatments. However, standardization of AMS strategies is necessary for their implementation in clinical practice across distinct settings of care. Prospective clinical trials involving older patients are required, ideally focusing on the population older than 80 years of age, which is often neglected and poorly represented. In the meanwhile, clinicians are advised to prescribe judiciously to prevent unnecessary treatment and decrease the risk of inappropriate prescriptions in older patients with infectious diseases.
References
Htwe TH, Mushtaq A, Robinson SB, Rosher RB, Khardori N. Infection in the elderly. Infect Dis Clin N Am. 2007;21:711–43. https://doi.org/10.1016/j.idc.2007.07.006. (ix).
Gavazzi G, Krause KH. Ageing and infection. Lancet Infect Dis. 2002;2:659–66. https://doi.org/10.1016/s1473-3099(02)00437-1.
Zalacain R, Torres A, Celis R, Blanquer J, Aspa J, Esteban L, Menendez R, Blanquer R, Borderias L. Community-acquired pneumonia in the elderly: Spanish multicentre study. Eur Respir J. 2003;21:294–302. https://doi.org/10.1183/09031936.03.00064102.
Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med. 2002;113(Suppl 1A):5S-13S. https://doi.org/10.1016/s0002-9343(02)01054-9.
Gregersen H, Pedersen J, Drewes AM. Deterioration of muscle function in the human esophagus with age. Dig Dis Sci. 2008;53:3065–70. https://doi.org/10.1007/s10620-008-0278-y.
Lee J, Anggiansah A, Anggiansah R, Young A, Wong T, Fox M. Effects of age on the gastroesophageal junction, esophageal motility, and reflux disease. Clin Gastroenterol Hepatol. 2007;5:1392–8. https://doi.org/10.1016/j.cgh.2007.08.011.
Greenwald DA. Aging, the gastrointestinal tract, and risk of acid-related disease. Am J Med. 2004;117(Suppl 5A):8S-13S. https://doi.org/10.1016/j.amjmed.2004.07.019.
Feldman M. The mature stomach. Still pumping out acid? JAMA. 1997;278:681–2.
Haruma K, Hamada H, Mihara M, Kamada T, Yoshihara M, Sumii K, Kajiyama G, Kawanishi M. Negative association between Helicobacter pylori infection and reflux esophagitis in older patients: case-control study in Japan. Helicobacter. 2000;5:24–9. https://doi.org/10.1046/j.1523-5378.2000.00003.x.
Nakamura K, Ogoshi K, Makuuchi H. Influence of aging, gastric mucosal atrophy and dietary habits on gastric secretion. Hepatogastroenterology. 2006;53:624–8.
Lamberts R, Brunner G, Solcia E. Effects of very long (up to 10 years) proton pump blockade on human gastric mucosa. Digestion. 2001;64:205–13. https://doi.org/10.1159/000048863.
Boxel OS, Hagenaars MP, Smout AJ, Siersema PD. Socio-demographic factors influence use of proton pump inhibitors among users of nonsteroidal anti-inflammatory drugs. Clin Gastroenterol Hepatol. 2009. https://doi.org/10.1016/j.cgh.2009.05.017.
Mazzei T. The difficulties of polytherapy: examples from antimicrobial chemotherapy. Intern Emerg Med. 2011;6(Suppl 1):103–9. https://doi.org/10.1007/s11739-011-0680-x.
Iwamoto M, Wenning LA, Nguyen BY, Teppler H, Moreau AR, Rhodes RR, Hanley WD, Jin B, Harvey CM, Breidinger SA, et al. Effects of omeprazole on plasma levels of raltegravir. Clin Infect Dis. 2009;48:489–92. https://doi.org/10.1086/596503.
Wiley JW. Aging and neural control of the GI tract: III. Senescent enteric nervous system: lessons from extraintestinal sites and nonmammalian species. Am J Physiol Gastrointest Liver Physiol. 2002. https://doi.org/10.1152/ajpgi.00224.2002.
Orr WC, Chen CL. Aging and neural control of the GI tract: IV. Clinical and physiological aspects of gastrointestinal motility and aging. Am J Physiol Gastrointest Liver Physiol. 2002;283:G1226–31. https://doi.org/10.1152/ajpgi.00276.2002.
Ciccocioppo R, Di Sabatino A, Luinetti O, Rossi M, Cifone MG, Corazza GR. Small bowel enterocyte apoptosis and proliferation are increased in the elderly. Gerontology. 2002;48:204–8. https://doi.org/10.1159/000058351.
Weitschies W, Friedrich C, Wedemeyer RS, Schmidtmann M, Kosch O, Kinzig M, Trahms L, Sorgel F, Siegmund W, Horkovics-Kovats S, et al. Bioavailability of amoxicillin and clavulanic acid from extended release tablets depends on intragastric tablet deposition and gastric emptying. Eur J Pharm Biopharm. 2008;70:641–8. https://doi.org/10.1016/j.ejpb.2008.05.011.
Saltzman JR, Kowdley KV, Perrone G, Russell RM. Changes in small-intestine permeability with aging. J Am Geriatr Soc. 1995;43:160–4. https://doi.org/10.1111/j.1532-5415.1995.tb06382.x.
Kinirons MT, Crome P. Clinical pharmacokinetic considerations in the elderly. An update. Clin Pharmacokinet. 1997;33:302–12. https://doi.org/10.2165/00003088-198917040-00003.
Ruan XC, Tan PY, Tan Y. Clarithromycin and glipizide drug-drug interaction leading to refractory hypoglycemia. Cureus. 2019;11:e4800–e4800. https://doi.org/10.7759/cureus.4800.
Parekh TM, Raji M, Lin Y-L, Tan A, Kuo Y-F, Goodwin JS. Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas. JAMA Intern Med. 2014;174:1605–12. https://doi.org/10.1001/jamainternmed.2014.3293.
Liao SH, Hu SY, How CK, Hsieh VC, Chan CM, Chiu CS, Hsieh MS. Risk for hypoglycemic emergency with levofloxacin use, a population-based propensity score matched nested case-control study. PLoS ONE. 2022;17: e0266471. https://doi.org/10.1371/journal.pone.0266471.
Westphal JF. Macrolide—induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol. 2000;50:285–95. https://doi.org/10.1046/j.1365-2125.2000.00261.x.
Pereira JM, Paiva JA. Antimicrobial drug interactions in the critically ill patients. Curr Clin Pharmacol. 2013;8:25–38.
Forbes GB, Reina JC. Adult lean body mass declines with age: some longitudinal observations. Metabolism. 1970;19:653–63. https://doi.org/10.1016/0026-0495(70)90062-4.
Klotz U, Avant GR, Hoyumpa A, Schenker S, Wilkinson GR. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest. 1975;55:347–59. https://doi.org/10.1172/JCI107938.
Hanratty CG, McGlinchey P, Johnston GD, Passmore AP. Differential pharmacokinetics of digoxin in elderly patients. Drugs Aging. 2000;17:353–62. https://doi.org/10.2165/00002512-200017050-00003.
Morike K, Schwab M, Klotz U. Use of aminoglycosides in elderly patients. Pharmacokinetic and clinical considerations. Drugs Aging. 1997;10:259–77. https://doi.org/10.2165/00002512-199710040-00003.
Rolan PE. Plasma protein binding displacement interactions—why are they still regarded as clinically important? Br J Clin Pharmacol. 1994;37:125–8. https://doi.org/10.2165/00003495-198325050-00003.
Benet LZ, Hoener BA. Changes in plasma protein binding have little clinical relevance. Clin Pharmacol Ther. 2002;71:115–21. https://doi.org/10.1067/mcp.2002.121829.
Koyama H, Mori S, Sugioka N, Nishihara T, Nakajima K. Age-related alteration of haloperidol-serum protein binding. J Pharm Pharmacol. 2003;55:77–83. https://doi.org/10.1211/002235702540.
Butler JM, Begg EJ. Free drug metabolic clearance in elderly people. Clin Pharmacokinet. 2008;47(297–321):4752. https://doi.org/10.2165/00003088-200847050-00002.
Bartels AL, Kortekaas R, Bart J, Willemsen AT, de Klerk OL, de Vries JJ, van Oostrom JC, Leenders KL. Blood-brain barrier P-glycoprotein function decreases in specific brain regions with aging: a possible role in progressive neurodegeneration. Neurobiol Aging. 2008. https://doi.org/10.1016/j.neurobiolaging.2008.02.002.
Toornvliet R, van Berckel BN, Luurtsema G, Lubberink M, Geldof AA, Bosch TM, Oerlemans R, Lammertsma AA, Franssen EJ. Effect of age on functional P-glycoprotein in the blood-brain barrier measured by use of (R)-[(11)C]verapamil and positron emission tomography. Clin Pharmacol Ther. 2006;79:540–8. https://doi.org/10.1016/j.clpt.2006.02.004.
Arakawa R, Ito H, Okumura M, Morimoto T, Seki C, Takahashi H, Takano A, Suhara T. No inhibitory effect on P-glycoprotein function at blood-brain barrier by clinical dose of clarithromycin: a human PET study with [(1)(1)C]verapamil. Ann Nucl Med. 2010;24:83–7. https://doi.org/10.1007/s12149-009-0336-3.
Wynne H. Drug metabolism and ageing. J Br Menopause Soc. 2005;11:51–6.
Le Couteur DG, Fraser R, Hilmer S, Rivory LP, McLean AJ. The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance. Clin Pharmacokinet. 2005;44:187–200. https://doi.org/10.2165/00003088-200544020-00004. (4424).
Le Couteur DG, McLean AJ. The aging liver. Drug clearance and an oxygen diffusion barrier hypothesis. Clin Pharmacokinet. 1998;34:359–73. https://doi.org/10.2165/00003088-199834050-00003.
Zeeh J, Platt D. The aging liver: structural and functional changes and their consequences for drug treatment in old age. Gerontology. 2002;48:121–7. https://doi.org/10.1159/000052829.
Anantharaju A, Feller A, Chedid A. Aging liver. A review. Gerontology. 2002;48:343–53. https://doi.org/10.1159/000065506.
Tateishi T, Fujimura A, Shiga T, Ohashi K, Ebihara A. Influence of aging on the oxidative and conjugative metabolism of propranolol. Int J Clin Pharmacol Res. 1995;15:95–101.
Davies RO, Gomez HJ, Irvin JD, Walker JF. An overview of the clinical pharmacology of enalapril. Br J Clin Pharmacol. 1984;18(Suppl 2):215S-229S. https://doi.org/10.2165/00003495-198500301-00004.
Schmucker DL. Liver function and phase I drug metabolism in the elderly: a paradox. Drugs Aging. 2001;18:837–51. https://doi.org/10.2165/00002512-200118110-00005.
Shi S, Morike K, Klotz U. The clinical implications of ageing for rational drug therapy. Eur J Clin Pharmacol. 2008;64:183–99. https://doi.org/10.1007/s00228-007-0422-1.
Wauthier V, Verbeeck RK, Calderon PB. The effect of ageing on cytochrome p450 enzymes: consequences for drug biotransformation in the elderly. Curr Med Chem. 2007;14:745–57. https://doi.org/10.2174/092986707780090981.
Kinirons MT, O’Mahony MS. Drug metabolism and ageing. Br J Clin Pharmacol. 2004;57:540–4. https://doi.org/10.1111/j.1365-2125.2004.02096.x.
Woodhouse KW, James OF. Hepatic drug metabolism and ageing. Br Med Bull. 1990;46:22–35. https://doi.org/10.1093/oxfordjournals.bmb.a072387.
O’Connell MB, Frye RF, Matzke GR, St Peter JV, Willhite LA, Welch MR, Kowal P, LaValleur J. Effect of conjugated equine estrogens on oxidative metabolism in middle-aged and elderly postmenopausal women. J Clin Pharmacol. 2006;46:1299–307. https://doi.org/10.1177/0091270006292249.
Dorne JL, Walton K, Slob W, Renwick AG. Human variability in polymorphic CYP2D6 metabolism: is the kinetic default uncertainty factor adequate? Food Chem Toxicol. 2002;40:1633–56. https://doi.org/10.1016/s0278-6915(02)00117-5.
Parkinson A, Mudra DR, Johnson C, Dwyer A, Carroll KM. The effects of gender, age, ethnicity, and liver cirrhosis on cytochrome P450 enzyme activity in human liver microsomes and inducibility in cultured human hepatocytes. Toxicol Appl Pharmacol. 2004;199:193–209. https://doi.org/10.1016/j.taap.2004.01.010.
Schmucker DL. Aging and the liver: an update. J Gerontol A Biol Sci Med Sci. 1998;53:B315–20. https://doi.org/10.1093/gerona/53a.5.b315.
Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther. 1994;270:414–23.
Dilger K, Hofmann U, Klotz U. Enzyme induction in the elderly: effect of rifampin on the pharmacokinetics and pharmacodynamics of propafenone. Clin Pharmacol Ther. 2000;67:512–20. https://doi.org/10.1067/mcp.2000.106872.
Platten HP, Schweizer E, Dilger K, Mikus G, Klotz U. Pharmacokinetics and the pharmacodynamic action of midazolam in young and elderly patients undergoing tooth extraction. Clin Pharmacol Ther. 1998;63:552–60. https://doi.org/10.1016/S0009-9236(98)90106-0.
Shakunthala N. New cytochrome P450 mechanisms: implications for understanding molecular basis for drug toxicity at the level of the cytochrome. Expert Opin Drug Metab Toxicol. 2010;6:1–15. https://doi.org/10.1517/17425250903329095.
Pai MP, Graci DM, Amsden GW. Macrolide drug interactions: an update. Ann Pharmacother. 2000;34:495–513. https://doi.org/10.1345/aph.19138.
Shi J, Montay G, Bhargava VO. Clinical pharmacokinetics of telithromycin, the first ketolide antibacterial. Clin Pharmacokinet. 2005;44:915–34. https://doi.org/10.2165/00003088-200544090-00003.
Quinney SK, Haehner BD, Rhoades MB, Lin Z, Gorski JC, Hall SD. Interaction between midazolam and clarithromycin in the elderly. Br J Clin Pharmacol. 2008;65:98–109. https://doi.org/10.1111/j.1365-2125.2007.02970.x.
Corsonello A, Abbatecola AM, Fusco S, Luciani F, Marino A, Catalano S, Maggio MG, Lattanzio F. The impact of drug interactions and polypharmacy on antimicrobial therapy in the elderly. Clin Microbiol Infect. 2015;21:20–6. https://doi.org/10.1016/j.cmi.2014.09.011.
Lee S, Ock M, Kim HS, Kim H. Effects of co-administration of sulfonylureas and antimicrobial drugs on hypoglycemia in patients with type 2 diabetes using a case-crossover design. Pharmacotherapy. 2020;40:902–12. https://doi.org/10.1002/phar.2450.
Abu Mellal A, Hussain N, Said AS. The clinical significance of statins-macrolides interaction: comprehensive review of in vivo studies, case reports, and population studies. Ther Clin Risk Manag. 2019;15:921–36. https://doi.org/10.2147/tcrm.S214938.
Wright AJ, Gomes T, Mamdani MM, Horn JR, Juurlink DN. The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers. CMAJ Can Med Assoc J = journal de l’Association medicale canadienne. 2011;183:303–7. https://doi.org/10.1503/cmaj.100702.
Pai MP, Momary KM, Rodvold KA. Antibiotic drug interactions. Med Clin N Am. 2006;90:1223–55. https://doi.org/10.1016/j.mcna.2006.06.008.
Park-Wyllie LY, Mamdani MM, Li P, Gill SS, Laupacis A, Juurlink DN. Cholinesterase inhibitors and hospitalization for bradycardia: a population-based study. PLoS Med. 2009;6: e1000157. https://doi.org/10.1371/journal.pmed.1000157.
Gill SS, Anderson GM, Fischer HD, Bell CM, Li P, Normand SL, Rochon PA. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Arch Intern Med. 2009;169:867–73. https://doi.org/10.1001/archinternmed.2009.43.
Hutson JR, Fischer HD, Wang X, Gruneir A, Daneman N, Gill SS, Rochon PA, Anderson GM. Use of clarithromycin and adverse cardiovascular events among older patients receiving donepezil: a population-based, nested case-control study. Drugs Aging. 2012;29:205–11. https://doi.org/10.2165/11599090-000000000-00000.
Mason JW. Antimicrobials and QT prolongation. J Antimicrob Chemother. 2017;72:1272–4. https://doi.org/10.1093/jac/dkw591.
Mortensen EM, Halm EA, Pugh MJ, Copeland LA, Metersky M, Fine MJ, Johnson CS, Alvarez CA, Frei CR, Good C, et al. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JAMA. 2014;311:2199–208. https://doi.org/10.1001/jama.2014.4304.
Sutton SS. Is cardiovascular risk a concern when prescribing azithromycin? Jaapa. 2017;30:11–3. https://doi.org/10.1097/01.Jaa.0000511033.34198.95.
Li X, Wang M, Liu G, Ma J, Li C. Association of macrolides with overall mortality and cardiac death among patients with various infections: a meta-analysis. Eur J Intern Med. 2016;28:32–7. https://doi.org/10.1016/j.ejim.2015.09.009.
Darpo B, Sager PT, Fernandes P, Jamieson BD, Keedy K, Zhou M, Oldach D. Solithromycin, a novel macrolide, does not prolong cardiac repolarization: a randomized, three-way crossover study in healthy subjects. J Antimicrob Chemother. 2017;72:515–21. https://doi.org/10.1093/jac/dkw428.
Giarratano A, Green SE, Nicolau DP. Review of antimicrobial use and considerations in the elderly population. Clin Interv Aging. 2018;13:657–67. https://doi.org/10.2147/cia.S133640.
Fliser D, Franek E, Joest M, Block S, Mutschler E, Ritz E. Renal function in the elderly: impact of hypertension and cardiac function. Kidney Int. 1997;51:1196–204. https://doi.org/10.1038/ki.1997.163.
Beck LH. Changes in renal function with aging. Clin Geriatr Med. 1998;14:199–209.
Miletic D, Fuckar Z, Sustic A, Mozetic V, Stimac D, Zauhar G. Sonographic measurement of absolute and relative renal length in adults. J Clin Ultrasound. 1998;26:185–9. https://doi.org/10.1002/(SICI)1097-0096(199805)26:4%3c185::AID-JCU1%3e3.0.CO;2-9.
Fuiano G, Sund S, Mazza G, Rosa M, Caglioti A, Gallo G, Natale G, Andreucci M, Memoli B, De Nicola L, et al. Renal hemodynamic response to maximal vasodilating stimulus in healthy older subjects. Kidney Int. 2001;59:1052–8. https://doi.org/10.1046/j.1523-1755.2001.0590031052.x.
Melk A, Halloran PF. Cell senescence and its implications for nephrology. J Am Soc Nephrol. 2001;12:385–93. https://doi.org/10.1681/ASN.V122385.
Neugarten J, Gallo G, Silbiger S, Kasiske B. Glomerulosclerosis in aging humans is not influenced by gender. Am J Kidney Dis. 1999;34:884–8. https://doi.org/10.1016/S0272-6386(99)70046-6.
Turnheim K. When drug therapy gets old: pharmacokinetics and pharmacodynamics in the elderly. Exp Gerontol. 2003;38:843–53. https://doi.org/10.1016/s0531-5565(03)00133-5.
Davies DF, Shock NW. Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest. 1950;29:496–507. https://doi.org/10.1172/JCI102286.
Hollenberg NK, Rivera A, Meinking T, Martinez G, McCullough M, Passan D, Preston M, Taplin D, Vicaria-Clement M. Age, renal perfusion and function in island-dwelling indigenous Kuna Amerinds of Panama. Nephron. 1999;82:131–8. https://doi.org/10.1159/000045389.
Fliser D, Ritz E. Serum cystatin C concentration as a marker of renal dysfunction in the elderly. Am J Kidney Dis. 2001;37:79–83. https://doi.org/10.1053/ajkd.2001.20628.
Musso CG, Oreopoulos DG. Aging and physiological changes of the kidneys including changes in glomerular filtration rate. Nephron Physiol. 2011;119(Suppl 1):1–5. https://doi.org/10.1159/000328010.
Dalle JH, Auvrignon A, Vassal G, Leverger G. Interaction between methotrexate and ciprofloxacin. J Pediatr Hematol Oncol. 2002;24:321–2. https://doi.org/10.1097/00043426-200205000-00021.
Wallace KL. Antibiotic-induced convulsions. Crit Care Clin. 1997;13:741–62. https://doi.org/10.1016/s0749-0704(05)70367-5.
Corsonello A, Pedone C, Incalzi RA. Age-related pharmacokinetic and pharmacodynamic changes and related risk of adverse drug reactions. Curr Med Chem. 2010;17:571–84. https://doi.org/10.2174/092986710790416326.
Mouton JW, Dudley MN, Cars O, Derendorf H, Drusano GL. Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs: an update. J Antimicrob Chemother. 2005;55:601–7. https://doi.org/10.1093/jac/dki079.
Noreddin AM, El-Khatib W, Haynes V. Optimal dosing design for antibiotic therapy in the elderly: a pharmacokinetic and pharmacodynamic perspective. Recent Pat Antiinfect Drug Discov. 2008;3:45–52. https://doi.org/10.2174/157489108783413191.
Noreddin AM, Haynes V. Use of pharmacodynamic principles to optimise dosage regimens for antibacterial agents in the elderly. Drugs Aging. 2007;24:275–92. https://doi.org/10.2165/00002512-200724040-00002.
Benson JM. Antimicrobial pharmacokinetics and pharmacodynamics in older adults. Infect Dis Clin. 2017;31:609–17. https://doi.org/10.1016/j.idc.2017.07.011.
Preston SL, Drusano GL, Berman AL, Fowler CL, Chow AT, Dornseif B, et al. Pharmacodynamics of levofloxacin: a new paradigm for early clinical trials. JAMA. 1998;279:125–9. https://doi.org/10.1001/jama.279.2.125.
Rodríguez-Gascón A, Solinís MÁ, Isla A. The role of PK/PD analysis in the development and evaluation of antimicrobials. Pharmaceutics. 2021;13:833. https://doi.org/10.3390/pharmaceutics13060833.
Zhuang L, He Y, Xia H, Liu Y, Sy SK, Derendorf H. Gentamicin dosing strategy in patients with end-stage renal disease receiving haemodialysis: evaluation using a semi-mechanistic pharmacokinetic/pharmacodynamic model. J Antimicrob Chemother. 2016;71:1012–21. https://doi.org/10.1093/jac/dkv428.
Jacobs MR. Optimisation of antimicrobial therapy using pharmacokinetic and pharmacodynamic parameters. Clin Microbiol Infect. 2001;7:589–96. https://doi.org/10.1046/j.1198-743x.2001.00295.x.
Pereira LC, Fátima MAD, Santos VV, Brandão CM, Alves IA, Azeredo FJ. Pharmacokinetic/pharmacodynamic modeling and application in antibacterial and antifungal pharmacotherapy: a narrative review. Antibiotics. 2022;11:986. https://doi.org/10.3390/antibiotics11080986.
Vacaroiu IA, Cuiban E, Geavlete BF, Gheorghita V, David C, Ene CV, Bulai C, Lupusoru GE, Lupusoru M, Balcangiu-Stroescu AE et al. Chronic kidney disease-an underestimated risk factor for antimicrobial resistance in patients with urinary tract infections. 2022;10: 2368. https://doi.org/10.3390/biomedicines10102368
Wang TZ, Kodiyanplakkal RPL, Calfee DP. Antimicrobial resistance in nephrology. Nat Rev Nephrol. 2019;15:463–81. https://doi.org/10.1038/s41581-019-0150-7.
Aloy B, Launay-Vacher V, Bleibtreu A, Bortolotti P, Faure E, Filali A, Gauzit R, Gilbert M, Lesprit P, Mahieu R, et al. Antibiotics and chronic kidney disease: dose adjustment update for infectious disease clinical practice. Med Mal Infect. 2020;50:323–31. https://doi.org/10.1016/j.medmal.2019.06.010.
Wu C-C, Tai C-H, Liao W-Y, Wang C-C, Kuo C-H, Lin S-W, Ku S-C. Augmented renal clearance is associated with inadequate antibiotic pharmacokinetic/pharmacodynamic target in Asian ICU population: a prospective observational study. Infect Drug Resist. 2019;12:2531–41. https://doi.org/10.2147/IDR.S213183.
Falcone M, Paul M, Tiseo G, Yahav D, Prendki V, Friberg LE, Guerri R, Gavazzi G, Mussini C, Tinelli M. Considerations for the optimal management of antibiotic therapy in elderly patients. J Glob Antimicrob Resist. 2020;22:325–33. https://doi.org/10.1016/j.jgar.2020.02.022.
Pea F. Antimicrobial treatment of bacterial infections in frail elderly patients: the difficult balance between efficacy, safety and tolerability. Curr Opin Pharmacol. 2015;24:18–22. https://doi.org/10.1016/j.coph.2015.06.006.
Shlipak MG, Mattes MD, Peralta CA. Update on cystatin C: incorporation into clinical practice. Am J Kidney Dis. 2013;62:595–603. https://doi.org/10.1053/j.ajkd.2013.03.027.
van Daalen FV, Prins JM, Opmeer BC, Boermeester MA, Visser CE, van Hest RM, Branger J, Mattsson E, van de Broek MFM, Roeleveld TC, et al. Effect of an antibiotic checklist on length of hospital stay and appropriate antibiotic use in adult patients treated with intravenous antibiotics: a stepped wedge cluster randomized trial. Clin Microbiol Infect. 2017;23(485):e1-485.e8. https://doi.org/10.1016/j.cmi.2017.01.019.
de Vroom SL, van Daalen FV, Zieck SE, Mathôt RAA, van Hest RM, Geerlings SE. Does dose reduction of renally cleared antibiotics in patients with impaired renal function lead to adequate drug exposure? A systematic review. Clin Microbiol Infect. 2021;27:352–63. https://doi.org/10.1016/j.cmi.2020.11.032.
Bathini L, Jandoc R, Kuwornu P, McArthur E, Weir MA, Sood MM, Battistella M, Muanda FT, Liu A, Jain AK, et al. Clinical outcomes of failing to dose-reduce cephalosporin antibiotics in older adults with CKD. Clin J Am Soc Nephrol. 2019;14:197. https://doi.org/10.2215/CJN.10710918.
Muanda FT, Sood MM, Weir MA, Sontrop JM, Ahmadi F, Yoo E, Kim RB, Silverman MS, Knoll GA, Garg AX. Association of higher-dose fluoroquinolone therapy with serious adverse events in older adults with advanced chronic kidney disease. JAMA Netw Open. 2022;5:e2224892–e2224892. https://doi.org/10.1001/jamanetworkopen.2022.24892.
Cojutti PG, Ramos-Martin V, Schiavon I, Rossi P, Baraldo M, Hope W, Pea F. Population pharmacokinetics and pharmacodynamics of levofloxacin in acutely hospitalized older patients with various degrees of renal function. Antimicrob Agents Chemother. 2017. https://doi.org/10.1128/aac.02134-16.
Ebihara F, Hamada Y, Kato H, Maruyama T, Kimura T. Importance and reality of TDM for antibiotics not covered by insurance in Japan. Int J Environ Res Public Health. 2022;19:2516. https://doi.org/10.3390/ijerph19052516.
Patel VC, Williams R. Antimicrobial resistance in chronic liver disease. Hep Int. 2020;14:24–34. https://doi.org/10.1007/s12072-019-10004-1.
Gallaher CE, Shawcross DL. Management of multidrug-resistant infections in cirrhosis. Semin Liver Dis. 2022;42:173–87. https://doi.org/10.1055/a-1765-0056.
Fernández J, Acevedo J. New antibiotic strategies in patients with cirrhosis and bacterial infection. Expert Rev Gastroenterol Hepatol. 2015;9:1495–500. https://doi.org/10.1586/17474124.2015.1100075.
Bunchorntavakul C, Chavalitdhamrong D. Bacterial infections other than spontaneous bacterial peritonitis in cirrhosis. World J Hepatol. 2012;4:158–68. https://doi.org/10.4254/wjh.v4.i5.158.
Adenote A, Dumic I, Madrid C, Barusya C, Nordstrom CW, Rueda Prada L. NAFLD and infection, a nuanced relationship. Can J Gastroenterol Hepatol. 2021;2021:5556354. https://doi.org/10.1155/2021/5556354.
Zoratti C, Moretti R, Rebuzzi L, Albergati IV, Di Somma A, Decorti G, Di Bella S, Crocè LS, Giuffrè M. Antibiotics and liver cirrhosis: what the physicians need to know. Antibiotics (Basel, Switzerland). 2021;11:31. https://doi.org/10.3390/antibiotics11010031.
Maraolo AE, Scotto R, Zappulo E, Pinchera B, Schiano Moriello N, Nappa S, Buonomo AR, Gentile I. Novel strategies for the management of bacterial and fungal infections in patients with liver cirrhosis: focus on new antimicrobials. Expert Rev Anti Infect Ther. 2020;18:191–202. https://doi.org/10.1080/14787210.2020.1725473.
Wiedermann CJ. Hypoalbuminemia as surrogate and culprit of infections. Int J Mol Sci. 2021;22:4496. https://doi.org/10.3390/ijms22094496.
Ulldemolins M, Roberts JA, Rello J, Paterson DL, Lipman J. The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients. Clin Pharmacokinet. 2011;50:99–110. https://doi.org/10.2165/11539220-000000000-00000.
Halilovic J, Heintz BH. Antibiotic dosing in cirrhosis. Am J Health Syst Pharm. 2014;71:1621–34. https://doi.org/10.2146/ajhp140031.
Oliveira JFP, Silva CA, Barbieri CD, Oliveira GM, Zanetta DMT, Burdmann EA. Prevalence and risk factors for aminoglycoside nephrotoxicity in intensive care units. Antimicrob Agents Chemother. 2009;53:2887–91. https://doi.org/10.1128/AAC.01430-08.
US FDA. Amoxicillin (Amoxil) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050542s24,050754s11,050760s10,050761s10lbl.pdf. Accessed 15 Feb 2023.
US FDA. Ampicillin/sulbactam (Unasyn) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050608s029lbl.pdf. Accessed 15 Feb 2023.
US FDA. Ciprofloxacin (Cipro IV) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/019857s062lbl.pdf. Accessed 15 Feb 2023.
US FDA. Ciprofloxacin (Cipro) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/019537s086lbl.pdf. Accessed 15 Feb 2023.
US FDA. Levofloxacin (Levaquin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021721s020_020635s57_020634s52_lbl.pdf. Accessed 15 Feb 2023.
US FDA. Moxifloxacin (Avelox) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021085s063lbl.pdf. Accessed 15 Feb 2023.
US FDA. Linezolid (Zyvox) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021130s032,021131s026,021132s031lbl.pdf. Accessed 15 Feb 2023.
US FDA. Azithromycin (Zitromax) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050710s039,050711s036,050784s023lbl.pdf. Accessed 15 Feb 2023.
US FDA. Clarithromycin (Biaxin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050662s042,050698s024,050775s013lbl.pdf. Accessed 15 Feb 2023.
US Food and Drug Administration. Erythromycin (Ery-Ped) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/050207s074,050611s036lbl.pdf. Accessed 20 Feb 2023.
US FDA. Erythromycin (Erithrocin) [package insert]. https://www.nebraskamed.com/sites/default/files/documents/for-providers/asp/tnmc-anti-infective-renal-dosing-guidelines.pdf. Accessed 15 Feb 2023.
US FDA. Metronidazole (Metronidazole) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/018890s052lbl.pdf. Accessed 15 Feb 2023.
US FDA. Rifampin (Rifadin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/050420s073,050627s012lbl.pdf. Accessed 15 Feb 2023.
US FDA. Tetracycline (Tetracycline) [package insert]. https://www.nebraskamed.com/sites/default/files/documents/for-providers/asp/tnmc-anti-infective-renal-dosing-guidelines.pdf. Accessed 15 Feb 2023.
US FDA. Doxycycline (Doryx) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050795s005lbl.pdf. Accessed 15 Feb 2023.
US FDA. Doxycyline (Vibramycin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050442s016lbl.pdf. Accessed 15 Feb 2023.
US FDA.Minocycline (Minocin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/050649023lbl.pdf. Accessed 15 Feb 2023.
US FDA. Tigecycline (Tigacyl) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021821s021lbl.pdf. Accessed 15 Feb 2023.
Kyriakidis I, Tragiannidis A, Munchen S, Groll AH. Clinical hepatotoxicity associated with antifungal agents. Expert Opin Drug Saf. 2017;16:149–65. https://doi.org/10.1080/14740338.2017.1270264.
Mourad A, Perfect JR. Tolerability profile of the current antifungal armoury. J Antimicrob Chemother. 2018;73:i26–32. https://doi.org/10.1093/jac/dkx446.
Dekkers BGJ, Veringa A, Marriott DJE, Boonstra JM, van der Elst KCM, Doukas FF, McLachlan AJ, Alffenaar J-WC. Invasive candidiasis in the elderly: considerations for drug therapy. Drugs Aging. 2018;35:781–9. https://doi.org/10.1007/s40266-018-0576-9.
US FDA. Sulfamethoxazole and trimethoprim (Bactrim) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/017377s068s073lbl.pdf. Accessed 15 Feb 2023.
Antoniou T, Gomes T, Juurlink DN, Loutfy MR, Glazier RH, Mamdani MM. Trimethoprim-sulfamethoxazole-induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system: a population-based study. Arch Intern Med. 2010;170:1045–9. https://doi.org/10.1001/archinternmed.2010.142.
Antoniou T, Gomes T, Mamdani MM, Juurlink DN. Trimethoprim/sulfamethoxazole-induced phenytoin toxicity in the elderly: a population-based study. Br J Clin Pharmacol. 2011;71:544–9. https://doi.org/10.1111/j.1365-2125.2010.03866.x.
Tan A, Holmes HM, Kuo Y-F, Raji MA, Goodwin JS. Coadministration of co-trimoxazole with sulfonylureas: hypoglycemia events and pattern of use. J Gerontol Ser A. 2014;70:247–54. https://doi.org/10.1093/gerona/glu072.
Baillargeon J, Holmes HM, Lin Y-L, Raji MA, Sharma G, Kuo Y-F. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012;125:183–9. https://doi.org/10.1016/j.amjmed.2011.08.014.
Chang SH, Chou IJ, Yeh YH, Chiou MJ, Wen MS, Kuo CT, See LC, Kuo CF. Association between use of non-vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA. 2017;318:1250–9. https://doi.org/10.1001/jama.2017.13883.
Lippi G, Favaloro EJ, Mattiuzzi C. Combined administration of antibiotics and direct oral anticoagulants: a renewed indication for laboratory monitoring? Semin Thromb Hemost. 2014;40:756–65. https://doi.org/10.1055/s-0034-1381233.
Parsons C, van der Steen JT. Antimicrobial use in patients with dementia: current concerns and future recommendations. CNS Drugs. 2017;31:433–8. https://doi.org/10.1007/s40263-017-0427-y.
Delgado A, Cordero GGE, Marcos S, Cordero-Ampuero J. Influence of cognitive impairment on mortality, complications and functional outcome after hip fracture: dementia as a risk factor for sepsis and urinary infection. Injury. 2020;51(Suppl 1):S19-s24. https://doi.org/10.1016/j.injury.2020.02.009.
Foley NC, Affoo RH, Martin RE. A systematic review and meta-analysis examining pneumonia-associated mortality in dementia. Dement Geriatr Cogn Disord. 2015;39:52–67. https://doi.org/10.1159/000367783.
Hariyanto TI, Putri C, Situmeang RFV, Kurniawan A. Dementia is a predictor for mortality outcome from coronavirus disease 2019 (COVID-19) infection. Eur Arch Psychiatry Clin Neurosci. 2021;271:393–5. https://doi.org/10.1007/s00406-020-01205-z.
Komagamine J, Yabuki T, Noritomi D, Okabe T. Prevalence of and factors associated with atypical presentation in bacteremic urinary tract infection. Sci Rep. 2022;12:5197–5197. https://doi.org/10.1038/s41598-022-09222-9.
Shah FA, Pike F, Alvarez K, Angus D, Newman AB, Lopez O, Tate J, Kapur V, Wilsdon A, Krishnan JA, et al. Bidirectional relationship between cognitive function and pneumonia. Am J Respir Crit Care Med. 2013;188:586–92. https://doi.org/10.1164/rccm.201212-2154OC.
Hogg E, Frank S, Oft J, Benway B, Rashid MH, Lahiri S. Urinary tract infection in Parkinson’s disease. J Parkinsons Dis. 2022;12:743–57. https://doi.org/10.3233/jpd-213103.
Chudiak A, Uchmanowicz I, Mazur G. Relation between cognitive impairment and treatment adherence in elderly hypertensive patients. Clin Interv Aging. 2018;13:1409–18. https://doi.org/10.2147/CIA.S162701.
Rohde D, Gaynor E, Large M, Mellon L, Bennett K, Williams DJ, Brewer L, Hall P, Callaly E, Dolan E, et al. Cognitive impairment and medication adherence post-stroke: a five-year follow-up of the ASPIRE-S cohort. PLoS ONE. 2019;14: e0223997. https://doi.org/10.1371/journal.pone.0223997.
Cho MH, Shin DW, Chang SA, Lee JE, Jeong SM, Kim SH, Yun JM, Son K. Association between cognitive impairment and poor antihypertensive medication adherence in elderly hypertensive patients without dementia. Sci Rep. 2018;8:11688. https://doi.org/10.1038/s41598-018-29974-7.
Leekha S, Terrell CL, Edson RS. General principles of antimicrobial therapy. Mayo Clin Proc. 2011;86:156–67. https://doi.org/10.4065/mcp.2010.0639.
Warstler A, Bean J. Antimicrobial-induced cognitive side effects. Mental Health Clin. 2016;6:207–14. https://doi.org/10.9740/mhc.2016.07.207.
Schliamser SE, Cars O, Norrby SR. Neurotoxicity of beta-lactam antibiotics: predisposing factors and pathogenesis. J Antimicrob Chemother. 1991;27:405–25. https://doi.org/10.1093/jac/27.4.405.
Karakan T, Ozkul C, Küpeli Akkol E, Bilici S, Sobarzo-Sánchez E, Capasso R. Gut-brain-microbiota axis: antibiotics and functional gastrointestinal disorders. Nutrients. 2021;13:389. https://doi.org/10.3390/nu13020389.
Ianiro G, Tilg H, Gasbarrini A. Antibiotics as deep modulators of gut microbiota: between good and evil. Gut. 2016;65:1906–15. https://doi.org/10.1136/gutjnl-2016-312297.
Lee KE, Kim JK, Kim DH. Orally administered antibiotics vancomycin and ampicillin cause cognitive impairment with gut dysbiosis in mice with transient global forebrain ischemia. Front Microbiol. 2020;11: 564271. https://doi.org/10.3389/fmicb.2020.564271.
Fröhlich EE, Farzi A, Mayerhofer R, Reichmann F, Jačan A, Wagner B, Zinser E, Bordag N, Magnes C, Fröhlich E, et al. Cognitive impairment by antibiotic-induced gut dysbiosis: analysis of gut microbiota-brain communication. Brain Behav Immun. 2016;56:140–55. https://doi.org/10.1016/j.bbi.2016.02.020.
Kim M, Park SJ, Choi S, Chang J, Kim SM, Jeong S, Park YJ, Lee G, Son JS, Ahn JC, et al. Association between antibiotics and dementia risk: a retrospective cohort study. Front Pharmacol. 2022;13: 888333. https://doi.org/10.3389/fphar.2022.888333.
Mehta RS, Lochhead P, Wang Y, Ma W, Nguyen LH, Kochar B, Huttenhower C, Grodstein F, Chan AT. Association of midlife antibiotic use with subsequent cognitive function in women. PLoS ONE. 2022;17: e0264649. https://doi.org/10.1371/journal.pone.0264649.
Molloy DW, Standish TI, Zhou Q, Guyatt G, Group TDS. A multicenter, blinded, randomized, factorial controlled trial of doxycycline and rifampin for treatment of Alzheimer's disease: the DARAD trial. 2013;28:463–470. https://doi.org/10.1002/gps.3846.
Bangert MK, Hasbun R. Neurological and psychiatric adverse effects of antimicrobials. CNS Drugs. 2019;33:727–53. https://doi.org/10.1007/s40263-019-00649-9.
Mörike K, Schwab M, Klotz U. Use of aminoglycosides in elderly patients. Pharmacokinetic and clinical considerations. Drugs Aging. 1997;10:259–77. https://doi.org/10.2165/00002512-199710040-00003.
Mizokami F, Mizuno T. Acute kidney injury induced by antimicrobial agents in the elderly: awareness and mitigation strategies. Drugs Aging. 2015;32:1–12. https://doi.org/10.1007/s40266-014-0232-y.
Mattappalil A, Mergenhagen KA. Neurotoxicity with antimicrobials in the elderly: a review. Clin Ther. 2014;36:1489-1511.e4. https://doi.org/10.1016/j.clinthera.2014.09.020.
Khan S, Loi V, Rosner MH. Drug-induced kidney injury in the elderly. Drugs Aging. 2017;34:729–41. https://doi.org/10.1007/s40266-017-0484-4.
Chinzowu T, Roy S, Nishtala PS. Risk of antimicrobial-associated organ injury among the older adults: a systematic review and meta-analysis. BMC Geriatr. 2021;21:617. https://doi.org/10.1186/s12877-021-02512-3.
Faulkner CM, Cox HL, Williamson JC. Unique aspects of antimicrobial use in older adults. Clin Infect Dis. 2005;40:997–1004. https://doi.org/10.1086/428125.
Al-Hasan MN, Al-Jaghbeer MJ. Use of antibiotics in chronic obstructive pulmonary disease: what is their current role in older patients? Drugs Aging. 2020;37:627–33. https://doi.org/10.1007/s40266-020-00786-7.
Maisch NM, Kochupurackal JG, Sin J. Azithromycin and the risk of cardiovascular complications. J Pharm Pract. 2014;27:496–500. https://doi.org/10.1177/0897190013516503.
Hirai T, Hosohata K, Ogawa Y, Iwamoto T. Clinical predictors of nephrotoxicity associated with teicoplanin: meta-analysis and meta-regression. Basic Clin Pharmacol Toxicol. 2022;130:110–21. https://doi.org/10.1111/bcpt.13679.
Patel S, Saw S. Daptomycin. Treasure Island: StatPearls Publishing; 2022.
Shenoy ES, Macy E, Rowe T, Blumenthal KG. Evaluation and management of penicillin allergy: a review. JAMA. 2019;321:188–99. https://doi.org/10.1001/jama.2018.19283.
Vardakas KZ, Kalimeris GD, Triarides NA, Falagas ME. An update on adverse drug reactions related to β-lactam antibiotics. Expert Opin Drug Saf. 2018;17:499–508. https://doi.org/10.1080/14740338.2018.1462334.
Lagacé-Wiens P, Rubinstein E. Adverse reactions to β-lactam antimicrobials. Expert Opin Drug Saf. 2012;11:381–99. https://doi.org/10.1517/14740338.2012.643866.
McDonald LC, Gerding DN, Johnson S, Bakken JS, Carroll KC, Coffin SE, Dubberke ER, Garey KW, Gould CV, Kelly C, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66:987–94. https://doi.org/10.1093/cid/ciy149.
Lucena MI, Sanabria J, García-Cortes M, Stephens C, Andrade RJ. Drug-induced liver injury in older people. Lancet Gastroenterol Hepatol. 2020;5:862–74. https://doi.org/10.1016/s2468-1253(20)30006-6.
Wang N, Nguyen PK, Pham CU, Smith EA, Kim B, Goetz MB, Graber CJ. Sodium Content of intravenous antibiotic preparations. Open forum Infect Dis. 2019;6:ofz508. https://doi.org/10.1093/ofid/ofz508.
Deshayes S, Coquerel A, Verdon R. Neurological adverse effects attributable to β-lactam antibiotics: a literature review. Drug Saf. 2017;40:1171–98. https://doi.org/10.1007/s40264-017-0578-2.
Zareifopoulos N, Panayiotakopoulos G. Neuropsychiatric effects of antimicrobial agents. Clin Drug Investig. 2017;37:423–37. https://doi.org/10.1007/s40261-017-0498-z.
Payne LE, Gagnon DJ, Riker RR, Seder DB, Glisic EK, Morris JG. Cefepime-induced neurotoxicity: a systematic review. Crit Care. 2017;21:276. https://doi.org/10.1186/s13054-017-1856-1.
Stahlmann R, Lode H. Safety considerations of fluoroquinolones in the elderly: an update. Drugs Aging. 2010;27:193–209. https://doi.org/10.2165/11531490-000000000-00000.
Alves C, Mendes D, Marques FB. Fluoroquinolones and the risk of tendon injury: a systematic review and meta-analysis. Eur J Clin Pharmacol. 2019;75:1431–43. https://doi.org/10.1007/s00228-019-02713-1.
Tanne JH. FDA adds “black box” warning label to fluoroquinolone antibiotics. Br Med J. 2008;337(7662):816. https://doi.org/10.1136/bmj.a816.
Kauffman CA. Fungal infections in older adults. Clin Infect Dis. 2001;33:550–5. https://doi.org/10.1086/322685.
Mistro S, Maciel IDM, de Menezes RG, Maia ZP, Schooley RT, Badaró R. Does lipid emulsion reduce amphotericin B nephrotoxicity? A systematic review and meta-analysis. Clin Infect Dis. 2012;54:1774–7. https://doi.org/10.1093/cid/cis290.
Soares JR, Nunes MC, Leite AF, Falqueto EB, Lacerda BE, Ferrari TC. Reversible dilated cardiomyopathy associated with amphotericin B therapy. J Clin Pharm Ther. 2015;40:333–5. https://doi.org/10.1111/jcpt.12237.
Stine JG, Sateesh P, Lewis JH. Drug-induced liver injury in the elderly. Curr Gastroenterol Rep. 2013;15:299. https://doi.org/10.1007/s11894-012-0299-8.
Hosford JD, von Fricken ME, Lauzardo M, Chang M, Dai Y, Lyon JA, Shuster J, Fennelly KP. Hepatotoxicity from antituberculous therapy in the elderly: a systematic review. Tuberculosis (Edinb). 2015;95:112–22. https://doi.org/10.1016/j.tube.2014.10.006.
Kass JS, Shandera WX. Nervous system effects of antituberculosis therapy. CNS Drugs. 2010;24:655–67. https://doi.org/10.2165/11534340-000000000-00000.
Drew WL, Buhles W, Erlich KS. Herpesvirus infections (cytomegalovirus, herpes simplex virus, varicella-zoster virus). How to use ganciclovir (DHPG) and acyclovir. Infect Dis Clin N Am. 1988;2:495–509.
US FDA. Zovirax (Aciclovyr) [package insert]. www.accessdata.fda.gov/drugsatfda_docs/label/2005/018828s030,020089s019,019909s020lbl.pdf. Accessed 1 Sep 2022.
Brandariz-Nuñez D, Correas-Sanahuja M, Maya-Gallego S, Martín Herranz I. Neurotoxicity associated with acyclovir and valacyclovir: a systematic review of cases. 2021;46:918–26. https://doi.org/10.1111/jcpt.13464
US FDA. Ganciclovir (Ganciclovir) [package insert]. www.accessdata.fda.gov/drugsatfda_docs/label/2017/209347lbl.pdf. Accessed 1 Sep 2022.
US FDA. Remdesivir (Veklury) [package insert]. www.accessdata.fda.gov/drugsatfda_docs/label/2020/214787Orig1s000lbl.pdf. Accessed 1 Sep 2022.
European Medicines Agency. Molnupiravir (Lagevrio) [package insert]. www.ema.europa.eu/en/documents/referral/lagevrio-also-known-molnupiravir-mk-4482-covid-19-article-53-procedure-conditions-use-conditions_en.pdf. Accessed 1 Sep 2022.
US FDA. Foscarnet (Foscavir) [package insert]. www.accessdata.fda.gov/drugsatfda_docs/label/2012/020068s018lbl.pdf. Accessed 1 Sep 2022.
US FDA. Oseltamivir (Tamiflu) [package insert]. www.accessdata.fda.gov/drugsatfda_docs/label/2011/021087s057lbl.pdf. Accessed 1 Sep 2022.
Electronic Medicines Compendium. Zanamivir (Ralenza) [package insert]. www.medicines.org.uk/emc/product/3809/smpc. Accessed 1 Sep 2022.
Sleijfer S, Bannink M, Van Gool AR, Kruit WH, Stoter G. Side effects of interferon-alpha therapy. Pharm World Sci. 2005;27:423–31. https://doi.org/10.1007/s11096-005-1319-7.
Li L, Wang X, Wang R, Hu Y, Jiang S, Lu X. Antiviral Agent therapy optimization in special populations of COVID-19 patients. Drug Des Devel Ther. 2020;14:3001–13. https://doi.org/10.2147/dddt.S259058.
Jourjy J, Dahl K, Huesgen E. Antiretroviral treatment efficacy and safety in older HIV-infected adults. Pharmacotherapy. 2015;35:1140–51. https://doi.org/10.1002/phar.1670.
Kayaaslan B, Guner R. Adverse effects of oral antiviral therapy in chronic hepatitis B. World J Hepatol. 2017;9:227–41. https://doi.org/10.4254/wjh.v9.i5.227.
Benedicto AM, Fuster-Martínez I, Tosca J, Esplugues JV, Blas-García A, Apostolova N. NNRTI and liver damage: evidence of their association and the mechanisms involved. Cells. 2021. https://doi.org/10.3390/cells10071687.
US FDA. Epavirenz (Sustiva) [package insert]. www.accessdata.fda.gov/drugsatfda_docs/label/2011/020972s038lbl.pdf. Accessed 1 Sep 2022.
Tsiodras S, Perelas A, Wanke C, Mantzoros CS. The HIV-1/HAART associated metabolic syndrome—novel adipokines, molecular associations and therapeutic implications. J Infect. 2010;61:101–13. https://doi.org/10.1016/j.jinf.2010.06.002.
US FDA. Ritonavir (Norvir) [package insert]. www.accessdata.fda.gov/drugsatfda_docs/label/2017/209512lbl.pdf. Accessed 1 Sep 2022.
Cantón R, Akova M, Langfeld K, Torumkuney D. Relevance of the consensus principles for appropriate antibiotic prescribing in 2022. J Antimicrob Chemother. 2022;77:i2–9. https://doi.org/10.1093/jac/dkac211.
Chandrasekhar D, Manaparambil H, Parambil JC. Outcome assessment of intervention on appropriateness of antibiotic use among geriatric patients: a prospective interventional study from a tertiary care referral hospital. Clin Epidemiol Global Health. 2019;7:536–41. https://doi.org/10.1016/j.cegh.2018.12.005.
Cantudo-Cuenca MR, Jimenez-Morales A, Martínez-de la Plata JE. Pharmacist-driven antimicrobial stewardship program in a long-term care facility by assessment of appropriateness. Sci Rep. 2021;11:18884–18884. https://doi.org/10.1038/s41598-021-98431-9.
Kadri SS, Lai YL, Warner S, Strich JR, Babiker A, Ricotta EE, et al. Inappropriate empirical antibiotic therapy for bloodstream infections based on discordant in-vitro susceptibilities: a retrospective cohort analysis of prevalence, predictors, and mortality risk in US hospitals. Lancet Infect Dis. 2021;21:241–51. https://doi.org/10.1016/s1473-3099(20)30477-1.
Loeb M, Simor AE, Landry L, Walter S, McArthur M, Duffy J, et al. Antibiotic use in Ontario facilities that provide chronic care. J Gen Intern Med. 2001;16:376–83. https://doi.org/10.1046/j.1525-1497.2001.016006376.x.
Magill SS, O’Leary E, Ray SM, Kainer MA, Evans C, Bamberg WM, et al. Assessment of the appropriateness of antimicrobial use in US hospitals. JAMA Netw Open. 2021;4: e212007. https://doi.org/10.1001/jamanetworkopen.2021.2007.
Rutten JJS, van Buul LW, Smalbrugge M, Geerlings SE, Gerritsen DL, Natsch S, et al. An electronic health record integrated decision tool and supportive interventions to improve antibiotic prescribing for urinary tract infections in nursing homes: a cluster randomized controlled trial. J Am Med Dir Assoc. 2022;23:387–93. https://doi.org/10.1016/j.jamda.2021.11.010.
Saatchi A, Reid JN, Povitz M, Shariff SZ, Silverman M, Morris AM, et al. Appropriateness of outpatient antibiotic use in seniors across two Canadian provinces. Antibiotics (Basel, Switzerland). 2021;10:1484. https://doi.org/10.3390/antibiotics10121484.
Tobia CC, Aspinall SL, Good CB, Fine MJ, Hanlon JT. Appropriateness of antibiotic prescribing in veterans with community-acquired pneumonia, sinusitis, or acute exacerbations of chronic bronchitis: a cross-sectional study. Clin Ther. 2008;30:1135–44. https://doi.org/10.1016/j.clinthera.2008.06.009.
van Buul LW, Veenhuizen RB, Achterberg WP, Schellevis FG, Essink RT, de Greeff SC, et al. Antibiotic prescribing in Dutch nursing homes: how appropriate is it? J Am Med Dir Assoc. 2015;16:229–37. https://doi.org/10.1016/j.jamda.2014.10.003.
Vergidis P, Hamer DH, Meydani SN, Dallal GE, Barlam TF. Patterns of antimicrobial use for respiratory tract infections in older residents of long-term care facilities. J Am Geriatr Soc. 2011;59:1093–8. https://doi.org/10.1111/j.1532-5415.2011.03406.x.
Nguyen-Hoang N, Bui QTH. Assessing the appropriateness of antimicrobial therapy in patients with sepsis at a Vietnamese national hospital. JAC-Antimicrobial Resistance. 2021;3: dlab048. https://doi.org/10.1093/jacamr/dlab048.
Núñez-Núñez M, Perez-Galera S, Girón-Ortega JA, Sandoval Fernández-Del-Castillo S, Beltrán-García M, De Cueto M, et al. Predictors of inappropriate antimicrobial prescription: eight-year point prevalence surveys experience in a third level hospital in Spain. Front Pharmacol. 2022;13:1018158. https://doi.org/10.3389/fphar.2022.1018158.
Uribe-Cano D, Bahranian M, Jolles SA, Taylor LN, Miller JJ, Adibhatla SN, Crnich CJ. Comparison of criteria for determining appropriateness of antibiotic prescribing in nursing homes. Infect Control Hosp Epidemiol. 2022;43:860–3. https://doi.org/10.1017/ice.2021.221.
Tarrant C, Krockow EM, Nakkawita WMID, Bolscher M, Colman AM, Chattoe-Brown E, Perera N, Mehtar S, Jenkins DR. Moral and contextual dimensions of “inappropriate” antibiotic prescribing in secondary care: a three-country interview study. 2020. https://doi.org/10.3389/fsoc.2020.00007.
Hung Y-P, Chen P-L, Ho C-Y, Hsieh C-C, Lee C-H, Lee C-C, Ko W-C. Prognostic effects of inappropriate empirical antimicrobial therapy in adults with community-onset bacteremia: age matters. 2022. https://doi.org/10.3389/fmed.2022.861032.
Zhu F, Li C, Chu F, Tian X, Zhu J. Target dysbiosis of gut microbes as a future therapeutic manipulation in Alzheimer’s disease. Front Aging Neurosci. 2020;12: 544235. https://doi.org/10.3389/fnagi.2020.544235.
Pouwels KB, Hopkins S, Llewelyn MJ, Walker AS, McNulty CA, Robotham JV. Duration of antibiotic treatment for common infections in English primary care: cross sectional analysis and comparison with guidelines. BMJ. 2019;364: l440. https://doi.org/10.1136/bmj.l440.
Xiao B, Wang M, Hu X, Li J, Wang F, Sun J. Antibiotic de-escalation principle in elderly patients with chronic obstructive pulmonary disease complicated with severe pneumonia. Exp Ther Med. 2017;13:1485–9. https://doi.org/10.3892/etm.2017.4135.
Kim YJ, Park KH, Park DA, Park J, Bang BW, Lee SS, et al. Guideline for the antibiotic use in acute gastroenteritis. Infect Chemotherapy. 2019;51:217–43. https://doi.org/10.3947/ic.2019.51.2.217.
Helde-Frankling M, Bergqvist J, Bergman P, Björkhem-Bergman L. Antibiotic treatment in end-of-life cancer patients-a retrospective observational study at a palliative care center in Sweden. Cancers (Basel). 2016. https://doi.org/10.3390/cancers8090084.
Rodriguez-Mañas L. Urinary tract infections in the elderly: a review of disease characteristics and current treatment options. Drugs Context. 2020. https://doi.org/10.7573/dic.2020-4-13.
van Heijl I, Schweitzer VA, Zhang L, van der Linden PD, van Werkhoven CH, Postma DF. Inappropriate use of antimicrobials for lower respiratory tract infections in elderly patients: patient- and community-related implications and possible interventions. Drugs Aging. 2018;35:389–98. https://doi.org/10.1007/s40266-018-0541-7.
Bennett NJ, Imam N, Ingram RJ, James RS, Buising KL, Bull AL, Chen CS, Thursky KA, Worth LJ. Skin and soft tissue infections and current antimicrobial prescribing practices in Australian aged care residents. Epidemiol Infect. 2019;147:e87–e87. https://doi.org/10.1017/S0950268819000128.
Majumder MAA, Rahman S, Cohall D, Bharatha A, Singh K, Haque M, Gittens-St Hilaire M. Antimicrobial stewardship: fighting antimicrobial resistance and protecting global public health. Infect Drug Resist. 2020;13:4713–38. https://doi.org/10.2147/idr.S290835.
Elango D. General Principles of Antimicrobial Therapy. In: Paul A, Anandabaskar N, Mathaiyan J, Raj GM (eds). Introduction to Basics of Pharmacology and Toxicology. Vol 2. Essentials of Systemic Pharmacology: From Principles to Practice. Singapore: Springer Nature Singapore; 2021. pp. 795-806. https://doi.org/10.1007/978-981-33-6009-9.
Melander RJ, Zurawski DV, Melander C. Narrow-spectrum antibacterial agents. MedChemComm. 2018;9:12–21. https://doi.org/10.1039/C7MD00528H.
Raineri E, Crema L, Dal Zoppo S, Acquarolo A, Pan A, Carnevale G, Albertario F, Candiani A. Rotation of antimicrobial therapy in the intensive care unit: impact on incidence of ventilator-associated pneumonia caused by antibiotic-resistant Gram-negative bacteria. Eur J Clin Microbiol Infect Dis. 2010;29:1015–24. https://doi.org/10.1007/s10096-010-0964-5.
De Waele JJ, Schouten J, Beovic B, Tabah A, Leone M. Antimicrobial de-escalation as part of antimicrobial stewardship in intensive care: no simple answers to simple questions-a viewpoint of experts. Intensive Care Med. 2020;46:236–44. https://doi.org/10.1007/s00134-019-05871-z.
Wu JH, Langford BJ, Daneman N, Friedrich JO, Garber G. Antimicrobial stewardship programs in long-term care settings: a meta-analysis and systematic review. J Am Geriatr Soc. 2019;67:392–9. https://doi.org/10.1111/jgs.15675.
Zimmerman S, Sloane PD, Bertrand R, Olsho LE, Beeber A, Kistler C, Hadden L, Edwards A, Weber DJ, Mitchell CM. Successfully reducing antibiotic prescribing in nursing homes. J Am Geriatr Soc. 2014;62:907–12. https://doi.org/10.1111/jgs.12784.
US FDA. Amoxicillin/clavulanate (Augmentin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/050564s053s055,050575s040s042,050597s047s049,050720s026s028,050725s028s030,050726s022s024lbl.pdf. Accessed 15 Feb 2023.
US FDA. Cefazolin (Ancef) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/50461slr139_ancef_lbl.pdf. Accessed 15 Feb 2023.
US FDA. Cefepime (Maxipime) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/050679s036lbl.pdf. Accessed 15 Feb 2023.
US FDA. Cefotaxime (Claforan) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/050547s071,050596s042lbl.pdf. Accessed 15 Feb 2023.
US FDA. Cefoxitin (Mefoxin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/050517s047lbl.pdf. Accessed 15 Feb 2023.
US FDA. Ceftazidime (Fortaz) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/050578s062lbl.pdf. Accessed 15 Feb 2023.
US FDA. Ceftriaxone (Rocephin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/0550585s063lbl.pdf. Accessed 15 Feb 2023.
US FDA. Cefuroxime (Ceftin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/050605s042lbl.pdf. Accessed 15 Feb 2023.
US FDA. Cefuroxime (Zinacef) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2001/50643s11lbl.pdf. Accessed 15 Feb 2023.
US FDA. Cephalexin (Keflex) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/050405s097lbl.pdf. Accessed 15 Feb 2023.
US FDA. Clindamycin hidrochloride (Cleocine) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/050162s092s093lbl.pdf. Accessed 15 Feb 2023.
US FDA. Clindamycin (Cleocin Phosphate) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050441s055,050639s016lbl.pdf. Accessed 15 Feb 2023.
US FDA. Daptomycin (Cubicin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208385s005lbl.pdf. Accesseed 15 Feb 2023.
US FDA. Ertapenem (Invanz) [package insert. https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021337s019lbl.pdf. Accessed 15 Feb 2023.
US FDA. Imipenem and cilastatin (Primaxin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/050587s074lbl.pdf. Accessed 15 Feb 2023.
US FDA. Isoniazid (Isoniazid) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/008678s028lbl.pdf. Accessed 15 Feb 2023.
US FDA. Meropenem (Merrem) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/050706s037lbl.pdf. Accessed 15 Feb 2023.
US FDA. Piperacillin/Tazobactam (Zosyn) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/050684s88s89s90_050750s37s38s39lbl.pdf. Accessed 15 Feb 2023.
US FDA. Nitrofurantoin (nitrofurantoin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020064s019lbl.pdf. Accessed 15 Feb 2023.
US FDA. Oxacillin (oxacillin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/050640s017lbl.pdf. Accessed 15 Feb 2023.
US FDA. Ticarcillin (Timentin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/050590s069,050658s031lbl.pdf. Accessed 15 Feb 2023.
US FDA. Vancomycin (Vancocin) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/050606s028lbl.pdf. Accessed 15 Feb 2023.
US FDA. Vancomycin hydrochloride (Vancocin HCL) [package insert]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/060180s047lbl.pdf. Accessed 15 Feb 2023.
Marriott DJE, Cattaneo D. Special issue on the therapeutic drug monitoring of anti-infective drugs: editorial. Ther Drug Monit. 2022;44:1–2. https://doi.org/10.1097/ftd.0000000000000951.
Crnich CJ, Jump R, Trautner B, Sloane PD, Mody L. Optimizing antibiotic stewardship in nursing homes: a narrative review and recommendations for improvement. Drugs Aging. 2015;32:699–716. https://doi.org/10.1007/s40266-015-0292-7.
Mandelli G, Dore F, Langer M, Garbero E, Alagna L, Bianchin A, et al. Effectiveness of a multifaced antibiotic stewardship program: a pre-post study in seven Italian ICUs. J Clin Med. 2022. https://doi.org/10.3390/jcm11154409.
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Soraci, L., Cherubini, A., Paoletti, L. et al. Safety and Tolerability of Antimicrobial Agents in the Older Patient. Drugs Aging 40, 499–526 (2023). https://doi.org/10.1007/s40266-023-01019-3
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DOI: https://doi.org/10.1007/s40266-023-01019-3