Role of Amikacin in the Management of Ventilator-Associated Pneumonia

Abstract

Ventilator-associated pneumonia accounts for 60% of healthcare-associated infection deaths. It results from invasion of the lower respiratory tract by microorganisms and affects patients 48 hours after they have been intubated and have received mechanical ventilation. Prompt diagnosis using a combination of clinical, radiographic, microbiological, and laboratory assessment can help prevent exacerbation of symptoms and provide immediate treatment. Usage of antibiotics for therapy has proven clinically useful; however, emerging resistance of microorganisms to these medications has been continuously evolving. This article focuses on amikacin and how its emerging role in treating VAP has improved patient outcomes and increased their chances of recovery with minimal adverse effects.

1. Introduction

Ventilator-associated events (VAEs) are mainly caused due to pneumonia, fluid overload, ARDS, and atelactasis, and about 40% of ventilator-associated pneumonias (VAP) meet the criteria for VAE [1]. VAP manifests as pneumonia occurring more than 48 hours subsequent to patients undergoing intubation and mechanical ventilation. An overwhelming 86% of all hospital-acquired pneumonias are linked to mechanical ventilation, with VAP’s mortality rates fluctuating between 0 and 50%, contingent upon the specific pathogens identified. When specifying areas of the hospital most affected by VAP, a study by Song et al. showed that there was no true difference seen between the incidence of VAP in medical intensive care units(MICU) when compared to surgical intensive care units(SICU), neither was there a significant difference in mortalities (P = 0.228); however, the length of stay for MICU patients with VAP was significantly prolonged as compared to those who had not contracted VAP, averaging on 6 and 8.5 days, respectively (P < 0.001) [2]. Hence, apart from its medical implications, VAP also imposes significant financial burdens on patients due to prolonged hospital stays. Furthermore, effective treatment necessitates diligent nursing care, respiratory therapy, and prudent antibiotic administration.

Selecting the appropriate therapy for VAP mandates adherence to certain principles, including awareness of prevalent organisms, local resistance patterns within the ICU, a rationale for antibiotic selection, and considerations for de-escalation or cessation of antibiotic therapy. Studies have underscored the criticality of timely initiation of appropriate antibiotic treatment for VAP, as delays have been correlated with increased mortality rates.

In case of absence of risk factors for multidrug-resistant bacteria, clinicians typically opt for empirical therapy targeting Streptococcus pneumoniae, methicillin-sensitive Staphylococcus aureus, Haemophilus influenzae, and susceptible gram-negative enteric organisms [3]. This empirical regimen typically comprises an antipseudomonal cephalosporin (such as cefepime or ceftazidime), an antipseudomonal carbapenem (such as imipenem or meropenem), or a β-lactam/β-lactamase inhibitor (such as piperacillin-tazobactam), coupled with an aminoglycoside (such as amikacin or gentamicin) or an antipseudomonal fluoroquinolone (like ciprofloxacin or levofloxacin). Recent research has highlighted the potential efficacy of inhaled antibiotics, particularly amikacin. This chapter aims to delve deeper into this aspect [4].

1.1 Pathogenesis

With the increasing burden of disease and ICU admissions, understanding the development and pathogenesis of ventilator-associated pneumonia (VAP) is crucial for devising effective treatment strategies.

Microorganisms causing VAP must first access the normally sterile lower respiratory tract, where they adhere to the mucosa and establish infection. There are four primary mechanisms through which microorganisms gain access: aspiration of microbe-laden secretions from the oropharynx, direct extension from contiguous infections, inhalation of contaminated air or medical aerosols, and hematogenous carriage from remote infection site [5].

In non-intubated patients, the oropharyngeal flora primarily consists of viridans streptococci, Haemophilus species, and anaerobes, maintained by factors like the flow and content of saliva. However, in critically ill patients, especially in ICUs, there’s a significant shift toward aerobic gram-negative bacilli and Staphylococcus aureus [6]. Various factors such as reduced mucosal immunoglobulin A, increased protease production, and altered airway receptors contribute to bacterial adherence to the orotracheal mucosa in mechanically ventilated patients.

Aspiration of oropharyngeal contents overwhelms compromised host defenses, leading to VAP development. The stomach serves as a potential reservoir for VAP-causing bacteria [7], particularly in conditions like elevated gastric pH due to factors such as treatment with acid-suppressing medications or enteral nutrition. Gastric microorganisms can reflux up the esophagus and are aspirated into the trachea, implicating the stomach in VAP development.

Furthermore, the endotracheal tube (ETT) acts as a conduit for microbial colonization, providing a direct route for bacteria to bypass upper respiratory tract defenses. Biofilm formation on the ETT surface further facilitates bacterial adhesion and colonization, promoting the persistence of infection despite antimicrobial therapy.

Ventilator-induced lung injury (VILI) plays a significant role in VAP pathogenesis. Mechanical ventilation disrupts the normal physiological mechanisms of airway clearance and immune defense, leading to impaired mucociliary clearance [8], reduced cough reflex, and compromised alveolar macrophage function. Additionally, high tidal volumes and positive end-expiratory pressure (PEEP) can cause barotrauma and volutrauma, resulting in lung tissue damage and inflammation, which further predisposes the lung to infection.

In summary, VAP pathogenesis is multifactorial, involving microbial colonization facilitated by the endotracheal tube, disruption of normal lung defense mechanisms by mechanical ventilation, and dysregulation of the host immune response. Understanding these intricate processes is essential for developing targeted preventive strategies and optimizing management approaches to reduce the burden of VAP in critically ill patients.

In understanding the intricate processes of VAP pathogenesis, we are better equipped to develop targeted preventive strategies and optimize management approaches. Now, let us delve into the crucial aspect of diagnosing VAP to ensure timely and effective interventions for improving patient outcomes.

1.2 Diagnosis of VAP

VAP requires the implementation of multiple clinical manifestations for its prompt diagnosis. The recommended diagnostic measures are as follows: (i) radiographic assessment (manifestation of new or progressive lung infiltrates and consolidation or cavitation); (ii) laboratory assessment (white blood cell count >4 or at least 12×10³ cells/mm³); (iii) clinical assessment (such as a body temperature < 36°C or > 38°C, new onset or increase of purulent aspirates, wheezing, rales, rhonchi, or progressive worsening of gas exchange); (iv) microbiological criteria (showcasing positive culture result from suctioned sputum, bronchoscopy, blind bronchoalveolar lavage, or pleural fluid) [9, 10, 11]. Several criteria have been proposed for diagnosing VAP in clinical settings, which is summarized in the Table 1.

Clinical criteria used in diagnosing ventilator-associated pneumonia
Johnson criteria	Clinical Pulmonary Infection Score (CPIS)	Centers for Disease Control and Prevention (CDC)
Presence of a new or progressive radiographic infiltrate	Temperature 0 point: 36.5–38.4 C 1 point: 38.5–38.9 2 points: < 36 or > 39 Oxygenation (PaO2/FiO2) 0 point: PaO2/FiO2 > 240 or ARDS 2 points: PaO2/FiO2 < 240 and no ARDS	Radiology signs Two or more serial chest radiographs with at least 1 of the following: new or progressive and persistent infiltrate consolidation cavitation
Plus at least two of three clinical features: fever >38°C leukocytosis or leukopenia purulent secretions	Tracheal secretions (score) 0 point: < 14 1 point: > 14 2 points: purulent sputum Culture of tracheal aspirate 0 point: minimal or no growth 1 point: moderate or more growth - 2 points: moderate or greater growth	Microbiological criteria At least one of the following: positive growth in blood culture unrelated to any previous infection growth seen in culture or pleural field positive quantitative culture from bronchoalveolar lavage (>10^4) or protected specimen brushing (>10^3) 5% or more of cells with intracellular bacteria on direct microscopic examination of Gram-stained BAL fluid histopathological evidence of presence of pneumonia
	Blood leukocytes (cells/μL) 0 point: 4000–11,000 1 point: < 4000 or > 11,000 2 points: > 500 band forms Pulmonary radiography 0 point: no infiltrate 1 point: diffuse or patchy infiltrates 2 points: localized infiltrate	Clinical signs At least 1 of the following: fever (temperature > 38°C) leukopenia (< 4000 WBC) or leukocytosis (> 12,000 WBC) altered mental status seen in adults over the age of 70 with no other recognized cause Plus at least 2 of the following: onset of newly developed purulent sputum, or change in character and quality of sputum increased respiratory secretions within the lung, or increased suctioning requirements seen onset of any of the following: worsening cough, dyspnea, tachypnea bronchial sounds or rales progressive worsening of gas exchange - increased oxygen requirements for the body
	Total score of >6 points suggests ventilator-associated pneumonia

Table 1.

Criteria for diagnosis of ventilator-associated pneumonia.

The National Nosocomial Infection Surveillance (NNIS) system, developed in the 1970s by the Centers for Disease Control (CDC), was implemented to study the distribution of hospital acquired infections. It was compared to 292 bronchoalveolar lavage (BAL) fluid cultures obtained from trauma patients and was found to have a sensitivity of 84% and a specificity of 69% [12].

Subsequently, Pugin et al. [13]. proposed the Clinical Pulmonary Infection Score (CPIS), which takes into account the following six variables: fever, white blood cell count, tracheal aspirates, oxygenation of the blood, radiographic consolidation, and semiquantitative cultures of tracheal aspirates using Gram stain. This criterion originally showed 93% sensitivity and 100% specificity; however, it only included results from 28 patients. Along with that, the results were compared to quantitative cultures of BAL fluid using a bacterial index (sum of the logarithm of all bacterial species recovered), which cannot be accounted for as an acceptable gold standard for diagnosis of VAP.

When compared to a pathological diagnosis, CPIS showed sensitivity between 72 and 77% and specificity between 42 and 85% [14, 15]. Pham et al. [16]. compared quantitative BAL fluid culture to diagnose VAP and concluded that CPIS had a sensitivity of 30% and specificity of 80%.

Johnson et al. [17] suggested that diagnosis of VAP should be made by onset of a new or worsening consolidation in chest radiology along with evidence of any two of the following variables: fever >38°C, increased white blood cell count, and purulent secretions. When Fabregas et al. [14]. chose to compare immediate post-mortem lung biopsies, its sensitivity was only 69%, and specificity reached 75%, proving this criterion to have low accuracy. Despite this relatively low accuracy, these criteria were approved by the American Thoracic Society Consensus Conference for correct diagnosis of VAP [18].

VAP is also classified based on the onset of symptoms. Development in less than 4 days of admission is considered early-onset VAP, and it most commonly arises as a result of microorganisms sensitive to antibiotics. On the other hand, development of VAP more than 4 days after admission is classified as late-onset VAP and is usually due to MDR pathogens [9].

Delayed diagnosis, along with a delay in its required therapy, may lead to worsening symptoms in patients with VAP. Similarly, a false diagnosis will lead to unwarranted treatment and its associated complications. An early and clinically accurate diagnosis is key in managing patients with VAP [16].

1.3 Management of VAP

Current guidelines prepared by a joint committee of American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) consider late-onset VAP a risk for MDR pathogens, so they aim to focus more on identification of risk factors and prompt administration of empiric therapy so as to not exacerbate symptoms.

Pathogens that are most often seen to be causing VAP include gram-negative bacteria such as P. aeruginosa, Escherichia coli, Acinetobacter species, K. pneumoniae, and Gram-positive bacteria such as Staphylococcus aureus [9].

Antibiotics that target specific pathogens of VAP are ideally recommended for treatment of clinically suspected VAP to allow for coverage of Staphylococcus aureus, Pseudomonas aeruginosa, and other gram-negative bacilli so as to minimize overtreatment and its subsequent outcomes. The Table 2 summarizes different treatment modalities for VAP proposed over the years.

Guideline	Empiric treatment recommendation	Aerosolized antibiotic recommendation	Duration of antibiotic therapy
Qiu [19]	—	For VAP/HAP patients infected with gram-negative bacteria, that is, identified as multidrug-resistant, a combination of systemic antibiotics and aerosol inhalation antibiotics can be considered to improve the cure and clearance rate of respiratory bacteria responsible for causing pneumonia.	—
Qu [20]	For HAP/VAP patients with risk factors of MDR Pseudomonas aeruginosa and other MDR gram-negative bacilli infection or high risk of death, the combination of two different types of antibiotics is recommended.; HAP/VAP patients who are not critical/have no risk factors for MDR infection can be given a single antibiotic as empirical treatment	—	—
	—	The administration of nebulized colimycin (sodium colistimethate) and/or aminoglycosides is suggested; the suggested treatment as multidrug-resistant gram-negative bacilli are proven to be sensitive to the aforementioned drug combination when no other antibiotics are being used	The recommended duration for antibiotic treatment in the case of HAP should be less than 7 days except during specific situations like immunosuppression, empyema, necrotizing or abscessed pneumonia
Torres et al, [5]	It may be advisable to base empiric treatment plans on local prevalence of pathogens linked to VAP and their susceptibility to antibiotics.	—	Using a 7–8-day course of antibiotic therapy is suggested in VAP patients who are not diagnosed with immunodeficiency, cystic fibrosis, empyema, lung abscess, cavitation, or necrotizing pneumonia and having a good clinical response to therapy
Kalil [21]	It may be advisable to base empiric treatment plans on local prevalence of pathogens linked to VAP and their susceptibility to antibiotics.	Patients that are known to have been infected by gram-negative bacilli leading to VAP, which are susceptible only to aminoglycoside or polymyxins, are advised to receive both inhaled and systemic antibiotics, as opposed to just systemic antibiotics alone	For patients with VAP, a 7-day course of antimicrobial therapy rather than a longer duration is recommended

Table 2.

Guidelines for the management of ventilator-associated pneumonia.

1.4 Empirical antibiotics

Twenty-one recommendations on empiric therapy for treatment of VAP were gathered from a compilation of four guidelines [5, 18, 22, 23]. All the guidelines advised for the implementation of an empirical treatment plan are based on local prevalence of pathogens linked to VAP and their susceptibility to antibiotics. Due to this, narrow-spectrum antibiotics such as ertapenem, cefotaxime, moxifloxacin, or levofloxacin were recommended for patients with a lower likelihood of developing multidrug resistance (MDR) infection and early-onset VAP [23].

Antibiotic combination therapy was considered suitable if the pathogen was considered empirically to be multidrug resistant. The 2016 guidelines from the Infectious Diseases Society of America (IDSA) [24] recommended empirical dual therapy targeting both gram-negative bacteria and MRSA, with vancomycin or linezolid as the standard suggested treatment.

1.5 Etiological treatment

Fifteen recommendations on etiological treatment for VAP were gathered. Once the infecting pathogen is identified, its corresponding antimicrobial treatment plan should be administered with reference to the results obtained from in vitro drug sensitivity tests. This detailed treatment plan can be seen in the IDSA 2016 guideline [24], CMA 2018 guideline [24], and IDST 2018 guideline [21]; however, the CMA 2018 guideline and IDST 2018 guideline did not give any recommendations on strength.

The 2016 JAID guideline [21] recommendeds sulbactam (SBT) and ampicillin (ABPC) as the first-choice drug for respiratory infections caused by Acinetobacter Baumann. The CMA 2018 guideline also recommends SBT in combination with polymyxin, tigecycline, or doxycycline. However, the IDSA 2016 guideline warned against the use of tigecycline for patients with VAP caused by Acinobacter species, since it was related to worsening of outcomes compared with other therapies.

2. Aerosol inhalation antibiotic therapy

Four guidelines [5, 25, 26, 27] recommend aerosol inhalation antibiotic therapy for the treatment of VAP, while the 2018 CMA guidelines reinforce improved cure rate and clearance rate of respiratory bacteria causing pneumonia for patients infected with multi-drug resistant gram-negative bacteria.

2.1 Duration of antibiotic treatment

The IDSA 2016 guideline and SFAR 2018 guidelines [27] strongly recommend a 7-day course of antimicrobial treatment, while the ERS 2017 guideline [28] weakly recommends a 7–8-day course of antibiotic therapy. The IDSA 2016 guideline reported a decrease in antibiotic exposure and antibiotic resistance without increasing mortality or recurrent disease, hence reducing cost and side effects.

Timely commencement of management and appropriate dosage of therapy are crucial for critically ill patients to ensure adequate treatment and reduction of morbidity and mortality. Over the years, various antibiotic therapies have been used to treat VAP based on isolated microorganisms.

Active agents against methicillin-resistant Staphylococcus aureus like vancomycin and linezolid have been used to treat VAP in patients with antimicrobial resistance. However, based on current research, the most effective antimicrobial agents against P. aeruginosa are antipseudomonal antibiotics. They can be further classified into β-lactams (ticarcillin, piperacillin, aztreonam, imipenem, cefsulodin, cefoperazone, and ceftazidime), non–β-lactams (like ciprofloxacin, levofloxacin, amikacin, gentamicin, tobramycin, colistin, polymyxin), and most recent aminoglycosides, fluoroquinolones, and fosfomycin. The combination of ceftazidime and amikacin is regarded as the primary treatment plan for antipseudomonal chemotherapy [29]. Table 3 reflects the different antibiotic groups used against various organisms.

Drug	Spectrum	Labeled indications
Ceftobiprole	Nonextended spectrum β-lactamase, non-AmpC, and non-carbapenemases-producing Enterobacterales, P. aeruginosa, MRSA	EMA: HAP excluding VAP, CAP, ABSSSI
Ceftazidime-avibactam	ESBL, KPC, AmpC, and some OXA (e.g., OXA 48)-producing Enterobacterales, MDR P. aeruginosa, MDR A. baumannii	FDA: HAP/VAP, cUTIs, cIAIs; EMA: all those infections due to aerobic gram-negative organisms with limited treatment options
Ceftolozane-tazobactam	ESBL-producing Enterobacterales, MDR P. aeruginosa, some anaerobes, Streptococcus spp., MSSA	FDA: HAP/VAP, cUTIs, cIAIs; EMA: HAP/VAP, cUTIs, cIAIs
Meropenem-vaborbactam	ESBL, KPC, AmpC-producing Enterobacterales, non-MDR P. aeruginosa, non-MDR A. baumannii, Streptococcus spp.; MSSA	FDA: cUTI, including pyelonephritis.; EMA: cUTI (including pyelonephritis), HAP, VAP, cIAI, and infections due to aerobic GNB with limited treatment options
Imipenem-relebactam cilastatin	ESBL, KPC-producing Enterobacterales, MDR P. aeruginosa, Streptococcus spp., MSSA	FDA: HAP/VAP, cIAI, cUTI; EMA: infections due to aerobic GNB with limited or no other therapeutic options
Cefiderocol	ESBL, CRE (class A, B, and D enzymes), CR P. aeruginosa, S. maltophilia, A. baumannii, Streptococcus spp.	FDA: cUTI, HAP/VAP EMA: infections due to aerobic GNB with limited therapeutic options

Table 3.

Different antibiotics used for different organisms causing ventilator-associated pneumonia.

3. Ceftolozane-tazobactam

Ceftolozane-tazobactam is a combination of a fifth-generation cephalosporin with a β-lactamase inhibitor. Ceftolozane is capable of overcoming bacterial resistance, and using it in combination with tazobactam expands its activity against β-lactamases-producing Enterobacterales [30]. During in vitro studies, ceftolozane–tazobactam shows increased activity against P. aeruginosa, since it is more active against MDR or extremely drug-resistant (XDR) strains [31] A multicenter Italian cohort study included 101 patients treated with ceftolozane–tazobactam for severe infections caused by P. aeruginosa. Overall, 84 patients showed clinical success out of 101 (83.2%) after treatment. A clinical success rate of 75% was also seen in the subgroup of nosocomial pneumonia [32].

3.1 Meropenem-vaborbactam

Meropenem–vaborbactam is a β-lactamase inhibitor combined with a carbapenem made with the intention of exhibiting high activity against MDR Enterobacterales [33].

The in vitro activity of meropenem–vaborbactam against gram-negative isolates was tested on hospitalized patients with pneumonia, including VAP, which showed the highest susceptibility rates against Enterobacterales isolates (98.0%). Along with this, meropenem–vaborbactam was seen as the most active β-lactam tested (82.1% susceptible) against P. aeruginosa isolates, with amikacin (86.0%) and colistin (99.4%) showing higher susceptibility rates [34].

3.2 Imipenem-relebactam

Imipenem is a cabapenem antibiotic that is used in combination with relebactam, a bicyclic diazabicyclooctane β-lactamase inhibitor. The addition of relebactam to imipenem increases the activity of the carbapenem against gram-negative bacteria, including strains that are not susceptible to imipenem such as P. aeruginosa and some β-lactamase-producing Enterobacterales [29]. The rate of sensitivity of P. aeruginosa to imipenem–relebactam was approximately 90% [35].

3.3 Cefiderocol

Cefiderocol is a cephalosporin that exhibits activity against gram-negative bacilli, including Enterobacterales, allowing it to remain stable in the presence of all classes of β-lactamases. A CREDIBLE-CR study trial was carried out to compare cefiderocol with BAT for treating HAP, VAP, cUTI, or bloodstream infections due to carbapenem-resistant gram-negative bacilli.

Nosocomial pneumonia was present in 45% of the patients, and almost 25% of them were diagnosed with VAP. The most common isolates found from this test were A. baumannii (46%, 54 patients), K. pneumoniae (33%, 39 patients), and P. aeruginosa (19%, 22 patients).

Regarding patients with HAP and VAP who were infected by A. baumannii, mortality was seen to be much higher in the cefiderocol group (42%) when compared with the BAT group (18%) [36].

3.4 Amikacin in VAP

Timely commencement of management and appropriate dosage of therapy are crucial for critically ill patients to ensure adequate treatment and reduce morbidity and mortality. Over the years, various antibiotic therapies have been used and are still used to treat VAP based on the microorganism isolated [37].

Amikacin is an aminoglycoside that targets more resistant gram-negative bacilli causing VAP, such as Acinetobacter baumanii and Pseudomonas aeruginosa, which are some of the most difficult nosocomial infections to treat. Amikacin kills bacteria by binding to the 30S bacterial ribosome subunit, which interferes with a reading of the genetic code and hence inhibits protein synthesis by, for example, eliciting premature protein termination and incorporating incorrect amino acid resulting in insufficient protein synthesis for the survival of the microorganism. Over the years, amikacin has been used increasingly and has shown good outcomes in treating VAP.

Amikacin is widely used in two forms—intravenous and nebulized. Initially, it was used in its IV form alongside medications such as carbapenems, cephalosporins, penicillins, and beta-lactamase inhibitors [38]. Introduction of amikacin to treatment guidelines dramatically altered care of patients in ICUs for the better, particularly in hospitals with high gentamicin and tobramycin resistance. Of 2661 gram-negative isolated in a study, an estimate of 2.0% were found to be resistant to gentamicin, while only 1.3% were resistant to amikacin [39]. This is because amikacin reduces the inactivation of bacterial acetylase, adenylase, and phosphorylase relatively more than other aminoglycosides [40].

However, the recent introduction of nebulized form of amikacin has revolutionized treatment and prevention of VAP in critically ill patients. When aerosolized amikacin was combined with IV forms of the antibiotics listed earlier, it showed to improve patient outcomes and increased chances of recovery. In order to prove this, a trial was done on 90 patients with VAP who were categorized randomly into three equal groups: Group I received IV amikacin and meropenem. Group II received the same as Group I with nebulized amikacin. Group III received IV amikacin, nebulized amikacin, and meropenem. Groups II and III showed a higher cure rate (53.33% and 66.67%, respectively) compared to Group I (26.67%, P = 0.007). Group II showed relatively significant reduction in ventilator days (5.32 ± 1.86 vs. 7.3 ± 2.1 days, respectively, P < 0.001) and reduction in ICU stay (11.87 ± 2.6 vs. 15.3 ± 3.1 days, respectively, P < 0.001) compared to Group I. Group III showed significant reduction in days of ventilation (4.22 ± 1.32 vs. 5.32 ± 1.86, respectively, P = 0.011) and a particularly significant reduction in ICU stay (9.21 ± 1.17 vs. 11.87 ± 2.6, respectively, P < 0.001) compared to Group II [41].

A combination of nebulized and IV amikacin is also a combination frequently used. A 5-year observational study was conducted, which had 154 patients diagnosed with VAP caused by P aeruginosa, who were split into two categories: (i) 79 consecutive patients treated with IV amikacin from January 2011 to August 2013, and (ii) 75 consecutive patients received nebulized amikacin administered from September 2013 to February 2016. In both groups, amikacin was taken for 1 to 5 days with an IV β-lactam for 10–14 days. Results showed that the aerosol group had a clinical cure rate of 72%, while the IV group showed 58%, with a significant difference of p = 0.02 between the two groups. This proves the significance of nebulized amikacin in treatment of VAP, and it does so by providing better oxygenation and organism clearance by allowing more product to reach the site of infection, that is, the lungs [42].

Additional benefits to using aerosolized forms of amikacin are that it has even proven to cause fewer side effects like nephrotoxicity and lessens the duration of mechanical ventilation and ICU stay. A recent study was carried out on 64 mechanically ventilated patients with gram-negative VAP. The patients were divided into two groups: Group A was treated with nebulized amikacin plus IV amikacin and included 32 patients, while 32 patients in group B were treated with IV amikacin alone. Both groups were given treatment for a duration of 8 days. The results of this study showed that Group A had a significant improvement of oxygenation before and after treatment (p 0.006), compared to group B that showed no significant difference (p 0.212). The length of stay was 21.5 days in Group A and 25.5 days in Group B, with a relatively significant reduction in group A (p 0.037). The duration of mechanical ventilation in Group A of 19 days was much less than Group B that showed 23 days, with a significant reduction (p 0.045) of ventilator days.

Additionally, Group B showed a significant rise of creatinine level after treatment (p < 0.001), while no significant rise in creatinine level was found in Group A after treatment. A noteworthy difference between groups A and B (p 0.003) was also seen after the end of treatment. The mortality was 19 (60%) in Group A and 26 (80%) in Group B.

As time progressed and more research was conducted, nebulized forms of amikacin began to replace its IV form when it was found that repeated doses of aerosolized amikacin could be safely administered and bring about improvement in mechanically ventilated patients without causing serious side effects or increasing mortality. A study was conducted that involved administering aerosol amikacin administered with IV treatment in ventilated patients who acquired gram-negative pneumonia. Patients were randomized where one group received aerosolized amikacin daily with placebo (normal saline) 12 hours later, one received amikacin twice daily, and the other placebo twice daily [43]. The results revealed that the mean number of IV antibiotics were two times greater with placebo than with twice-daily amikacin (P < 0.02). For daily and twice-daily amikacin, the serum Cmax were 1.3 and 1.8 μg/ml, respectively, on day 1, and 2.3 and 3.2 μg/ml on day 3. Mean trough levels were 0.87 and 1.49 μg/ml. Tracheal aspirate levels (mean) on day 3 were found to be 6.9 mg/ml (daily) and 16.2 mg/ml (twice daily). This shows that mechanically ventilated patients with gram-negative pneumonia can safely be treated with repeated doses of adjunctive inhaled amikacin as it is well tolerated by most while simultaneously lessening the need for frequent IV antibiotic use.

Recent study done by Lu et al. proves that nebulized form of amikacin works best against intermediate strains and reduces chances of developing antibiotic resistance. In this study, 40 patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa were studied in a comparative phase II trial. Twenty patients infected with susceptible or intermediate strains were treated with nebulized ceftazidime and amikacin (25 mg·kg⁻¹·d⁻¹). Seventeen patients infected with susceptible strains received intravenous ceftazidime and amikacin (15 mg·kg⁻¹·d⁻¹). After 8 days of treatment, acquisition of antibiotic resistance was seen exclusively in the intravenous group. Moreover, in the aerosol group, four patients infected with intermediate strains were treated successfully [44].

Furthermore, it has also been seen that if administered via inhalation prophylactically within the right time frame, amikacin has shown to reduce chances of development of VAP in the first place. A study enrolled 850 patients who underwent randomization to have 417 placed in the amikacin group and 430 in the placebo group. Amikacin nebulizations were administered thrice daily at a dose of 20 mg/kg in 337 patients (81%) in the amikacin for 28 days. The results showed that ventilator-associated pneumonia developed in 62 patients (15%) in the amikacin group and in 95 patients (22%) in the placebo group, with a difference in mean survival time to ventilator-associated pneumonia of 1.5 days, 95% confidence interval [CI]of 0.6 to 2.5, and P = 0.004. Similarly, 74 patients (18%) in the amikacin group developed infection-related ventilator-associated complication, while 111 patients (26%) in the placebo group developed similar complications (hazard ratio, 0.66; 95% CI, 0.50 to 0.89), proving that inhaled amikacin can reduce the burden of ventilator-associated pneumonia in ICU patients [45].

3.5 Prevention of VAP

With better understanding of the pathophysiology of VAP, new advancements have been made for the prevention of VAP. These include non-pharmacological as well as pharmacological interventions.

4. Non-pharmacological preventative strategies

4.1 Utilization of preventative bundles

Preventative bundles, consisting of evidence-based preventive measures, are implemented to maximize efficacy. Although challenging to procure and implement due to the necessity of continuous surveillance to ensure compliance and measure improvements, several studies have proven their effectiveness in reducing the occurrence of VAP. For instance, in one study, the incidence of VAP decreased from 8.6 per 1000 ventilator days before bundle implementation to 2.0 per 1000 ventilator days after (P < 0.001) [46]. Similar studies have reported comparable results.

4.2 Modification of artificial airways

Efforts have been made to improve the design of endotracheal tubes (ETTs) to enhance sealing properties. For instance, researchers found that the ratio between the diameter of the cuff and the tracheal internal lumen, cuff length, and cuff pressures were associated with tracheal sealing (Li Bassi et al.) [47]. Additionally, subglottic secretion suction (SSS) has shown consistent evidence of benefits in reducing VAP incidence (Mao et al.) [48]. Meta-analyses have confirmed that SSS is associated with a decrease in VAP incidence, decreased ventilator days, and ICU length of stay. A new ETT, the PneuX, has been evaluated in clinical settings, featuring a low-volume, low-pressure silicone cuff and a continuous tracheal seal monitor system [4].

4.3 Adjustment of body position

Studies have demonstrated that semi-recumbent positions with higher head-of-the-bed orientation reduce the risk of clinically suspected VAP compared to supine positions. Moderate quality evidence supports this finding [49].

5. Pharmacological preventative strategies

5.1 Oropharyngeal decontamination

Decontamination agents such as chlorhexidine and hydrogen peroxide have been widely successful in preventing VAP, as oral hygiene plays a significant role in the development of respiratory infections. High-quality evidence supports the efficacy of chlorhexidine in reducing the incidence of VAP compared to placebo or usual care. Similarly, hydrogen peroxide has shown significant effectiveness in reducing VAP incidence [50].

5.2 Prophylactic antimicrobials

Antimicrobials administered intravenously, nebulized, or to the gastrointestinal tract have been used to prevent VAP. However, concerns about antibiotic resistance arise in the time of multidrug resistance. Studies have shown a lower incidence of gram-negative bacilli and multidrug-resistant bacteria VAP in patients who received colistin, but the long-term deleterious effects of antibiotic resistance require further evidence [51].

5.3 Probiotics

Probiotics, microorganisms administered as individual strains or combinations, have shown promise in reducing VAP incidence. A 2016 meta-analysis supports their use as a preventive strategy to maintain gastrointestinal homeostasis and inhibit colonization [52]. However, larger randomized trials are needed to conclusively establish their benefits.

6. Implications

Despite showing good response to eradicating gram-negative bacilli in ventilated patients, numerous studies have revealed why treatment with amikacin might not be sufficient. One of the biggest reasons for this is antibiotic resistance. Studies from as early as the 1980s have documented the development of resistance to amikacin, along with multiple other antimicrobials [53]. Resistance can develop due to several reasons such as alteration of the target site, enzymatic inactivation of the drug, or establishment of a permeability barrier to the drug [54]. Another common risk factor found to cause amikacin resistance was insufficient dosage and frequently changing medications and doses. Since then, hospitals globally have been taking necessary precautions to prevent or at least slow down the rate at which resistance is developing. This is done by restricting treatment to one antimicrobial at a time and ensuring it is administered at the right dosage [55].

As mentioned earlier, aminoglycosides like amikacin are often paired with other antimicrobials to broaden the antibacterial spectrum and reduce chances of resistance. However, combination therapy with amikacin was found to result in a significantly higher incidence of adverse effects, most noteworthy one being nephrotoxicity [3].

As the fields of medicine and pharmacology are ever evolving to continuously improve quality of care provided to patients and combat restrictions, alternative combination therapies have been found to show better responses to treating VAP by reducing ICU mortality, decreasing duration of mechanical ventilation, and lessening duration of ICU stay while being a lot more cost effective. Furthermore, these new medications also produce lesser side effects than combination treatments with amikacin [6].

In addition to these recent advancements, a recent study found that nebulized amikacin might not have a major role to play in treating VAP. When compared with a placebo, it was found that there was no particular difference in survival rates of either groups: 191 (75%) patients in the Amikacin Inhale group survived compared to 196 (77%) patients in the placebo group (odds ratio 0·841, 95% CI 0·554–1·277; p = 0·43), further raising doubts about the active and significant role of inhaled amikacin with intravenous antibiotic treatment in mechanically ventilated patients who have acquired gram-negative VAP [1].

Nevertheless, despite aminoglycosides being an older group of antibiotics, they continue to be clinically valuable, particularly amikacin for its broad-spectrum bactericidal activity especially against gram-negative bacteria if used correctly with adequate monitoring, dosing, and administration timings to reduce development of side effects and resistance.

7. Conclusion

Based on current research, amikacin has proven successful in treating ventilator-associated pneumonia with minimal adverse effects such as nephrotoxicity and has markedly reduced the duration of mechanical ventilation and ICU stay. Its nebulized form demonstrates the most effective response against intermediate strains and has also been used prophylactically in the prevention of VAP. Utilization of the aforementioned preventative, diagnostic, and therapeutic recommendations may allow for improved outcomes seen in mechanically ventilated patients suffering from ventilator-associated pneumonia.