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Geriatrics & Gerontology
Infections are important factors contributing to the morbidity and mortality among elderly patients. High rates of consumption of antimicrobial agents by the elderly may result in increased risk of toxic reactions, deteriorating functions of various organs and systems and leading to the prolongation of hospital stay, admission to the intensive care unit, disability, and lethal outcome. Both safety and efficacy of antibiotics are determined by the values of their plasma concentrations, widely affected by physiologic and pathologic age-related changes specific for the elderly population. Drug absorption, distribution, metabolism, and excretion are altered in different extents depending on functional and morphological changes in the cardiovascular system, gastrointestinal tract, liver, and kidneys. Water and fat content, skeletal muscle mass, nutritional status, use of concomitant drugs are other determinants of pharmacokinetics changes observed in the elderly. The choice of a proper dosing regimen is essential to provide effective and safe antibiotic therapy in terms of attainment of certain pharmacodynamic targets.
- elderly
- pharmacokinetics
- antibiotics
- dosing
- infections
1. Introduction
The global population aging in the 21st century is unprecedented. In the Western world persons over 65 years are the fastest growing cohort [1], which outnumbers the population of children below five years old and attracts the attention of researchers all over the world [2]. It is predicted that by 2100 in Europe people over 65 will make up 31% of the total population, and people over 80 will reach about 15% [3].
Age-related physiological and pathological changes, poor functional status, poor nutrition, and comorbidities predispose older adults to infections and their complications [4,5]. The incidence and severity of infections increase with advancing age [6,7]. Compared to younger age groups, elderly patients are more prone to pneumonia, skin and soft tissue infections, urinary tract infections and septicemia [1,4]. An additional problem is a substantial risk of antibiotic (AB) resistance; its typical risk factors in the elderly include frequent contact with the healthcare system, frequent AB exposure, depressed immune system, frailty, and comorbidity [4]. Elderly patients are considered the high-risk group for the development of healthcare-associated infections caused by multidrug-resistant (MDR) bacteria [8,9,10]. The elderly population has longer hospital stays compared to younger adults and a significantly higher mortality rate (25%) compared to the general population (10%) [6,11,12]. Infections aggravate the course of concomitant chronic diseases, including cardiovascular and cognitive disorders, and contribute to the emergence of a new comorbidity [13].
High infectious morbidity leads to high consumption of antimicrobial agents by the elderly. ABs are among the most frequently prescribed medicines to seniors [14,15,16] and their use is accompanied by a significant rate of side effects and clinically relevant drug-drug interactions compared to younger counterparts [14]. Adverse drug reactions (ADRs) are an important cause of morbidity and mortality in the elderly [17,18,19] and their risk is significantly increased in the presence of comorbidity and polypharmacy [19,20,21,22].
The choice of optimal antimicrobial agent for the elderly is challenging [23]. Finding the right balance between efficacy, safety and tolerability of antibiotics is difficult for several reasons including significant changes in body tissue composition, a progressive physiological decline of organ functions, frailty, comorbidity, and polypharmacy [24]. All these factors can cause significant alterations in antimicrobials pharmacokinetics (PK) and pharmacodynamics (PD) leading to altered efficacy, safety, and tolerance. The problem is compounded by the fact that elderly patients represent a heterogeneous group that should be treated individually [25,26].
2. Factors Influencing AB Prescribing in the Elderly
Infections in the elderly may be caused by a more diverse group of pathogens compared to the younger population [6,27,28]. For example, there is a higher prevalence of Gram-negative bacilli in pneumonia and a lower prevalence of E. coli in urinary tract infections [6].
Common infections do not manifest with classic symptoms in the elderly. Aged patients may have neither fever nor leukocytosis [29]. An absence of fever and a lack of respiratory symptoms has been described in 40–60% of elderly patients with community-acquired pneumonia [30]. The only clinical presentation of pneumonia in up to 20–50% of the elderly may be an altered mental status including delirium and confusion, a sudden decline in functional capacity, and worsening of underlying diseases [28]. The high prevalence of unusual and/or multidrug-resistant pathogens in the elderly makes AB susceptibility testing highly desirable, though in the real clinical practice, antibiotics may be prescribed empirically as even subtle clinical manifestations may herald the onset of life-threatening infectious disease and delayed therapy can worsen treatment outcomes [28].
Appropriate AB dosing requires knowledge of the pharmacokinetic and pharmacodynamic properties of AB which are often altered due to aging processes, including age- or disease-related decline of kidney and liver functions. To select an optimal AB for the concrete patient, it is necessary to identify all comorbidities, concomitant drugs, and dietary supplements, and collect the patient’s allergic history. Consideration should be given to the factors associated with poor treatment compliance such as poor vision and/or hearing, physical dexterity, cognitive impairment, or mental illness [21,31,32,33]. These patients require treatment supervision by relatives or caregivers.
Elderly patients are at high risk of potential harm associated both with missed treatment and excessive AB therapy [31,34]. In long-term care facilities 50–75% of residents receive at least one course of AB each year with 30–50% of AB prescriptions being unnecessary or inappropriate in terms of drug choice, dosing regimen and/or duration of treatment [35]. Inappropriate drug selection and use may lead to medication-related problems, including ADRs, therapy failure and withdrawal events alongside the spread of AB resistance [34,36].
Compared to younger counterparts, older patients are more vulnerable to AB side effects and clinically relevant consequences of drug interactions [14]. The risk of ADR development is especially high in patients with comorbidity and polypharmacy [19,20,21,22]. ADRs are an important cause of morbidity and mortality in elderly patients [17,18,19].
Increased risk of AB-induced toxicity, ADRs, and negative outcomes in elderly patients with infectious diseases may be mediated by the changed PK of AB resulting in the changed PD.
3. AB Dosing Regimens in the Elderly
The main aim of AB therapy in elderly patients is to provide a proper balance between efficacy (PK/PD target attainment) and safety. Changed PK parameters may lead both to decreased or increased AB exposure contributing to negative treatment outcomes. Dose adjustment is a typical approach in the management of the elderly with infections. Decreased metabolizing capacity and declined renal clearance result in the need to decrease the standard adult dose of AB, while ARC specific for critically ill patients may dictate the necessity to use a higher dose.
Table 1, Table 2, Table 3, Table 4 and Table 5 include information about the proposed regimens of AB dosing depending on age, renal function, and hepatic function along with data on concentrations reported to cause toxic reactions.
Table 1. Beta-lactam AB dosing depending on age, renal function, and hepatic impairment.
| Drug | Regimen for Patients with Different Renal Function |
PK/PD Target in the Elderly |
Regimen for Patients with Hepatic Impairment | Safety | References |
|---|---|---|---|---|---|
| Penicillin group | |||||
| Ampicillin/Sulbactam | mean age > 65 years: 2 g of ampicillin/ 1 g of sulbactam every 8 h (normal renal function) |
75–100 % T > MIC (MIC90 = 1 mg/L) |
NA | Transient low-level elevations of ALT or AST in serum indicating transient liver damage | [322,323] |
| mean age > 75 years: 1 g of ampicillin/ 0.5 g of sulbactam every 6 h (10 ≤ CLCR < 50 mL/min) |
40% T > MIC (MIC = 8 μg/mL) |
||||
| Piperacillin/Tazobactam | mean age 85 (82–87) years: 4.5 g every 24 h (CLCR 0–19 mL/min/1.73 m2) |
fCss/MIC ≥ 1 MIC ≤ 8 mg/L |
4.5 g every 4–6 h (loading dose) 4.5 g every 6 h (maintenance dose) |
Plasma concentration ≥ 157.2 μg/mL—risk of neurotoxicity | [324,325,326] |
| mean age 85 (82–87) years: 9 g every 24 h (CLCR 20–39 mL/min/1.73 m2) |
|||||
| mean age 85 (82–87) years: 11.25 g every 24 h (CLCR 40–59 mL/min/1.73 m2) |
|||||
| mean age 85 (82–87) years: 13.5 g every 24 h (CLCR 60–79 mL/min/1.73 m2) |
|||||
| Cephalosporins | |||||
| Cefepime | frail patients: 1 g every 12 h (CLCR = 30 mL/min) |
fT > 50% MIC (susceptible strains) |
1–2 g every 8–12 h (loading dose) 1–2 g every 8–12 h (maintenance dose) |
Plasma concentration ≥ 38.1 mg/L—risk of neurotoxicity | [325,327,328] |
| frail patients: 1 g every 8 h (CLCR 30–60 mL/min) |
|||||
| frail patients: 2 g every 8 h (normal renal function) |
fT > 80% MIC (susceptible strains) |
||||
| Ceftriaxone | mean age > 65 years: 1 g every 48 h (eGFRcys 10 mL/min/1.73 m2) [326] |
unbound fraction of ceftriaxone >MIC (MIC = 0.5–1 mg/L) [326] |
1–2 g every 12 h (loading dose) 1–2 g every 12 h (maintenance dose) [322] |
Plasma concentration ≥ 22 mg/L—risk of neurotoxicity and ceftriaxone-induced encephalopathy [327] |
[329,330] |
| mean age > 65 years: 2 g every 48 h (eGFRCR-cys 40 mL/min/1.73 m2) [326] |
|||||
| Ceftazidime/avibactam | age 66 years (clinical case): 0.94 g every 12 h (CLCR 30–40 mL/min) |
100% fT > 4 × MIC for ceftazidime 99% fT > 4 mg/L for avibactam (MIC = 1.5/4 mg/L) |
2.5 g every 8 h (loading dose) 2.5 g every 8 h (maintenance dose) |
Concentration in cerebrospinal fluid ≥ 9.4 mg/L—risk of neurotoxicity | [325,331,332] |
| Ceftobiprole | CLCR < 50 mL/min: 0.5 g as a 2-h intravenous infusion every 12 h |
30–40% T > MIC MIC = 2 mg/L |
NA | NA | [333] |
| CLCR < 30 mL/min: 0.25 g as a 2-h intravenous infusion every 12 h |
|||||
| Carbapenems | |||||
| Doripenem | mean age > 60 years, mean CLCR = 53.0 mL/min: 0.5 g every 8 h [258] |
40% fT > MIC (MIC = 2 μg/mL) [258] |
NA | NA | [258] |
| Ertapenem | mean age 73.1 ± 4.8 years: 1 g every 24 h (normal renal function) |
AUC0-24 746.1 ± 79.4 μg·h/mL at 1 day AUC0-24 681.9 ± 47.0 μg·h/mL at 7 day |
1 g every 12 h (loading dose) 1 g every 12 h (maintenance dose) |
Plasma concentration > 79.2 µg/mL—risk of neurotoxicity | [325,334,335] |
| Meropenem | mean age > 65 years, CLCR ≤ 50 mL/min: 1 g every 8 h; |
40% fT> MIC (MIC≤ 2–8 mg/L) |
2 g every 8 h (loading dose) 1 g every 8 h (maintenance dose) |
Plasma concentration ≥ 64.2 μg/mL—risk of neurotoxicity Cmin ≥ 44.45 μg/mL—risk of nephrotoxicity |
[259,336] |
| mean age > 65 years, CLCR > 100 mL/min: 2 g every 8 h |
40% T > MIC (MIC > 8 mg/L) |
||||
| Biapenem | mean age > 65 years: 0.3 g every 8 h |
40% T > MIC (MIC = 2 μg/mL) |
NA | NA | [337] |
ALT—Alanine transaminase; AST—Aspartate transaminase; AUC0-24—Area under the plasma concentration-time curve over the last 24-h dosing interval; CLCR—Creatinine clearance; Cmin—Minimum concentration; eGFRcys—Glomerular filtration rate estimated from cystatin C; MIC—Minimum inhibitory concentration; %T > MIC—Percent of time for total drug concentration remains above the minimum inhibitory concentration; fT > MIC—Percent of time for free drug concentration remains above the minimum inhibitory concentration; AUC—Area under curve; fCss > MIC—Free plasma steady-state concentration above the MIC.
Table 2. Aminoglycosides dosing depending on age, renal function, and hepatic impairment.
| Drug | Regimen for Patients with Different Renal Function |
PK/PD Target in the Elderly |
Regimen for Patients with Hepatic Impairment | Safety | References |
|---|---|---|---|---|---|
| Amikacin | mean age > 70 years: 1.8 g every 72 h (CLCR = 40–50 mL/min) 1.8 g every 48 h (CLCR = 60–90 mL/min) |
Cmax > MIC (MIC ≤ 8 mg/L) |
NA | Cmin > 4 μg/mL—risk of nephrotoxicity | [312] |
| Gentamicin | Geriatric population, CLCR > 60 mL/min: 3 mg/kg every 24 h |
Cmax > MIC (MIC = 1 μg/mL) |
NA | Cmin > 2 μg/mL—risk of nephrotoxicity | [338] |
CLCR—Creatinine clearance; Cmin—Minimum concentration; Cmax—Maximum concentration; MIC—Minimum inhibitory concentration.
Table 3. Glycopeptides and Lipopeptides dosing depending on age, renal function, and hepatic impairment.
| Drug | Regimen for Patients with Different Renal Function |
PK/PD Target in the Elderly |
Regimen for Patients with Hepatic Impairment | Safety | References |
|---|---|---|---|---|---|
| Glycopeptides | |||||
| Vancomycin | mean age ≥ 65 years: 1.0 g every 8 (CLCR > 50 mL/min) 1.0 g every 12 h (CLCR ≤ 50 mL/min) |
Cmin, ss > MIC |
NA | Cmin > 20 mg/L—risk of nephrotoxicity | [290] |
| Lipopeptides | |||||
| Daptomycin | eGFRcys = 20 mL/min: age 65 years: 600 mg (loading dose) 350 mg (maintenance dose) every 24 h age 75 years: 550 mg (loading dose) 300 mg (maintenance dose) every 24 h age 85 years: 500 mg (loading dose) 250 mg (maintenance dose) every 24 h age 95 years: 450 mg (loading dose) 200 mg (maintenance dose) every 24 h |
(fAUCss)/MIC ≥ 66.6 | NA | Risk of toxic reactions at Cmin > 24 mg/L and Cmax > 60 mg/L | [339,340] |
CLCR—Creatinine clearance; Cmin—Minimum concentration; Cmin, ss—Minimum plasma concentration at up to 24 h after administration; Cmax—Maximum concentration; eGFRcys—Glomerular filtration rate estimated from cystatin C; MIC—Minimum inhibitory concentration; (fAUCss)/MIC—Ratio of the area under the unbound concentration from 0 to 24 h at steady state time curve to the MIC.
Table 4. Fluoroquinolones dosing depending on age, renal function, and hepatic impairment.
| Drug | Regimen for Patients with Different Renal Function |
PK/PD Target in the Elderly |
Regimen for Patients with Hepatic Impairment | Safety | References |
|---|---|---|---|---|---|
| Levofloxacin | mean age 81 years: CLCR 0–19 mL/min: 125 mg every 48 h (MIC = 0.125 mg/L) 250 mg every 48 h (MIC = 0.25 mg/L) 500 mg every 48 h (MIC = 0.5 mg/L) CLCR 20–39 mL/min: 500 mg every 48 h (MIC = 0.125 mg/L) 500 mg every 48 h (MIC = 0.25 mg/L) 750 mg every 48 h (MIC = 0.5 mg/L) CLCR 40–59 mL/min: 500 mg every 48 h (MIC = 0.125 mg/L) 500 mg every 48 h (MIC = 0.25 mg/L) 500 mg every 24 h (MIC = 0.5 mg/L) CLCR 60–79 mL/min: 500 mg every 48 h (MIC = 0.125 mg/L) 750 mg every 48 h (MIC = 0.25 mg/L) 750 mg every 24 h (MIC = 0.5 mg/L) CLCR > 80 mL/min: 750 mg every 48 h (MIC = 0.125 mg/L) 750 mg every 24 h (MIC = 0.25 mg/L) 500 mg every 12 h (MIC = 0.5 mg/L) |
AUC0-24/MIC ratio (≥95.7) | NA | NA | [261] |
| Moxifloxacin | No age adjustment 400 mg every 24 h per os |
AUC0-24ss 46.67 µg·h/mL |
NA | NA | [341] |
CLCR—Creatinine clearance; MIC—Minimum inhibitory concentration; AUC0-24/MIC—Ratio of area under the concentration-time curve during a 24-h period to minimum inhibitory concentration; AUC0-24ss—Area under the baseline-corrected plasma concentration versus time curve from time 0 to 24 h at steady state.
Table 5. Linezolid and polymyxin B dosing depending on age, renal function, and hepatic impairment.
| Drug | Regimen for Patients with Different Renal Function |
PK/PD Target in the Elderly |
Regimen for Patients with Hepatic Impairment | Safety | References |
|---|---|---|---|---|---|
| Tedizolid | No age adjustment 200 mg every 24 h |
fAUC/MIC (MIC ≤0.5 μg/mL) |
NA | NA | [303] |
| Polymyxin B | Median age 68 years (IQR: 63–73), median CRCL 89 (IQR: 68–106) mL/min, bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae: 1.25 mg/kg every 12 h |
AUC0-24ss/MIC ≥ 54.4 | NA | Risks of nephrotoxicity (manifesations may vary from proteinuria to acute kidney injury) and neurotoxicity | [319,342] |
fAUC/MIC—The ratio of the area under the bound (unbound) concentration time curve to the MIC; MIC—Minimum inhibitory concentration; AUC0-24ss/MIC—Area under the baseline-corrected plasma concentration versus time curve from time 0 to 24 h at steady state.
This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11061633
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