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Vol. 45. Núm. S1.
Páginas 64-76 (diciembre 2021)
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Vol. 45. Núm. S1.
Páginas 64-76 (diciembre 2021)
REVIEW
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Personalized antimicrobial therapy in critical and elderly patients
Terapia antimicrobiana personalizada en pacientes críticos y en edad avanzada
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Santiago Grau1,6,
Autor para correspondencia
sgrau@psmar.cat

Author of correspondence Santiago Grau, Hospital del Mar, Passeig Marítim, 25-19, 08003 Barcelona. Spain
, Marta de Antonio-Cusco1, Sara Ortonobes-Roig2, Ibai Los-Arcos3,6, María Jesús Jiménez4, Dolors Soy5
1 Pharmacy Department, Hospital del Mar, Barcelona. Spain
2 Pharmacy Department, Corporació Sanitària Parc Taulí, Sabadell (Barcelona). Spain.
3 Department of Infectious Diseases, Hospital Vall d’ Hebron, Barcelona. Spain
4 Pharmacy Department, Hospital Universitario 12 de Octubre, Madrid. Spain
5 Pharmacy Department, Hospital Clínic, Barcelona. Spain.
6 Universitat Autònoma de Barcelona, Barcelona. Spain
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Tablas (5)
Table 1. Challenges of antimicrobial therapy in geriatric patients
Table 2. Challenges of antimicrobial therapy in critical care patients
Table 3. Individualization of new intensive care units antimicrobial therapies
Table 4. Advantages and inconvenients of pK/pD models
Table 5. pK monitoring in clinical practice137
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Abstract
Objective

Personalized therapy in the treatment of infections is essential to ensure optimization of antimicrobial drug levels. This strategy, together with an understanding of the activity of these drugs, decreases the risk of bacterial resistance and improves the drugs’ safety profile. Alternative routes of administration, such as inhalation, and the information provided by pharmacokinetic models, are essential given the limitation of antimicrobial activity allowed by the new antimicrobials.

Method

A non-systematic review of the literature is presented as a way of tackling and finding solutions to the problem. A search for high-quality articles on the research topic was conducted.

Results

A total of 370 articles were detected, which were subjected to a further selection to discard low quality papers by a team of five clinical pharmacists and an intensivist. Finally, 153 articles were included in the review.

Conclusions

The geriatric and the critical care patient population require the administration of antimicrobials with close monitoring. The routes of administration recommended for the first group are discouraged for the second. The inhaled route often results in high plasma concentrations in patients with respiratory infections. Pharmacokinetic models are a valuable tool in the treatment of geriatric patients, who are often excluded from clinical trials.

KEYWORDS:
Geriatrics
Critically ill patient
Antimicrobials
Pharmacokinetics-pharmacodynamics
Inhaled route
Resumen
Objetivo

La terapia personalizada en el tratamiento de las infecciones es esencial para garantizar la optimización de los niveles de fármaco alcanzados en el paciente tratado. Adicionalmente, esta estrategia, juntamente con el conocimiento de la actividad antimicrobiana de estos fármacos, disminuye la posibilidad de desarrollar resistencias bacterianas y mejora el perfil de seguridad de estos fármacos. Las terapias por vías alternativas, como la inhalada, y el soporte de la información facilitada por modelos farmacocinéticos son esenciales debido a la limitación de la actividad aportada por los nuevos antimicrobianos.

Método

Se presenta una revisión no sistemática de la literatura como medida de orientación de la problemática y soluciones a lo expuesto anteriormente. Se ha efectuado una búsqueda de artículos de alta calidad sobre el tópico planteado.

Resultados

Se detectaron 231 artículos que sufrieron una selección posterior, en base a la calidad de los trabajos valorada por un equipo de cinco farmacéuticos clínicos y un médico intensivista. Finalmente, se incluyeron 153 artículos que soportan la revisión que se ha desarrollado.

Conclusiones

La población geriátrica y la integrada por pacientes críticos presenta la necesidad de utilización de los antimicrobianos con una estrecha monitorización. Vías de administración recomendadas en la primera, están desaconsejadas en la segunda. La vía inhalada es una vía que suele relacionarse con elevadas concentraciones en pacientes con infecciones respiratorias. Los modelos farmacocinéticos son un soporte de gran valor para poblaciones como la geriátrica debido a que es mayoritariamente excluida de los ensayos clínicos.

PALABRAS CLAVE:
Geriatría
Paciente crítico
Antimicrobianos
Farmacocinética-farmacodinamia
Vía inhalada
Texto completo
Introduction

The need for personalized therapy in the field of infectious diseases stems from the fact that, historically, many clinical trials of antimicrobials have been carried out in wide-ranging populations with different characteristics, often overlooking those patients that require greater precision in the prescription of these drugs1. The CORDIS programs are the main source of European Union funding for these purposes since 1990. These currently include the development of the program “Training towards personalized antibiotic treatment (TIPAT)”, furnished with a total amount of almost €4M and having 2024 as its completion date1. The aim of the program is to combat the threat from increased bacterial resistance, especially in the context of severe infections. The goal is to increase the efficacy of these therapies while minimizing the risk of resistance, and gaining knowledge about the interrelations between patients, pathogens and drugs within the action framework of TIPAT. It includes an interdisciplinary network with wide experience in the field and is designed to integrate the biological and pharmacological data associated with pathogen-patient interaction on the basis of personalized therapies. These programs attempt to integrate clinical pharmacology, immunology and microbiology with a view to producing innovative methodologies that allow for the personalization of antimicrobial therapy. The TIPAT is aimed at hospitals, the pharmaceutical industry and regulatory agencies, and is also designed to include scientific innovation that helps to control and reduce bacterial resistance by optimizing the use of antimicrobial agents.

Numerous factors, including patient status, microbiological etiology and infection site, are essential for the personalization of antimicrobial therapy2. Furthermore, personalized therapy using the latest antimicrobial agents is limited, making it necessary to resort to alternative administration routes when using these drugs.

The aim of the present review is to describe the most relevant information on personalized antimicrobial therapy in critical and older patients, as well as to gain knowledge regarding its application with the latest available antimicrobial agents.

Methods

The search of the literature included papers published on Medline from January 2000 to May 2021. This was a non-systematic review carried out by five hospital pharmacists and one intensive care specialist. The search identified 370 articles, of which 153 (41.4%) were selected after excluding studies that were not directly related to our review's objective.

Geriatric population

How to address the increasing average age of the population is, without a doubt, one of the challenges facing the Spanish health system. Estimates tell us that by 2050 one fourth of the world population will be made up of people of over 60 years of age3. The use of antibiotics in geriatric care is widespread4 and a balance between efficacy, safety and tolerability is not easy to guarantee5. If we focus on prescription of antimicrobials, it is thus necessary to be familiar with the pharmacokinetic and pharmacodynamic (pK/pD) alterations these agents undergo in association with old age, as well as their main pharmacological interactions and most common side effects6.

The principal barriers preventing proper therapeutic management of infections in the geriatric population are shown in Table 1.

Table 1.

Challenges of antimicrobial therapy in geriatric patients

Challenge  Pathophysiology and impact  Antimicrobial examples 
Diagnostic difficulties  Atypical presentation of infectious diseases Immunosenescence  − Inappropriate or unnecessary antimicrobial therapies 
  Absorption: decreased gastric depletion, lower gastric motility, decreased gastric flow and pH alterations.  − Reduced bioavailability (azithromycin, itraconazole) 
Pharmacokinetic and pharmacodynamic changesDistribution: increased fatty tissue, decreased body water, sarcopenia, malnutrition, hypoalbuminemia 
  • I ncreased distribution volume of lipophilic antimicrobials (rifampicin, quinolones, macrolides, oxazolidinones)

  • Decreased distribution volume of hydrophilic antimicrobials (beta-lactams, aminoglycosides, glycopeptides)

  • Decreased plasma protein binding rate (ceftriaxone)

 
Metabolism: decreased phase 1 metabolizing enzymes (cytochrome P450); no alterations of phase 2 metabolism  − I ncreased half-life of hepatically metabolized antimicrobials (macrolides, quinolones, antifungals, azoles, antiretrovirals) 
  Elimination: decreased renal function  − Accumulation of renally eliminated antimicrobials (beta-lactams, glycopeptides, aminoglycosides, daptomycin, ciprofloxacin, levofloxacin, cotrimoxazole) 
Practical aspects of drug administrationParenteral administration (endovenous, intramuscular, subcutaneous)  − Alternative subcutaneous administration (ceftriaxone, cefepime, ertapenem) 
Enteral administration (oral, tubes)  − I ncompatibilities with enteral nutrition (quinolones) 
Prevention of adverse effects 
  • Enhancement resulting from polypharmacy and comorbidities

  • Increased risk of hospitalization

 
  • Cardiotoxicity: macrolides, quinolones

  • Hematological toxicity: linezolid

  • Nephrotoxicity: vancomycin, colistin, aminoglycosides

  • Neurotoxicity: beta-lactams, quinolones, carbapenems

  • Gastrointestinal toxicity (Clostridioides difficile infection)

 
Pharmacological interactions 
  • Polypharmacy: competition for cytochrome P450

  • Increased risk of adverse effects

 
  • Myopathies: statins and macrolides

  • Digitalis intoxication: digoxin and macrolides

  • Hyperpotassemia: ACE inhibitors or ARBs and cotrimoxazole

  • Hypoglycemia: sulfonylureas and quinolones

 

ACE: angíolensín-converlíng enzíme inhibitors; ARBs: angiotensin receptor bloquers.

Diagnostic difficulties

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.

Changes in pK/pD

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.

Practical aspects of drug administration

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.

Prevention of adverse effects

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.

Pharmacological interactions

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.

New antimicrobials in older patients

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.

Critical patients in the adult populationEpidemiology of infections in intensive care units

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.

Table 2.

Challenges of antimicrobial therapy in critical care patients

Challenge  Pathophysiology and impact  Observations and antimicrobial examples 
Pharmacokinetic and pharmacodynamic changes 
  • Absorption: malabsorption, decreased/increased gastric emptying, decreased/increased intestinal motility

  • Distribution: increased capillary permeability, hypoalbuminemia, malnutrition, mechanical ventilation, extracorporeal circuits (renal replacement therapy, cardiopulmonary bypass, ECMO, drainage), ascites, pancreatitis, burn patients, hydric overload, hyperbilirubinemia

  • Metabolism: inflammation and immunosuppression, alterations in drug metabolising enzymes, plasma carriers and proteins

  • Elimination: hyperfiltration (sepsis, surgery, trauma, burn patients), kidney failure, CRRT, ECMO, alterations in hepatic excretion (bile duct obstruction, cholestasis, cirrhosis)

  • Parenteral administration (endovenous, intramuscular, subcutaneous)

  • Enteral administration (oral, tubes)

 
  • Decreased bioavailability: first pass effect (penicillin G, remdesivir), gastric pH alkalization resulting from prophylactic treatment of stress ulcers (ketoconazole, itraconazole), manipulation of the pharmaceutical presentation to administer by tube, interaction with enteral nutrition (quinolones), ion chelation (tetracyclines, ciprofloxacin)

  • Increased bioavailability: decreased gastric emptying (doxycycline, isoniazid, minocycline, sulphonamides), interaction with enteral nutrition (itraconazole, nitrofurantoin)

  • Gastrointestinal dysmotility induced by sedoanalgesics

  • Increased gastrointestinal motility resulting from the use of prokinetic agents

  • Increased regional hypoperfusion caused by vasopressors

  • Atrophy of the intestinal mucosa resulting from prolonged fasting

  • Increased Vd of hydrophilic antimicrobials (beta-lactams, aminoglycosides, glycopeptides, linezolid, colistin)

  • The Vd of lipophilic antimicrobials (fluoroquinolones, macrolides, lincosamides, tigecycline)

  • Decreased PPB rates (ceftriaxone, daptomycin, ertapenem)

  • Drugs that are eliminated through the kidneys: beta-lactams, glycopeptides, aminoglycosides, daptomycin, ciprofloxacin, levofloxacin, cotrimoxazole, ganciclovir

  • Drugs that are eliminated through the liver: tigecycline, caspofungin

  • Drugs with high rates of extraction when using CRRT y ECMO (see Table 3)

  • Choice: intravenous route (bioavailability = 100%)

  • Avoid intramuscular and subcutaneous route, which are associated with erratic absorption in the presence of tissue hypoperfusion

  • Risk of extravasation

  • Pharmaceutic formula not suited to grinding or and/or partitioning

  • Incompatibilities with enteral nutrition (quinolones)

  • Increased bioavailability with enteral nutrition (itraconazole, nitrofurantoin)

  • Chelation from ion interaction (tetracyclines, ciprofloxacin)

 
Practical aspects of administration 
  • Inhaled/nebulized administration

  • Intrathecal/epidural/intraventricular

 
  • Increased epithelial lining fluid (ELF) concentrations together with decreased systemic exposure (amikacin, colistin, tobramycin, vancomycin)

  • Risk of bronchospasm (pH and hyperosmolarity). The possibility of administering bronchodilators previously should be considered

  • Variable drug deposition: type of nebulizer; proper technique in mecanically ventilated patients; MV and nebulizer position in the circuit

  • Strategy for severe cases. Risk/benefit assessment

  • Increased CSF concentrations together with decreased systemic exposure (amikacin, liposomal amphotericin B and amphotericin B deoxycholate, caspofungin, colistin, daptomycin, gentamicin, teicoplanin, tigecycline, tobramycin, vancomycin)

  • Dosing depends on drain aperture

  • Requirements: sterile and apyrogenous; free from solid particles (0.22 micron filter); isosmotic (292-297 mOsm/L); pH value approaching 7.32; preservative free; glucose serum contraindicated; volume, 2-5 mL

 
Prevention of adverse effects 
  • Enhanced by polypharmacy and comorbidities

  • Increased ICU and hospital stays

 
  • Cardiotoxicity (QT interval prolongation): amphotericin B, atazanavir, azoles, chloroquine, macrolides, quinolones

  • Hemotoxicity: cotrimoxazole, ganciclovir, linezolid

  • Nephrotoxicity: aminoglycosides, acyclovir, colistin, vancomycin

  • Neurotoxicity: beta-lactams, carbapenems, quinolones

  • Gastrotoxicity (Clostridioides difficile infection)

  • Myopathies: statins and macrolides or daptomycin

  • Enhanced action of neuromuscular blockers: clindamycin, colistin, doxycycline, vancomycin

  • Digitalis intoxication: digoxin and macrolides

 
Pharmacological interactions 
  • Polypharmacy: competition for cytochrome P450

  • Increased risk of adverse effects

 
  • Increased risk of QT interval prolongation: amiodarone and voriconazole, haloperidol and azithromycin, methadone and levofloxacin

  • Hyperpotassemia: ACE inhibitors or ARBs and cotrimoxazole

  • Enhanced sedation: itraconazole and morphine, voriconazole y fentanyl

  • Decreased sedation: rifampicin and morphine, rifampicin and thiopental

  • Serotonin syndrome: linezolid and serotonin reuptake inhibitors

  • Drug-pathology interactions: myasthenia gravis and amikacin, cotrimoxazole and glucose-6-phosphate dehydrogenase deficiency

 
Development of multiresistances. PROA 
  • Presence of risk factors that increase infections caused by multiresistant microorganisms

  • Need for PROA programmes in ICUs

 
  • Limited therapeutic armamentarium for multi-resistant bacteria

  • Antimicrobial pK/pD optimization depending on the drug's nature and pattern of antimicrobial activity

 

ACE: angiotensin-converting in h ibitors; ARBs: angiotensin receptor bloquers; CFS: cerebrospinal fluid; CRRT: conlinuous renal replacemenl iherapy; ECMO: exlracorporea membrane oxygenation; iCU: intensive care unit; MV: mechanical ventilation; pD: pharmacodynamics; pK: pharmacokinetics; PPB: plasma protein binding; PROA: programmes for optimising the use of antibiotics; Vd: distribution volumen.

pK/pD alterationsPharmacokinetic alterations

The efficacy of antimicrobial therapy is crucial for the survival of critically ill patients47, the optimization of antimicrobial therapy should be a priority in the management of this population.

Absorption: Intravenous administration is the delivery route of choice in acute conditions, since the critically ill often suffer from enteric malabsorption55. This results from mesenteric hypoperfusion caused by the redistribution of the blood flow towards the outside of the gastrointestinal tract in order to regulate cardiovascular homeostasis in the presence of shock55. Such regional hypoperfusion may be enhanced by the action of vasopressors56. The use of subcutaneous and intramuscular antibiotics must therefore be avoided in these patients, in contrast to what applies in other populations.

In such settings, brief periods of enteral fasting may result in atrophy of the intestinal mucosa and loss of integrity of the tight junctions57. Other factors affecting absorption may include gastrointestinal dysmotility enhanced by sedoanalgesia due to slowing of gastric emptying58 alkalization of gastric pH due to prophylactic treatment of stress ulcers, preventing the passage of drugs of an acidic nature through the membranes; and/or loss of bioavailability of drugs when they are administered using a nasogastric tube59.

Distribution: Volume of distribution (Vd) is increased during septic processes due to capillary permeability caused by epithelial damage resulting from stimulation of different endogenous mediators by bacterial endotoxins60. All this has an effect on hydrophilic drugs because of their extracellular distribution, resulting in potentially suboptimal concentrations that may affect therapeutic efficacy60 and pose a risk for the development of resistance61. Other factors that are common in critical patients, such as mechanical ventilation, extracorporeal circuits, ascites and pancreatitis, may also increase the Vd of drugs62.

The presence of hypoalbuminemia in 40-50% of critical patients63 can have an influence on both Vd and clearance of antibiotics with high plasma protein binding (PPB) rates64.

Increased clearance can also take place in the context of hyperbiliru-binemia65 or elevated alpha-1-glycoprotein values65 because of displaced albumin.

Metabolism: Inflammation and immunosuppression associated with critical illness can alter the metabolizing enzymes of drugs, carriers and plasma proteins66.

Elimination: Between 20% and 60% of critical patients can present with higher rates of renal clearance due to increased cardiac output and vaso-dilation resulting from Systemic Inflammatory Response Syndrome (SIRS)67. Risk factors associated with the development of this condition include sepsis, surgery, trauma or burns68. Renal hyperfiltration has a strong impact on the standard dosing regimens of drugs that are eliminated through the kidneys, leading to subtherapeutic concentrations and clinical failure68.

At the other end of the spectrum, 78% of critical patients can suffer from acute kidney failure69, making it necessary to reduce doses of drugs that are cleared through the kidneys in order to avoid toxic concentrations of antimicrobial agents.

An additional consideration is the impact of potential liver failure, which alters the rate of excretion of drugs that are subject to biliary elimination.

Extracorporeal techniques like extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT) may also have a significant impact on the elimination of certain antimicrobials, depending on the properties of the drugs themselves and on the techniques employed.

PK/PD optimization of the main families of ICU antimicrobials

Strategies for pK/pD optimization of the most common families of ICU antimicrobial agents are described below.

Aminoglycosides: Because of their hydrophilic nature, the Vd of these products is increased, leading to decreased maximum concentration (Cmax) levels. Since their efficacy depends on concentration, one strategy is to optimize the length of dosing intervals to allow higher Cmax values while reducing the risk of nephrotoxicity70. Plasma monitoring of the drug's concentration and knowledge of its MIC value with reference to the pathogen are indispensable for adequate follow-up in these cases70.

Beta-lactam agents: These highly hydrophilic drugs have an increased Vd which reduces their concentration levels considerably. It has been shown that prolonged administration and loading doses of these drugs makes it possible to achieve pK/pD goals, and thus achieve free concentrations four times higher than the MIC for 100% of the dosing interval (100% fT ≥ 4 x MIC)71. In cases of severe infection, in the absence of kidney failure, pneumonia or actual or suspected pathogens with lower sensitivity levels, the above should therefore be the strategy of choice72.

Fluoroquinolones: Due to their lipophilic nature, these drugs have a high distribution reaching optimal concentrations both at intracellular and extracellular levels and in neutrophils and lymphocytes73. The pK of these antibiotics has a low impact on critical ilness. However, based on previous experience in the presence of hyperfiltration and high MICs, doses of levofloxacin and ciprofloxacin might require being increased to 750 mg/24 h74 and 400 mg/8 h75 respectively. When dosing has to be adjusted it is preferable to lengthen the dosing intervals, since the activity of these agents is concentration dependent.

Glycopeptides (vancomycin): The drugs in this group are relatively hydrophilic antibiotics64. Continuous infusion of vancomycin has shown to be superior to intermittent infusion: minimization of maximum plasma concentrations results in a 2.6 higher likelihood of reaching the pharmacokinetic goal, while reducing nephrotoxicity by 53%76.

Lipopeptide (daptomycin): As a result of its high rate of PPB (%), clearance of the therapeutically active free fraction of this drug may be increased in conditions of hypoalbuminemia, hyperbilirubinemia and/or elevated alpha-1-glycoprotein63. Therefore, achieving optimal efficacy parameters in critical populations usually requires doses reaching AUC/MIC values of up to 400 and 800 respectively for bacteriostatic or bactericidal action to have effect77.

Oxazolidinones (linezolid): It has been observed78 that 30 to 40% of patients treated with linezolid do not reach optimal pK/pD concentrations, which in the case of critical patients have been set at values of 80-120 for AUC/MIC79 and a T > MIC of 100%80. To achieve this, it could be necessary to prolong perfusion time and/or increase the dose in cases of obesity81 or hyperfiltration82 or in patients receiving CRRT83, especially in individuals whose isolates exhibit high MIC values. Patients with kidney failure84, or who are older85, underweight or cirrhotic, can reach high plasma concentrations of the drug and develop linezolid induced thrombocytopenia as a result86.

Table 3 shows ICU application of individualized new antimicrobial therapies.

Table 3.

Individualization of new intensive care units antimicrobial therapies

Antimicrobial  Antimicrobial properties  Optimal pK/pD index  Dose optimization strategy  Dosing adjustments  Dosing in extracorporeal techniques 
  CAZ:      Renal impairment: depending on perfusion:  IHD (dialyses 80%88): 1 g/0.25 every 24 hours (after dialysis88
  Hydrophilic (log P = −1.6)134 MP = 456.5 Da134 PPB < 10%134 Vd = 0.21-0.28 L/kg134 Renal excretion: 85% unmodified88 Biliary excretion < 1%88      Prolonged over 2 h:   
    CAZ:    − CrCl 31-50: 1 g/0.25 g every 8 hours87  CVVHF: 1 g/0.25 g every 8 hours93 
    %100 fT > 4 × MIC89  Administration of loading dose followed by prolonged or continuous perfusion90− CrCl 16-30 mL/min: 0.7 g/0.1875 g every 12 hours87  CVVHD: 2 g/0.5 g every 8 hours194 
  • Ceftazidime/avibactam

  • Standard dose: 2 g/0.5 g every 8 hours via 2 hour perfusion87

 
      − CrCl 6-15 mL/min: 0,7 g/0.1875 g every 24 hours87  Clearance depends significantly on the dialysate rate. AVI clearance is rapid, especially at high dialysate rates95 
  AVI:    Based on ceftazidime data: 15 mg/kg + 6 g on continuous infusion (CrCl < 60 mL/min)9  Continuous (based on ceftazidime data):  CVVHDF: 2 g/0.5 g every 8 hours at dialysate rates of 1.5 L/g88 
  Hydrophilic (log P = −3,6) 134. MP = 265.25 Da134 PPB = 5.7-8.2%134 Vd = 0.3 L/kg134 Renal excretion: 95% unnmodified88  AVI:    The loading dose should not be adjusted   
        − CrCl 31-50 mL/min: 4 g/1 g on continuous perfusion pump in 24 hours91  ECMO: data not available for CAZ-AVI. For CAZ the literature suggests little impact96, although prolonged therapies could be associated with increased plasma concentration levels of the drug 
    %fT > CT    − CrCl 11-29 mL/min: 2 g/0.5 g on continuous perfusion pump in 24 hours92   
        Hepatic impairment: not required87   
  • Ceftolozane/tazobactam

  • Standard dose: 1 g/0.5 g-2 g/1 g every 8 hours via 1 hour perfusion97

 
CEF:      Renal impairment:   
  Hydrophilic (log P ceftolozane = −6,2)134 MP = 666.7 Da134 PPB = 30%134 Vd = 0.2 L/kg134 Renal excretion: 95% unmodified88      − CrCl > 50 mL/min: IAI and UTI: 1 g/0.5 g every 8 hours97   
    CEF:       
    %100 fT > 4 × MIC89    VAP and HAP: 2 g/1 g every 8 hours97  IHD (dialyses 60%88): IAI and UTI: 500 mg/250 mg loading dose followed by 100 mg/50 mg every 8 hours (after dialysis) 97 VAP and HAP: 1.5/0.75 g loading dose followed by 300 mg/150 mg every 8 hours (after dialysis) 97 Alternative: 1 g/0.5 g loading dose 3 days per week after dialysis88 CVVHF and CVVHD: 1 g/0.5 g every 8 hours88, 99 CVVHDF: 2 g/1 g every 8 hours88 
        − CrCl 30-50 mL/min: IAI and UTI: 0.5 g/0.25 g every 8 hours129 VAP and HAP: 1 g/0.5 every 12-8 hours, 0.5 g/0.25 g every 8 hours97   
  TAZ:    Administration of loading dose followed by prolonged or continuous perfusion98  − CrCl 15-29 mL/min: IAI and UTI: 250 mg/125 mg every 8 hours97 VAP and HAP: 500 mg/25 mg every 8 hours97   
  Hydrophilic (log P tazobactam = −1.4)134 MP = 300.29 Da134 PPB = 16-21%134 Vd = 0.3 L/kg134 Renal excretion: 70% unmodified88         
    TAZ:    − CrCl < 15 mL/min: 1 g/0.5 g every 24 hours IAI and UTI: 500 mg/250 mg loading dose followed by 100 mg/50 mg every 8 hours91   
    % fT > CT    VAP and HAP: 1.5/0.75 g loading dose followed by 300 mg/150 mg every 8 hours91  ECMO: increased Vd91; minimum CS91. Decrease of 37% in tazobactam clearance88. No adjustment is required88 
        Hepatic impairment: not required97   
 
  • MER:

  • Hydrophilic (log P = −0.6) 134 MP = 383.5 Da134 PPB = 2%134 Vd = 0.25 L/kg134

  • Renal excretion: 70% unmodified88 Biliary excretion: minimal88

 
    Renal impairment:   
        − CrCl 39-20 mL/min: 2 g/2 g every 8 hours101  IHD (dialyses < 50%88): 0.5 g/0,5 g every 12 hours after dialysis88 
        − CrCl 19-10 mL/min: 1 g/1 g every 12 hours101   
    %100 fT > 4 × MIC89  Administration in prolonged, 3 hour perfusion100  − CrCl<10 mL/min: 0.5 g/0.5 g every 12 hours101  CVVHF: 0.5 g/0.5 g every 8 hours for a flow rate of 1-2 L/h or 1 g/1 g every 8 hours for a flow rate of 3-4 L/h88 
  • Meropenem/vaborbactam

  • Standard dose: 2 g/2 g every 8 hours via 3 hour perfusion100

 
  • VAB:

  • Hydrophilic (log P = 1.02)134 MP = 297.14 Da134 PPB = 33%134 Vd = 0,3 L/kg134 Renal excretion: 80-90% unmodified88

 
% fT > CT  Based on meropenem data: 2 g/2 g every 8 hours on continuous infusion9  Hepatic impairment: not required10  CVVHD: no data available for MER-VAB 
        Continuous (based on meropenem data): The loading dose should not be adjusted  CVVHDF: no data available for MER-VAB. For MER: 1 g-2 g/8 h88 
        − CrCl 30-49 mL/min: 1 g/1 g every 8 hours on continuous infusion91  ECMO: no data available for MER-VAB; however, the literature suggests very little impact from MER (increased Vd, minimal CS)91 
        − CrCl 10-29 mL/min: 1 g/1 g every 12 hours on continuous infusion91  The characteristics of isavuconazole might cause it to exhibit plasma concentration alterations in the presence of extracorporeal techniques. Monitoring of the drug's concentration levels is recommended 
  • Isavuconazole

  • Standard iv/oral dose: 200 mg every 8 hours for 48 hours + 200 mg every 24 hours (12 hours or 24 hours after the loading dose)102

 
Highly lipophilic (log P = 4.14) 134 MP = 437.5 Da134 PPB > 99%134 Vd = 5 L/kg134 Renal excretion 40% inactive metabolites and < 1% like isavuconazole88    Loading dose: 200 mg every 8 h × 6 doses (48 hrs)88  Renal impairment: no adjustment required, even in terminal kidney failure cases102  It does not dialyse, and therefore does not require adjustments during dialysis102. In one case of a patient on sustained low efficiency dialysis a reduction of 42% in ISA concentrations was reported105 
    f AUC/MIC = 25-50103  Maintenance dose: 200 mg daily (beginning 12-24 hrs after last loading dose)88  Hepatic impairment: in Child-Pugh class C cases it might be necessary to reduce the dose by 50%. This should be avoided if possible104  ECMO: one case was reported of high sequestration and deposition of isavuconazole on the circuit. Doubling of the standard dose could be required106 

AVI: avibaclam; CAZ: ceflazdidime; CEF: ceftolozane; CrCl: creatinine clearance; CRRT: continuous renal replacement therapy; CS: circuit sequestration; CVVHD: continuous venovenous hemodialysis; CVVHDF: continuous venovenous hemodiafiltration; CVVHF: continuous venovenous hemofiltration; fAUC/MIC: area under the unbound drug concentration-time curve; fCMI > MIC: percentage of a 24-h time period that the unbound drug concentration exceeds the MIC; HAP: pulmonary hypertension arterial; HD: intermittent hemodialysis; ISA: isavuconazole; MER: meropenem; MP: molecular weight; PPB: plasma protein binding; PPB: plasmatic protein binding; TAZ: Tazobactam; VAB: vaborbactam; VAP: ventilator associated pneumonia; Vd: distribution volume.

Inhaled antimicrobial therapy as a strategy to improve respiratory drug concentrations

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.

AntibioticsAminoglycosides

Tobramycin is the most widely used aminoglycoside in nebulized form. One meta-analysis showed that nebulized tobramycin afforded the greatest benefit in long-term treatment for Pseudomonas aeruginosa infection in cystic fibrosis patients113. The high doses required and the need for prolonged use, however, create some concern regarding its potential renal toxicity, which has been described in some specific cases114,115.

Another drug of this group that is used in nebulized form is amikacin. The risk of systemic absorption with the standard formulation is similar to that of endovenous amikacin and can cause potential side effects108. Nebulized liposomal amikacin, a newly developed formulation, increases local concentration of the drug while reducing its systemic absorption. Its use in patients with cystic fibrosis was well tolerated, but did not show to be superior to conventional nebulized tobramycin116. In one clinical trial, nebulized liposomal amikacin produced a higher negativization rate of germ cultures when it was added to standard treatment of pulmonary infections with Mycobacterium avium complex that were resistant to conventional treatment117. It has thus become a promising new drug in the treatment regimen of respiratory infections caused by nontuberculous mycobacteria.

Colistin

Nebulized colistin is formulated as colistimethate sodium, which subsequently becomes colistin sulfate in vivo108. It is, so far, the most frequently used nebulized antibiotic in the treatment of respiratory infections caused by multi-resistant gram-negative bacilli. A variety of doses is used in VAP patients, ranging from 1 million IUs every 12 hours to 5 million IUs every 8 hours108, making it difficult to compare the data. Although one meta-analysis showed a lower mortality rate when nebulized colistin was added to endovenous colistin to treat VAP118, the usefulness of nebulized antimicrobials in the context of VAP, as pointed out before, continues to be controversial, as are the adequate dosing levels of colistin in its nebulized form. Given that systemic absorption of nebulized colistimethate sodium is practically null, no nephrotoxicity associated to nebulized treatment has been described115.

Aztreonam

Aztreonam lysine is a nebulized drug formulation that has been approved for the treatment of P. aeruginosa infection in patients diagnosed with cystic fibrosis107. However, it has not been shown to have a similar benefit in clinical trials including patients with non-cystic fibrosis bronchiectasis119.

Fluoroquinolones

Among the antibiotics in this group, nebulized ciprofloxacin has been given the most frequent use. Specifically, a liposomal ciprofloxacin formulation was used in phase 3 clinical trials in patients with non-cystic fibrosis bronchiectasis. The results of the two clinical trials that were conducted turned out to be contradictory: one of them showed a benefit, over time, in preventing respiratory exacerbations, while the other did not confirm this finding120. Further studies are, therefore, needed to determine the potential benefits of this nebulized drug in daily clinical practice.

AntifungalsNebulized amphotericin B

Nebulized amphotericin B, especially in it liposomal formulation, has been widely used for antifungal prophylaxis in lung transplant patients121. Although no clinical trials are available for this population, the data published in different studies are favorable in terms of drug's long-term effectiveness, tolerability and influence on respiratory function tests122,123. On the basis of accumulated experience in prophylaxis, it has also been used for antifungal therapy, but studies are limited to case descriptions124.

Azoles

Experience with nebulized azoles is more limited, but some studies have shown that the physico-chemical characteristics of both posaconazole and voriconazole are well suited to nebulisation125. Cases of lung transplant patients with invasive fungal infections, treated adequately with these nebulized azoles have already been reported125,126.

Echinocandins

The physico-chemical characteristics of micafungin and anidulafungin have been described as appropriate for nebulisation127. Two cases were recently reported of lung transplant patients with tracheobronchitis from Scopulariopsis spp. who were treated successfully with nebulized micafungin128. These drugs could, therefore, be potentially used on an individualized basis in these infections, which are difficult to treat and exhibit resistance to most antifungal agents.

Personalization of antimicrobial therapy using pK/pD models

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.

Table 4.

Advantages and inconvenients of pK/pD models

Advantages  Inconvenients 
Rapid access to data and results as compared to clinical trials  Need for prior premises and assumptions that must be as rigorous, precise and accurate as possible 
Cost savings  The model's robustness must be fully guaranteed 
  The mathematical-statistical techniques used for model validation can be complex and slow to run 

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.

Table 5.

pK monitoring in clinical practice137

Required data 
− One or more serum concentrations of the antibiotic (pK) 
− Population pK parameters (estimated in advance) 
− Software application (Bayesian method) 
− Therapeutic target: pK/pD index 

pD: pharmacodynamic; pK: pharmacokinetic.

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.

Funding

No funding.

Conflict of interest

No conflicts of interests.

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