Different factors lead to alterations in the way infectious diseases present themselves in the elderly. These patients are normally afflicted with reduced integrity of physical barriers like the skin or the connective tissue. Immunosuppression is also frequent, and the general immune response to face new infections is of little effect7. As people age, immunosenescence increases the risk of morbimortality following infectious diseases6, due to alterations in cell function and systemic cytokine levels which negatively affect the immune system8. This all leads to nonspecific symptoms such as general disorientation, fatigue, falls or loss of weight, making it difficult to diagnose infections. This atypical presentation of disease has been recently associated with increased mortality9.

In the context of ageing, the pK/pD behavior of antibiotics is mostly affected by kidney function deterioration and patient frailty4. The main alterations take place in each of the pharmacokinetic (pK) stages of the drugs for the reasons described below.

Absorption: In the elderly, gastric depletion and motility are usually decreased, as is gastrointestinal blood flow, and the digestive pH suffers alterations10. This alters drug absorption, thus affecting antibiotic bioavailability. The incidence of achlorhydria in geriatric patients is high, reducing bioavailability levels of different antimicrobial agents11. Lower drug availability is made worse by the frequent use of acidity suppressants or calcium salts12. In addition, the decreased function of intestinal transporter glycoprotein-P can affect the bioavailability of some antibiotics10.

Distribution: Ageing increases the body's content in fat and reduces body water4,6. Drugs that are soluble in fat, such as rifampicin, quinolones, macrolides, oxazolidinones, tetracyclines, amphotericin B and most imidazole antifungals, have their half-life extended due to an increased volume of distribution (Vd). In some chronic pathologies, like chronic heart failure or ascites due to cirrhosis of the liver, the amount of water in the body is increased, favoring the distribution of hydrophilic drugs like aminoglycosides, beta-lactam antibiotics and glycopeptides13. Loading doses of hydrophilic antibiotics are recommended in cases of severe infection in patients with increased body water13.

Variations in plasma protein levels in geriatric patients also affect drug distribution. Malnutrition and decreased albumin can also increase the free fraction of antibiotics13, which is especially important in drugs with high plasma protein binding (PPB) rates, such as ceftriaxone14. In contrast, the elderly usually exhibit higher concentrations of alpha-1-acid glycoprotein, which reduces the free fraction of basic antimicrobials like macrolides.

Metabolism: Older patients have a decreased blood flow and lower metabolic rates in the liver, which can increase the half-life of hepatically metabolized drugs15. Such is the case with macrolides, quinolones, antifungals and azoles, whose hepatic extraction fractions are high10,15.

The metabolic activity of the liver depends on phase 1 and 2 metabolizing enzymes. As regards phase 1 enzymes, cytochrome P450 oxidases are decreased in older people, causing a slower metabolization rate of drugs that are CYP3A4 substrates16. However, phase 2 enzymes, such as transferases, are well preserved in the elderly, thus guaranteeing the biotransformation of drugs in the body, although it has been suggested that frailty may decrease phase 2 metabolism18.

Elimination: Clearance of antimicrobial agents is lower in geriatric patients because of the reduced excretory function of the lungs or the gastrointestinal system, although kidney function is the mainly affected one in this respect19. Comorbidities like high blood pressure, diabetes or cardiovascular disorders can aggravate kidney failure20.

An impaired kidney function increases serum concentrations of drugs, creating a higher risk of toxicity from hydrophilic antibiotics, which are mostly excreted through the kidney4. When using antibiotics that have limited therapeutic margins or are dosed by body weight, it is very important to adjust the dosing with great precision, especially in the case of hydrophilic agents.

Different formulas are available to estimate renal clearance. The most widely used of these is the equation of Cockroft and Gault, who in 1976 had already shown that a linear inverse correlation existed between kidney function and age21. The Cockroft-Gault equation is the recommended formula in geriatric populations, together with the CKD-EPI equation, which was validated in 200922.

The skin of older patients is thinner and more susceptible to bruising. This, together with the highly prevalent use of anticoagulants in geriatric populations, can complicate the safe placement of endovenous catheters in these patients23. Nonetheless, parenteral administration is widely used in extreme situations in which the patient's life is at risk6.

Intramuscular delivery is an alternative to endovenous administration, but it is not the method of choice in geriatric patients since it causes pain and is associated with a high risk of bruising. Because of this, subcutaneous administration is another parenteral approach that is widely used in geriatrics24. This form of delivery has a lower risk of causing thrombosis and catheter related infections25. The subcutaneous approach, which is not contraindicated in decoagulated patients24 and is less painful than intramuscular administration, is of greater comfort and convenience to geriatric patients and may be used at home.

Following subcutaneous delivery, the drug must diffuse into the intravascular space, a step that reduces maximum concentration and delays maximum time as compared to endovenous delivery, although the area under the curve is usually similar. The subcutaneous route prolongs exposure to the drug, thereby optimizing the pK/pD parameters of time-dependent antibiotics like beta-lactam agents. Therefore, the most frequently used subcutaneous drugs are: ceftriaxone, cefepime, ceftazidime, ertapenem and –among glycopeptides– teicoplanin. Subcutaneous administration is not recommended for concentration-dependent antimicrobials like aminoglycosides or quinolones24.

Disadvantages of subcutaneous delivery include the potential for causing edema or swelling, although these effects are infrequent (< 5%). Even so, it is not the approach of choice in emergency settings, since it does not allow for the administration of hyperosmolar solutions, and drug absorption depends on factors like perfusion and vascularization. Finally, it is not indicated in the presence of malnutrition or cachexia, which limits its use in geriatrics24,26,27.

It should be added, in the case of oral administration, that dysphagia can impede drug delivery28. This may be addressed by using pharmaceutical solutions or suspensions. Pharmacists can recommend the most appropriate form of preparation in the geriatric population, especially in patients who bear (naso)gastric tubes.

Age-related pK changes increase the risk of adverse effects associated with polypharmacy29. In addition, some antibiotics may be directly associated with severe adverse effects in the geriatric population, especially when underlying conditions or interactions exist5,30. A clear example of this is the presence of cardiovascular disease, which makes older people more vulnerable to the adverse effects of some antibiotics, like macrolides, that increase coronary-related mortality, while agents like quinolones prolong the QT interval and are associated with a higher risk of arrhythmia and a higher incidence of aortic aneurysms. The same family of drugs has been linked to increased levels of creatine kinase, having the potential for causing muscle toxicity in geriatric populations31.

These populations are especially susceptible to Clostridioides difficile infection32.

The efficacy of an antibiotic may be impaired because of concomitant administration of other drugs14. Proton pump inhibitors or histamine type 2 receptor antagonists reduce stomach acidity and interfere with the proper absorption of some antimicrobials like rilpivirine or posaconazole33. Most pharmacological interactions, however, take place through cytochrome P45034.

Frail geriatric patients are polymedicated and this increases their risk of adverse effects and pharmacological interactions35 in situations requiring, for example, the concomitant prescription of macrolides and statins, which can cause rhabdomyolysis and acute kidney damage36. A higher risk of hospitalization for digitalis intoxication has also been reported in patients treated with digoxin and macrolides, and to a lesser extent with azithromycin37. In the case of patients treated with ACE inhibitors or ARBs, potassium levels must be monitored when administering cotrimoxazole, since there is a greater risk of hyperpotassemia38. Severe hypoglycemic episodes are also frequent in older patients when certain macrolides and quinolones are administered together with sulphonylureas39. Finally, the prescription of antibiotics like ciprofloxacin or cotrimoxazole together with anticoagulant vitamin K antagonists can cause severe bleeding in elderly patients40.

There are few studies on the use of the newly available antimicrobial agents (ceftazidime-avibactam, ceftolozane/tazobactam, meropenem/vaborbactam or isavuconazole) in geriatric patients. However, isolated cases of patients treated with these antimicrobials have been described. Coinfections with carbapenemase producing Klebsiella pneumoniae and the SARS-CoV-2 virus worsen the prognosis, especially in older patients, with high mortality rates in spite of the use of ceftazidimine-avibactam41. In contrast, a single case of a geriatric patient suffering from meningitis who was successfully treated with this antibiotic has been reported42.

Given its antimicrobial spectrum and its safety and efficacy profile, ceftolozane/tazobactam has been proposed as an alternative in geriatric patients with skin and soft tissue infections or osteomyelitis43. Although only 11% of patients in the pivotal ceftolozane/tazobactam studies were older than 75, a higher incidence of adverse effects was noted, and correct dose adjustment in accordance with the patient's kidney function is recommended44,45.

In the case of the new antifungal agents, a phase 1 trial has been carried out to determine the pharmacokinetic profile of isavuconazole after a single oral dose in 48 healthy individuals, of which 24 were over 65 years of age. The study concluded that dose adjustment for age or sex is not required46.

Infections are one of the leading causes of morbimortality in intensive care units (ICUs), with mortality rates in excess of 50%47. An estimated 51% of patients admitted to ICUs present active infection, while 71% receive antimicrobial treatment, at a cost accounting for up to 40% of total ICU expenditure47.

ICU infections are usually the result or the consequence of the patient's critical illness48. This population is particularly vulnerable to infection because of the disruption of the physical barriers of the body (invasive devices, surgery, trauma, etc.) and the alterations in both the innate and adaptative immune systems. As a result, these patients present with exacerbated inflammation, hyporesponsiveness and/or circulating neutrophils with decreased chemotaxis48,49. Such imbalanced inflammatory and adaptative responses lead to tissue damage, sepsis, Acute Respiratory Distress Syndrome (ARDS) and/or multiorgan failure50.

It should be noted that certain drugs commonly used in ICUs are associated with complications such as pneumonia infection followed by the reduction of cough and swallowing reflexes derived from neuromuscular blockade and sedoanalgesia51.

Of the pathogens isolated in critical care units, 67% are gram-negative microorganisms, while 37% and 16% are gram-positive microbes and fungi, respectively52.

Nosocomial infections are diagnosed in up to 32% of ICU patients and lead to a significant increase in mortality rates, especially in the presence of multi-resistant and extremely resistant microorganisms (MDRs/XDRs)53 whose presence is mainly due to inappropriate use of antimicrobials, severity of illness, the insertion of central venous catheters and prolonged periods of hospitalisation54.

The main barriers to adequate therapeutic management of infections in the adult ICU population are described in Table 2.

The use of nebulized antimicrobials maximizes drug concentration levels in the airways and the parenchyma of the lungs while minimizing systemic exposure and toxicity107. The effectiveness of inhaled antimicrobials correlates with the amount of drug deposited in the lungs, which in turn depends on three main parameters: airway anatomy, patient ventilation and characteristics of drug delivery aerosols108. The characteristics of the inhaled aerosol particles are the most easily adjustable factor and the one with greatest impact on the amount of drug that deposited in the airways and the parenchyma of the lungs. A nebulized drug that penetrates the alveolidense peripheral regions of the lungs with an efficacy of 90% should be made up of particles whose mass median aerodynamic diameter (MMAD) is between 1 and 5 µm in size109.

Nebulized antimicrobial treatment can be of use in different clinical scenarios, such as maintenance treatment to prevent respiratory exacerbations in patients with bronchiectasis (with or without cystic fibrosis) or patients with different respiratory infections like ventilator-associated pneumonia (VAP)108. However, the effectiveness of nebulized antibiotics in the treatment of mechanical VAP continues to be controversial. The 2016 clinical guide of the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS) puts forward the weak recommendation (based on very poor quality evidence) that VAP caused by gram-negative bacilli, which are only sensitive to aminoglycosides or polymyxins, should be treated with both nebulized and systemic antibiotics110. Subsequently, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) suggested the avoidance of nebulized treatment in these cases because of the poor quality of the evidence111. Finally, a meta-analysis including two new clinical trials in addition to the nine studies in the IDSA/ATS 2016 clinical guidelines suggested a benefit from nebulized antibiotics in the complementary treatment of VAP112. This benefit is mainly observed in infections caused by multi-resistant gram-negative bacilli with few therapeutic options.

The most important data on nebulized antimicrobial agents are described below.

An essential strategy in personalizing antimicrobial therapy consists in developing pK/pD models. Optimization of antimicrobial treatment requires knowledge of the pK/pD behavior of drugs following the administration of a given dose. The inherent variability of life (intraindividual, interindividual, in LADME processes and in terms of efficacy and/or toxicity regarding results) makes such optimization difficult. Measuring this variability, as well as identifying and quantifying the different factors that contribute to it, will help in the task of optimizing dosing regimens with adequate precision129,130.

Antibiotic therapy and population models. Studies of pK/pD in different populations make it possible to: (i) quantify pK parameter alterations of a drug in a given group of patients and determine intra- and interindividual variability; (ii) individualize/optimize dosing regimens on the basis of administered doses and blood concentration levels of the drug and population pK parameters; (iii) make recommendations on how to estimate optimal initial doses using clinical variables that are easily available at no further cost130,131.

The goal is to reach biophase concentration levels of the antibiotic that can eradicate the microorganism without causing toxic effects. The use, in clinical practice, of mathematical-statistical models based on pK/pD concepts makes it easier to predict therapeutic results and to design optimal dosing regimens131.

The information provided by the pK/pD population models is the basis for individualization after dosing. Knowledge of the drug's individual pK parameters (and individual concentration-time profiles) is required in order to relate them to the pharmacodynamic value associated to effect and toxicity. In the case of antimicrobials, the most widely accepted pD variable is the drug's MIC for the microorganism that is causing the infection.

The creation in antibiotic therapy of population pK/pD models for a given patient population provides information about the individuals included in the study and makes it possible to extrapolate to new patients within the same population in real time, using optimized initial and maintenance doses on the basis of the previously described pK/pD values.

The inclusion of covariables in the model allows for refinement and optimization of dosing regimens in special situations, such as: kidney failure, extreme old age, biochemical alterations, etc.132,133. The model also incorporates pK/pD process variability at different levels134,135.

These models are clearly an ideal tool for application and use in patient populations that are not included in clinical trials and for whom information on antimicrobial dosing and side effects may be contradictory, limited or even unknown. The models, however, can never serve as replacements for clinical trials in patients.

Table 4 shows the main advantages and drawbacks of pK/pD models134,135.

Population modelling. The application of pK in clinical practice requires the definition of specific mathematical-statistical models describing the evolution of drug concentrations over time. Such models are defined by mathematical equations that include the pK parameters associated with the drug's characteristic behavior and make it possible to predict what the concentration-time values will be following the administration of known doses of a given drug136.

The most common methods currently employed for estimating pK parameters can be divided into two main groups: (i) individual pK estimation methods and (ii) population pK estimation methods. The former ones assess the pK of a drug in an individual without considering the variability of pK parameters of other individuals. The latter aim at identifying and quantifying drug concentration variability among individuals belonging to a given population after receiving standard doses of a drug136.

Individualization of antibiotic dosing regimens is a good example of personalized therapy. Therapeutic monitoring of drug's blood concentration levels following a known dose of the antimicrobial agent is the tool employed to this end. PK monitoring, which is highly advisable in clinical practice, requires certain indispensable data for interpretation purposes (Table 5). After obtaining blood samples of an antimicrobial agent following the administration of a known dose of the drug, individual pK parameters (profile of concentration-time values) can be estimated, and the ideal pK/pD relationship for the antimicrobial type or family can be defined. This information is the basis for dosing regimen optimization. The calculation is performed using nonlinear regression mathematical-statistical analysis and the Bayesian method, since it is possible to estimate individual pK parameters on the basis of information regarding the drug's pK behavior within a given population (a priori data). Integration of populational pK data and local or regional MIC values for a given microorganism or antibiotic makes it possible to evaluate, by means of Monte Carlo simulations, the model's predictive capacity in terms of optimizing the pK/pD values of different dosing regimens of the antibiotic. These approaches help to make recommendations regarding initial antimicrobial dosing regimens, with a view to optimizing therapy from the very beginning of the treatment period on the basis of the covariables that have an influence on its variability.

PK models with the new antimicrobial agents. In the case of the new antibiotics, there is one study in patients with cystic fibrosis (CF) and infectious exacerbations caused by P. aeruginosa138. In this populational pK/pD model, the study's authors showed that the plasma clearance of ceftolozane/tazobactam was comparable to that of adult patients without CF. In contrast, a decreased central Vd was observed in patients with CF. On the basis of these data, the probability of reaching the therapeutic goal (fT>MIC: 60%) was assessed using Monte Carlo simulations, suggesting that a dose of 1.5 g/8 h, infused for 60 minutes, would reach the therapeutic target in 39%, 60% and 100% of cases for MIC values of 8, 4 and 2 mg/L, respectively. It was also shown that for a dose of 3 g/8 h, these same percentages optimized the therapeutic goal for MIC values of 16, 8 and 4 mg/L, respectively. These data will contribute to the optimization of dosing regimens in future CF patients.

Isavuconazole is a new antifungal for the treatment of invasive aspergillosis and mucormycosis. A pK population model was used to assess dose adjustment needs in patients with hepatic impairment139. The drug's clearance was found to decrease as a function of the degree of hepatic involvement, while the Vd was influenced by the patient's body mass index. These data made it possible to simulate the pK profiles of patients with varying degrees of hepatic impairment and to show that, in such patients, the average concentrations of isavuconazole in static balance exceed by less than twice the minimum concentration observed in healthy individuals, and that no side effects occur. In these conditions it was determined that isavuconazole did not require dose adjustment in patients with moderate liver failure.