PRIMARY ANTIBACTERIAL THERAPY IN CRITICALLY ILL PATIENTS IN INTENSIVE CARE

ABSTRACT

Initial empirical antibiotic therapy in critically ill patients admitted to intensive care units plays a pivotal role in reducing mortality and preventing infectious complications. This study evaluates key approaches to the selection of broad-spectrum antimicrobial agents based on infection type, microbiological profile, and clinical condition. The use of carbapenems, third-generation cephalosporins, and fluoroquinolones demonstrated a beneficial impact on hepatic and renal function, as evidenced by decreased urea and creatinine levels and improved glomerular filtration rate (GFR). Early administration of these agents enables rapid suppression of pathogenic microflora, which is especially critical in cases of sepsis and septic shock. Optimal empirical therapy should include at least two antibiotic classes targeting a wide range of potential pathogens, with dosing guided by pharmacokinetic and pharmacodynamic principles to maximize therapeutic efficacy and minimize toxicity. Antimicrobial regimens should be reassessed upon receipt of microbiological results or with clinical improvement. Serum procalcitonin is proposed as a valuable biomarker for guiding the duration and discontinuation of empirical therapy in septic patients.

АННОТАЦИЯ

Первичная эмпирическая антибиотикотерапия у тяжёлых пациентов в отделении интенсивной терапии играет ключевую роль в снижении смертности и предупреждении инфекционных осложнений. В настоящем исследовании проанализированы подходы к выбору антибактериальных препаратов широкого спектра действия в зависимости от типа инфекции, микробиологического профиля и состояния пациента. Установлено, что карбапенемы, цефалоспорины III поколения и фторхинолоны способствуют улучшению функции печени и почек, что подтверждается снижением уровня мочевины и креатинина, а также улучшением показателей СКФ. Быстрое назначение данных препаратов позволяет эффективно контролировать инфекционный процесс, особенно при сепсисе и септическом шоке. Подчёркивается необходимость применения не менее двух классов антибиотиков в стартовой терапии и своевременной коррекции схемы лечения по результатам микробиологического анализа. Использование прокальцитонина предложено в качестве биомаркера для оценки продолжительности терапии.

Keywords: intensive care, antibacterial therapy, infection, microbiology.

Ключевые слова: интенсивная терапия, антибактериальная терапия, инфекции, микробиология.

Introduction

Infections are among the primary complications in intensive care units (ICUs) and represent a leading cause of mortality among patients in these departments [1, p.2; 2, p.5]. The incidence of infectious complications increases significantly with the length of ICU stay due to several factors, including the use of invasive procedures, immune system suppression, and the presence of comorbid chronic diseases. Despite the wide availability of antimicrobial agents, the outcomes of treating infections in intensive care settings remain unsatisfactory. This is attributed to the polymicrobial nature of infections, the emergence of antibiotic resistance, and the critical importance of initiating treatment promptly [1, p.8; 3, p.3].

One of the major challenges in managing bacterial infections in ICUs is the high level of microbial resistance to conventional antibiotics. Many infections—especially those that develop during prolonged mechanical ventilation or involve invasive procedures—complicate the selection of appropriate antibiotic therapy. Furthermore, the rapid development of resistance during treatment often leads to recurrent infections, necessitating continuous adjustment of the therapeutic regimen [3, p.4; 4, p.7].

The complexity of treatment is further compounded by the unjustified or excessive use of antibiotics. In the ICU setting, empirical antibiotic therapy must often be initiated at the first clinical signs of infection without waiting for the results of bacteriological testing, as any delay may significantly worsen the patient’s prognosis [3, p.11; 5, p.9]. However, empirical therapy should be combined with timely microbiological diagnostics and subsequent de-escalation strategies to minimize the risks of resistance and adverse effects. Unfortunately, the incidence of hospital-acquired infections (HAIs) is currently on the rise [6, p.1]. According to the World Health Organization (WHO), HAIs affect approximately 8% of hospitalized patients and increase the average length of hospital stay by 6–8 days [6, p.3].

Depending on the patient population and the severity of their condition, the incidence of HAIs can vary from 9% to 80% [4, p.2; 5, p.6]. The type and severity of HAIs are typically associated with the nature of the disease and the specific hospital department. In therapeutic wards, the average incidence is 2–4 cases per 1,000 patients; in surgical wards, 5–10 per 1,000 patients; and in ICUs, between 2 and 62 cases per 100 patients [7, p.4]. In pediatric ICUs, HAI incidence ranges from 4.7% to 18.7% per 1,000 patient-days, while in mixed-profile ICUs the rate is 46.3%, and in burn ICUs, it reaches 34.4% [7, p.6]. HAIs complicate up to 47% of all intubations and tracheostomies [8, p.9].

Microbiological analyses of patients with confirmed HAIs show that bacteria are identified in approximately 73% of cases, fungi in 4%, and anaerobic organisms are rarely detected [9, p.5]. The etiology of infections in ICUs is dynamic; in 17–40% of cases, infections are polymicrobial in nature, with Gram-negative organisms playing a predominant role [9, p.11].

The etiological structure of infections in ICUs reveals that 53% are caused by Gram-negative pathogens, 27% by Gram-positive bacteria, and 20% by fungi [10, p.2]. Artificial airways are colonized with pathogenic bacteria shortly after intubation or tracheostomy. The most common pathogens include both Gram-positive and Gram-negative bacteria such as Staphylococcus aureus (including MRSA), Pseudomonas aeruginosa, and species of Klebsiella and Enterobacter [10, p.7].

In summary, the risk of infectious complications in ICUs is significantly higher than in general hospital wards. The majority of infections are observed in patients on mechanical ventilation, where the infection rate may reach as high as 79% [7, p.10; 10, p.13]. The most dangerous infections include pneumonia, gastrointestinal infections, and urinary tract infections. Mortality associated with Pseudomonas aeruginosa-induced pneumonia can reach up to 70%, reflecting the high lethality of lower respiratory tract infections [7, p.12; 10, p.14].

Factors contributing to the development of ICU infections: The patient’s underlying disease (particularly severe chronic illnesses); High severity score according to the APACHE II scale (>20); Age over 60 years; Presence of invasive diagnostic and therapeutic procedures (e.g., catheterization, intubation, tracheostomy); Prolonged mechanical ventilation; Use of antacids and H2-blockers that alter gastric acidity and promote bacterial colonization; Unsystematic or broad-spectrum use of antibiotics for prophylactic purposes [7, p.13; 10, p.14].

Objective of the Study: To evaluate the effectiveness of initial antibiotic therapy in critically ill ICU patients and determine the clinical impact of early treatment initiation.

Materials and Methods: A retrospective clinical-statistical analysis was conducted on n = 62 patients treated at the Intensive Care Unit of City Clinical Hospital №4 in Almaty, Kazakhstan, between January 1, 2022, and August 31, 2024.

Inclusion Criteria: Patients aged 18 years and older with a confirmed diagnosis of a severe infectious process (e.g., sepsis, pneumonia, urinary tract infections, intra-abdominal infections), who received antibiotic therapy and provided informed consent for participation (when obtainable).

Exclusion Criteria: Patients under 18 years of age, those who refused treatment, patients with viral infections requiring specific therapy, those with severe comorbidities preventing antibiotic use (e.g., end-stage cancer), patients who had already undergone antibiotic therapy for more than 72 hours, and individuals with severe allergic reactions.

For all patients included in the study, clinical complaints, laboratory and instrumental test results, pathological and histological findings, and infection severity levels were analyzed.

Statistical methods were applied to verify the collected data. Means and standard deviations (M±m) were calculated. The significance of differences between arithmetic means was assessed using Student’s t-test. Differences were considered statistically significant at p < 0.05. Statistical analyses were performed using Microsoft Office Excel.

Results. An analysis of demographic characteristics by sex and age was conducted among the studied cohort (Figure 1). The male population accounted for n = 35 (56.45%), while females comprised n = 27 (43.55%).

Figure 1. Distribution of study patients by sex (%)

The overall mean age was 56.10 ± 7.89 years, with a statistically significant difference between sexes of 4.87 ± 0.48 years (p < 0.01). The majority of patients were between 51 and 70 years of age (n = 27; 43.5%) (Table 1).

Table 1.

Distribution of study patients by age group (%)

Next, the study focused on patients with identified infectious complications. Sepsis was confirmed in 32.26% (n = 20) of all patients, with a prevalence of 37.5% in males (12 out of 32) and 26.67% in females (8 out of 30) (r = 0.75, p = 0.002). Pneumonia occurred in 24.19% of patients (r = 0.70, p = 0.004), intra-abdominal infections in 19.35% (r = 0.68, p = 0.005), urinary tract infections in 16.12% (r = 0.60, p = 0.006), and cases of phlegmon or abscess in 8.06% (r = 0.80, p = 0.001). All p-values were <0.05, confirming the statistical significance of differences in infection frequency between sexes (Table 2).

Table 2.

Classification of patients by identified infection type (%)

Microorganisms were identified in n = 53 patients, representing 85.5% of the total study cohort, confirming the high prevalence of infectious complications among critically ill ICU patients and corresponding to literature data.

Our study also confirmed the frequent detection of Staphylococcus aureus and Staphylococcus epidermidis, aligning with their documented importance in critically ill ICU populations (Table 3a).

Table 3a.

Identified causative agents in study patients (%)

Comparison with existing studies revealed notable similarities. According to Dulhunty J.M., Brett S.J., and colleagues, the most common pathogens were Candida (44%), Staphylococcus (28%), and Klebsiella (17–19%), consistent with our findings. In their cohort, sepsis was reported in 21.4% and pneumonia in 50% of cases (Table 3b) [3, p.7].

Our study also confirmed the frequent detection of Staphylococcus aureus and Staphylococcus epidermidis, aligning with their documented importance in critically ill ICU populations (Table 3a).

Table 3b.

Comparative analysis with other studies (% occurrence)

Anti-inflammatory therapy was administered in 85.48% of cases (r = 0.91), detoxification therapy in 72.58%, desensitization in 52.57%, and immunotherapy in only 3.23% of patients (2 individuals) (Table 4a).

To optimize therapeutic outcomes and reduce the risk of resistance, it is recommended to revise treatment regimens at 48–72 hours based on microbiological data and clinical progress [3, p.11; 8, p.6].

In most cases, switching to narrow-spectrum monotherapy after 3–5 days of empirical therapy is considered a safe strategy, allowing restriction of broad-spectrum agents such as carbapenems and piperacillin-tazobactam due to their association with resistance and adverse effects [3, p.12; 5, p.10; 7, p.9].

Third-generation cephalosporins were used in 80.65% of moderate infections. Carbapenems were the most frequently used (93.55%), followed by fluoroquinolones (91.93%), aminoglycosides (72.58%), glycopeptides (90.32%), and polymyxins (59.68%) (Table 4b).

Table 4a.

Main therapeutic strategies administered to patients (%)

Table 4b.

Main types of antibiotics administered to patients (%)

Additionally, we assessed key hematological parameters before and after antibacterial therapy. Notably, marked leukocytosis was observed in 65.5% of patients prior to treatment, decreasing to 38.13% post-treatment. Similarly, thrombocytosis decreased from 45.13% to 25.22%, neutrophilia from 73.08% to 18.19%, lymphocytosis from 24.8% to 6.09%, and elevated fibrinogen levels from 82.15% to 21.26%. C-reactive protein (CRP) decreased modestly from 33.02% to 21.75%, while procalcitonin levels dropped sharply from 27.12% to 2.23%.

Of particular significance is the decline in leukocytosis by 58.21%, neutrophilia by 75.11%, and fibrinogen by 74.12%, demonstrating the effectiveness of antibacterial therapy. However, CRP showed a decrease in only 21.75% of cases (Table 5).

Table 5.

Overall dynamics of laboratory parameters before and after antibacterial therapy (%)

According to numerous clinical studies, the incidence of drug-induced liver or kidney injury caused by antibacterial agents ranges from 13.5% to 65%. For example, amoxicillin/clavulanic acid is associated with 1 to 17 cases of hepatic injury per 100,000 prescriptions, with a higher incidence among males over the age of 65. Hepatotoxic effects typically occur approximately 17 days after the initiation of therapy, but may also manifest 6–7 weeks after drug discontinuation [4–8].

Ceftriaxone may induce complications in up to 25% of adults and 40% of pediatric patients in the form of biliary sludge or cholestatic hepatitis, typically occurring 9–11 days after therapy initiation. Ciprofloxacin and levofloxacin have been associated with long-term hepatocellular or cholestatic injury, manifesting from a few days to several weeks after administration [4–8].

Although fluoroquinolones are generally considered to have a low incidence of hepatotoxicity, including serious reactions, pharmacovigilance data from France reports a rate of less than one case per five million prescriptions of levofloxacin, which equates to an estimated 1–5% [4, p. 6-8].

With regard to nephrotoxicity, aminoglycosides are among the most nephrotoxic antibiotics, inducing varying degrees of renal injury in up to 30% of patients—most commonly presenting as acute tubular necrosis affecting the proximal renal tubules [4–8].

Nephrotoxicity has been reported in 2–5% of patients receiving cephalosporins, less than 1–2% with carbapenems, and 2–3% with fluoroquinolones. Polymyxins, however, are considered highly nephrotoxic, potentially causing renal injury in up to 50% of cases [4–8].

Below we present a summary of findings from multiple studies regarding the hepatotoxic and nephrotoxic potential of various antibiotic classes (Tables 6a and 6b).

Table 6a.

Frequency and characteristics of drug-induced liver injury associated with antibiotics [4–8]

Table 6b.

Frequency and characteristics of drug-induced kidney injury associated with antibiotics [4–8]

A comparative analysis was conducted to assess the changes in biochemical parameters before and after treatment with various antibiotic classes (Tables 7a and 7b).

Overall, alanine aminotransferase (ALT) demonstrated the greatest reduction in patients treated with carbapenems, decreasing from an average of 138.5 U/L to 65.8 U/L, indicating a significant improvement in hepatic function. Similarly, no pronounced cytolytic syndrome was observed in aspartate aminotransferase (AST) levels across all antibiotic groups (Table 7a).

In contrast, nephrotoxicity was more evident in the polymyxin and fluoroquinolone groups. A notable improvement was observed in serum urea among glycopeptide-treated patients (from 11.0 ± 3.8 mmol/L to 8.5 ± 3.0 mmol/L), and serum creatinine in the carbapenem group (from 135.4 ± 45.2 µmol/L to 110.7 ± 40.3 µmol/L). These findings further confirm that carbapenems yielded the most favorable outcomes overall (Table 7b).

Table 7a.

Changes in hepatic biochemical markers before and after treatment (ALT, AST)

Note: ALT – Alanine Aminotransferase; AST – Aspartate Aminotransferase

Table 7b.

Changes in renal biochemical markers before and after treatment (Creatinine, Urea, GFR)

Note: GFR – Glomerular Filtration Rate

Conclusion. This study investigated the outcomes of broad-spectrum antibiotic use in critically ill patients admitted to the intensive care unit. The results of both bacteriological and clinical analyses demonstrated the critical role of broad-spectrum antibiotics in initial empirical therapy. The use of such agents is justified and effective in intensive care settings, as it enables rapid suppression of pathogenic microflora prior to obtaining microbiological test results.

Broad-spectrum antibiotics—such as carbapenems, third-generation cephalosporins, and fluoroquinolones—were shown to have a positive effect on the recovery dynamics of hepatic and renal function. This was confirmed by reductions in urea and creatinine levels, along with improved glomerular filtration rate (GFR) values.

The application of these antibiotics facilitated the rapid control of infectious processes, particularly by minimizing the risk of progression in severe cases such as sepsis and septic shock. Their prompt use is essential for improving outcomes in such critical conditions.

Initial empirical therapy in patients with sepsis or septic shock should involve at least two classes of broad-spectrum antibiotics, targeting a wide range of potential pathogens. Dosage regimens should be guided by pharmacokinetic and pharmacodynamic principles to maximize efficacy and reduce toxicity.

Therapy should be re-evaluated once microbiological results become available or when there is noticeable clinical improvement. Serum procalcitonin levels may serve as a predictive biomarker for the discontinuation of empirical antibiotic therapy and as a tool to determine appropriate treatment duration in patients with sepsis.

References:

1. Ehrmann S, Barbier F, Demiselle J, Quenot JP et. al. Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia. N Engl J Med. 2023 Nov 30;389(22):2052-2062. doi: 10.1056/NEJMoa2310307. Epub 2023 Oct 25. PMID: 37888914.
2. Monti G, Bradic N, Marzaroli M, Konkayev A, Fominskiy E, Kotani Y, Likhvantsev VV, Momesso E, Nogtev P, Lobreglio R, Redkin I, et. al.  Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis: The MERCY Randomized Clinical Trial. JAMA. 2023 Jul 11;330(2):141-151. doi: 10.1001/jama.2023.10598. PMID: 37326473; PMCID: PMC10276329.
3. Dulhunty JM, Brett SJ, De Waele JJ, Rajbhandari D, Billot L, Cotta MO, Davis JS, Finfer S, Hammond NE, Knowles S, Liu X, McGuinness S, Mysore J, Paterson DL, Peake S, Rhodes A, Roberts JA, et. al.  Continuous vs Intermittent β-Lactam Antibiotic Infusions in Critically Ill Patients With Sepsis: The BLING III Randomized Clinical Trial. JAMA. 2024 Aug 27;332(8):629-637. doi: 10.1001/jama.2024.9779. PMID: 38864155; PMCID: PMC11170452.
4. Timsit JF, Ruppé E, Barbier F, Tabah A, Bassetti M. Bloodstream infections in critically ill patients: an expert statement. Intensive Care Med. 2020 Feb;46(2):266-284. doi: 10.1007/s00134-020-05950-6. Epub 2020 Feb 11. PMID: 32047941; PMCID: PMC7223992.
5. Abdul-Aziz MH, Hammond NE, Brett SJ, Cotta MO, De Waele JJ, Devaux A, Di Tanna GL, Dulhunty JM, Elkady H, Eriksson L, Hasan MS, Khan AB, Lipman J, Liu X, Monti G, Myburgh J, Novy E, et. al.  Prolonged vs Intermittent Infusions of β-Lactam Antibiotics in Adults With Sepsis or Septic Shock: A Systematic Review and Meta-Analysis. JAMA. 2024 Aug 27;332(8):638-648. doi: 10.1001/jama.2024.9803. PMID: 38864162; PMCID: PMC11170459.
6. Kollef MH, Nováček M, Kivistik Ü, Réa-Neto Á, Shime N, Martin-Loeches I, Timsit JF, Wunderink RG, Bruno CJ, Huntington JA, Lin G, Yu B, Butterton JR, Rhee EG. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2019 Dec;19(12):1299-1311. doi: 10.1016/S1473-3099(19)30403-7. Epub 2019 Sep 25. PMID: 31563344.
7. Shekar K, Abdul-Aziz MH, Cheng V, Burrows F, Buscher H, Cho YJ, Corley A, Diehl A, Gilder E, Jakob SM, Kim HS, Levkovich BJ, Lim SY, McGuinness S, Parke R, Pellegrino V, Que YA, Reynolds C, et. al.  Antimicrobial Exposures in Critically Ill Patients Receiving Extracorporeal Membrane Oxygenation. Am J Respir Crit Care Med. 2023 Mar 15;207(6):704-720. doi: 10.1164/rccm.202207-1393OC. PMID: 36215036.
8. Serpa PH, Deng X, Abdelghany M, Crawford E, Malcolm K, Caldera S, Fung M, McGeever A, Kalantar KL, Lyden A, Ghale R, Deiss T, Neff N, Miller SA, Doernberg SB, Chiu CY, DeRisi JL, Calfee CS, Langelier CR. Metagenomic prediction of antimicrobial resistance in critically ill patients with lower respiratory tract infections. Genome Med. 2022 Jul 12;14(1):74. doi: 10.1186/s13073-022-01072-4. PMID: 35818068; PMCID: PMC9275031.
9. SuDDICU Investigators for the Australian and New Zealand Intensive Care Society Clinical Trials Group. Effect of Selective Decontamination of the Digestive Tract on Hospital Mortality in Critically Ill Patients Receiving Mechanical Ventilation: A Randomized Clinical Trial. JAMA. 2022 Nov 15;328(19):1911-1921. doi: 10.1001/jama.2022.17927. PMID: 36286097; PMCID: PMC9607966.
10. Kaviani A, Ince D, Axelrod DA. Management of Antimicrobial Agents in Abdominal Organ Transplant Patients in Intensive Care Unit. Curr Transplant Rep. 2020;7(1):1-11. doi: 10.1007/s40472-020-00268-0. Epub 2020 Jan 24. PMID: 32432022; PMCID: PMC7222087.