Another type of common nosocomial infection caused by catheters in hospitals is CAUTI. Removal of the urinary catheter in the shortest time possible is a basic step to prevent infections. However, adhering to this rule in hospitals is very difficult. Long-term catheterization should only be recommended in very justified cases. From this perspective, identifying the risk factors for CAUTI is critical [
25,
26]. Letica-Kriegel et al. (2019), similarly to other authors, observed that when the duration of catheterization increased, the risk of infection also increased. Furthermore, they confirmed that approximately 12% of patients with an indwelling catheter developed CAUTI within 30 days. Some risk factors are predominantly associated with CAUTI [
27,
28]. The above-mentioned study defined two main hazards, i.e., sex (female) and those associated with mobility issues [
27]. Medina-Polo et al. (2021) determined in their study that a catheter in the upper urinary tract and immunosuppression are the other critical factors contributing to CAUTI caused by MDR bacteria [
29].
Microorganisms can survive not only in planktonic form, but also they frequently colonize medical devices and form mono- or inter-species communities. Biofilms have subsequently become more resistant to conventional drugs, often resulting in chronic infections in patients [
17,
32,
33,
34]. Svensson et al. (2021) noted that a strong biofilm production was significantly associated with recurrent infection [
34]. According to a meta-analysis of PubMed and Web of Sciences databases from January 2005 to May 2020 published by Pinto et al. (2021), strong biofilm producers tested in vitro and associated with BSI were strongly represented among the resistant strains. Methicillin-resistant
S. aureus (MRSA) was mainly mentioned. Moreover, biofilm producers were also highly linked to BSI persistence. It is of interest that this association was the highest for
Candida spp. As for UTIs, multi-resistant
E. coli was observed to be the predominant strong biofilm producer. The above-mentioned study clearly proved that biofilms must be assumed to be a BSI and UTI resistance factor [
33].
2.1. Central Line-Associated Bloodstream Infections Including Catheter-Related Infections
The term “central line” is defined as an intravascular access device or catheter that terminates at or close to the heart or in one of the major blood vessels. CVCBSI is a clinical definition used when diagnosing and treating patients that identifies the catheter as the source of BSIs. Catheter colonization is defined as the presence of ≥15 Colony-Forming Units (CFU) of a single organism per catheter. The colonization of a catheter by microorganisms together with CLABSI can be considered to be catheter-related infections (CRI) [
32,
35].
The ECDC published an updated document providing definitions of standardized protocols of data collection and reporting for hospitals participating in the surveillance of HAIs in ICUs across Europe. A BSI should be reported as a CRI when the same microorganism is cultured from the catheter, or symptoms improve within 48 h after removal of the catheter, or a BSI is reported as secondary to another infection [
3,
14]. This definition differs from the definition of the National Healthcare Safety Network of the USA Centers for Disease Control and Prevention of CLABSI, which includes all primary BSIs with a central line in place for at least 48 h on the date of the BSI [
36].
CVCs are generally inserted in around 50% of patients in ICUs. Because of direct contact with the bloodstream, there is a higher risk of septicemia leading to severe systemic infections, including sepsis. Therefore, the application of a CVC to a patient is the most frequent cause of hospital bacteremia, and about 40% of all primary BSIs are related to a CVC [
13,
35]. CVCs are tubular structures generally implanted into veins and used to deliver medication or nutrients to the patients, for hemodialysis and blood testing [
37]. This CVC is inserted through a peripheral vein or a proximal central vein, internal jugular, subclavian, or femoral vein. There are four types of CVC: non-tunneled pulmonary artery CVC, peripherally inserted CVC, tunneled CVC, and totally implantable CVC [
35].
Several European prevalence studies have been conducted by the ECDC [
5]. Plachouras et al. (2018) summarized the data from the last study, conducted in 2015–2016, in which 11 European countries were involved. The data showed that from a total of 141,955 patients from 617 ICUs, 2555 CLABSIs were identified, corresponding to a cumulative incidence of 1.8 episodes per 100 patients and representing 48% of all ICU-acquired BSIs [
38]. For comparison, the previous study, conducted by the European network for the surveillance of ICU-acquired infections in 2004—2005, collected data from nine countries. The incidence density of BSI ranged from 1 to 3.1 per 1000 patient days, where 60% of cases were diagnosed as CVCBSI [
13]. Generally, rates of catheter-related bloodstream infections (CRBSIs) higher than 2 per 1000 catheter-days should not be acceptable [
5,
13]. The CRBSI-related mortality and the annual costs associated with CRBSI in the European countries according to the study were about 1000–1584 deaths per year and costs of 35.9 to 163.9 million euros [
39]. The surveillance and introduction of bundles of care processes relating to the insertion and maintenance of CVCs produced a fall in the annual CRBSI from 3.4 to 0/1000 patient days with zero episodes [
39]. Novosad et al. (2020) compared data collected from the USA on the incidence of CLABSI infections during the period of 2011 to 2017 and revealed that around 50% of all ICU patients were with CVCs. Of the CLABSI, around 60% and 40% were adults and children, respectively [
40]. A case study conducted by Baier et al. (2020) showed that the healthcare costs of CLABSI analyzed in stem cell transplantation and cancer patients was estimated to amount to be 8810 € per case [
41]. According to the CLABSI prevention guidelines developed by the Asia Pacific Society of Infection Control, a pooled incidence density of CLABSI reached a value of 4 to 7 per 1000 catheter-days [
32].
Several factors, such as patient condition, duration of catheterization, type of catheter material, and catheterization handling have been shown to increase the risk of CVC infection [
42]. A highly contributing factor is the duration of catheterization, while a significant proportion of CRIs occurred after ≥15 days [
43]. As is mentioned in the “Guidelines for the Prevention of Intravascular Catheter-Related Infections”, the type of catheter material as well as insertion site has an impact on CLABSI occurrence. Catheter irregularities, the formation of a fibrin sheath, and thrombogenic potential could allow pathogenic microorganisms to adhere, resulting in biofilm formation [
35]. For example, the use of polyvinyl chloride or polyethylene materials can cause less complications associated with infections compared to other materials (Teflon, polyurethane) or steel needles [
44]. A comparative study by Pitiriga et al. (2020) confirmed this fact and showed that catheter insertion into the femoral vein was associated with a higher rate of BSI and catheter colonization compared to other sites such as a subclavian and internal jugular site. Another factor may be seasonal prevalence changes among microorganisms [
43]. A study by Blot et al. (2021) examined a seasonal variation of monthly hospital-acquired BSIs, including CLABSIs incidence rates, in the period of 2000 to 2014, with summer incidence spikes for
Enterobacterales (
E. coli,
K. pneumoniae, and
Enterobacter cloacae) and non-fermenters (
P. aeruginosa,
A. baumannii, and
Stenotrophomonas spp.) [
45].
Microorganisms isolated from CVCs (also CLABSI) represent a range from virulent microorganisms to the normal resident microbiome of the skin at the insertion site. From Gram-positive bacteria, specifically coagulase-negative staphylococci (CoNS), namely
S. epidermidis, then MRSA, enterococci (
Enterococcus faecalis and
Streptococcus spp.) were confirmed. From Gram-negative bacteria,
P. aeruginosa,
K. pneumoniae,
E. coli,
Enterobacter spp.,
A. baumannii, and
P. mirabilis are frequent sources of CRIs.
Corynebacterium spp. is less frequent. From yeasts,
Candida albicans and other
Candida spp. have been associated with catheter infections [
13,
46,
47,
48]. It is noteworthy that a high incidence of MDR related to CLABSI was observed [
49]. In general, there are increasing trends of CVC infections caused by Gram-negative bacteria [
50]. According to the Plachouras et al. (2018), the most commonly isolated microorganisms in ICU-acquired CLABSIs were Gram-positive bacteria, with 48.1%, and then Gram-negative bacteria with 42.6%. Other microorganisms were estimated to amount to 9.3%. The incidence among Gram-positive bacteria was as follows: CoNS (28.4%),
Enterococcus spp. (9.3%), and
S. aureus (8.7%). Among Gram-negative bacteria,
Klebsiella spp. (11.4%) was the most common, followed by
P. aeruginosa (7.4%).
Candida spp. belonged to the group “Others”, with 8.8%. [
51].
C. albicans is the most common
Candida spp. with CVC-related infections. The mortality rate of these infections can reach 50%, even with treatment [
52]. One of the most important virulence factors of
C. albicans is the ability to switch from the yeast form to the hyphal form. This morphological switching is an advantage that provides an appropriate base for the colonization of hyphae by other microorganisms, especially
S. aureus,
S. epidermidis, or enterococci [
53].
The above-mentioned microorganisms usually have a high capability to form biofilms. They can attach to both abiotic and biotic surfaces and transform from planktonic to sessile form and then aggregate into microcolonies embedded in EPS. In particular, microorganisms commonly isolated from BSIs, namely
Staphylococcus spp. and
Candida spp., are able to survive up to 20% in the polymicrobial community. In such mixed biofilms,
C. albicans can contribute to increased bacterial resistance to antibiotics, the survival and growth of anaerobic bacteria under aerobic conditions or lead to an increase in their virulence. Moreover, these biofilms are much more resistant to treatment and the host immune response. Biofilms are therefore often responsible for the dangerous contraindications associated with CRI and can develop into a chronic condition [
54].
Many techniques have been used to prevent the formation of biofilm by targeting different stages of biofilm formation. Conventional approaches for the prevention of CLABSI include general precautions such as aseptic maintenance during CVC insertion [
55]. Conducting staff training and implementing strict guidelines in a few hospitals in the USA produced a significant reduction in CLABSI cases [
23,
56]. In case of infection, non-essential catheter removal should be considered [
13,
57]. Another well-known strategy, antibiotic lock therapy, is the most tested. A controlled release of the antibiotics assists the penetration of antimicrobial compounds through the barrier of a biofilm [
58]. Other approaches for preventing CVC-related infection, such as antimicrobial CVC, needleless IV access devices, antimicrobial dressing, etc., are in use as well [
59,
60]. One of the antibiotic combinations used in the impregnation of CVC is minocycline/rifampin, or for infants, miconazole and rifampin [
61]. The use of different coatings, such as chlorhexidine and gluconate or silver sulfadiazine, reduced the risk for CRBSI compared to the standard non-coated catheters [
62]. However, the study of Cui et al. (2020) suggests that there is a doubt of whether sufficient antibacterial function can be maintained with prolonged duration of catheter placement due to the blood flow [
63].
Another promising strategy is coatings comprising naturally occurring antimicrobial peptides with a strong antibacterial/antibiofilm potential [
64]. Catheter lock therapy is useful, especially in cases of uncomplicated long-term catheter-related BSI caused by CoNS or
Enterobacteriaceae. A catheter lock solution, taurolidine, has provided promising results among children as taurolidine prevents biofilm formation and has broad-spectrum bactericidal and antifungal activity [
47]. Kumar et al. (2021) introduced this antimicrobial lock therapy as the best economically viable option. They utilized S-nitroso-N-acetyl-l-cysteine ethyl ester (SNACET) as the catheter lock solution as it generates nitric oxide, which manifests antimicrobial properties. Parameters such as stability and release were analyzed, and the efficacy of microbial adhesion against
S. aureus and
E. coli showed an over 99% reduction. SNACET has also been used for catheter coating. This catheter provided a 90% reduction in bacterial adhesion, providing a novel idea for tackling CVC infections [
65]. Polysaccharides are interesting molecules for antifouling applications. Research conducted by Bujold et al. (2020) reported that low-dose unfractioned heparin decreased the incidence of CLABSI among critically ill children [
66].
Experience obtained in material chemistry research suggests that a combination of antifouling and fouling release properties of a material could significantly improve its properties because of resistance to protein absorption and bacterial adhesion [
67].
2.2. Catheter-Associated Urinary Tract Infection
UTIs are very common. Most UTIs are considered to be uncomplicated, well-treatable infections occurring in healthy individuals. Unlike them, complicated UTIs are associated with different serious diagnosis or when the infection is caused by a resistant microorganism that significantly increases the risk of therapy failure. UTIs are prevalent around the world and represent approximately 40% of hospital-acquired infections. They usually occur after instrumentation such as nephrostomy tubes, ureteric stents, suprapubic tubes, or Foley catheters. Among UTIs, 75% to 80% of infections are associated with using catheters [
68,
69]. The study of Gunardi et al. (2021) confirmed this observation: out of 109 catheterized patients, 78% with a urinary catheter were documented as being positive compared to only 37.62% of samples isolated from urine [
70].
Urinary catheters are tubular structures made of latex or silicone material used to prevent retention during the patient’s surgical procedure. An indwelling catheter has a high risk of forming a biofilm compared to intermittent catheters present in the body for a short time (for up to 7 days) [
23]. CAUTI is defined as a symptomatic UTI in a person with a catheter. This definition remains controversial, but is more or less globally accepted [
69,
71]. The prevention of CAUTI is discussed in the Centers for Disease Control and Prevention (CDC)/Healthcare Infection Control Practices Advisory Committee’s document “Guideline for Prevention of Catheter-associated Urinary Tract Infection”, which was updated in June 2019. The main mission of this guideline is to formulate recommendations and explicit links between the evidence and recommendations. The document includes key questions focused on (i) who should receive urinary catheters; (ii) benefits and risks; (iii) the best practices for preventing CAUTI [
71]. The distinction between CAUTI and non-catheter-associated UTI is elaborated in the CDC/National Healthcare Safety Network document [
72].
CAUTIs are responsible for causing mild catheter encrustation and bladder stones as well as septicemia, endotoxic shock, and pyelonephritis. Usually, a person with a catheter for over 30 days has been colonized, often with two to three types of microorganisms. As the main pathogens associated with UTIs are significant candidates for antibiotic treatment, they are a frequent source of horizontally transmitted resistance [
73]. Management of these infections is important in two respects: (i) providing proper treatment, and (ii) reducing costs associated with an HAI [
74]. Despite advances in prevention guidelines, there remains a lack of knowledge concerning the risk factors for CAUTI [
75].
Gunardi et al. (2021) analyzed a bacterial suspension of 109 catheters and the urine of catheterized patients. They confirmed that gender and the duration of catheterization are the two main risk factors associated with CAUTI. The most frequently isolated microorganisms from a urinary catheter were
E. coli (28.1%) followed by
Candida spp. (17.8%),
K. pneumoniae (15.9%), and
E. faecalis (13.1%), and biofilm-producing microorganisms were observed in 40% of isolates. Surprisingly, they did not find a correlation between biofilm and age or diabetes mellitus, which have generally been known as risk factors of CAUTI. The authors also observed that bacteriuria prior to catheterization as a single parameter cannot be directly associated with the formation of a biofilm [
70].
Microorganisms frequently colonize the surface of a urinary catheter, resulting in the formation of biofilms. Microorganism, such as
E. coli,
Enterococci spp.,
S. aureus,
P. aeruginosa,
P. mirabilis, and
Candida spp. are also frequently isolated from the infected patient’s catheters [
76].
Medina-Polo et al. (2021) determined that a catheter in the upper urinary tract and immunosuppression are the other critical factors contributing to CAUTI caused by MDR bacteria. They described that resistant bacteria occurred in 100 out of 438 (22.8%) positive cultures among patients with HAIs. The majority of resistant microorganisms were found in patients with a catheter in the upper urinary tract. Of the microorganisms, 28.4% of cultures were identified within the
Enterobacteriaceae family (23.8% and 44.7% in
E. coli and
Klebsiella spp., respectively). As for resistance, 7% of
Enterobacteriaceae showed resistance to carbapenems (1.3% and 10% for
E. coli and
Klebsiella spp., respectively). The rate of
P. aeruginosa resistant to at least three antibiotic groups was 36.3% [
29].
Several strategies have been introduced to tackle CAUTI. The most important is to reduce unnecessary catheterization and discontinue catheters as soon as possible. Patients with asymptomatic bacteriuria can generally be treated initially with catheter removal or catheter exchange and do not necessarily need antimicrobial therapy [
77].
In infection, the treatment procedure should be based on the preliminary diagnosis and identification of biofilm-forming microorganisms, as biofilm manifests increased resistance compared to the free-floating planktonic cells. The minimal inhibitory concentration (MIC) of amdinocillin determined for
E coli is 0.4 µg/mL, whereas 400 mg/kg is required for eradication of biofilm [
78]. Experiences suggest that sub-lethal doses of antibiotics against
K. pneumoniae biofilm can further promote resistance against an extended broad spectrum of beta-lactam antibiotics [
79].
Vallée et al. (2017) utilized temocillin, which possesses an immense urinary and prostatic diffusion property. Moreover, it manifests a high bactericidal activity as it kills bacteria, producing an extended spectrum of beta-lactamases [
80]. The research group of Ji et al. (2020) studied cranberry juice’s effectiveness on patients with UTI with short-term catheters and proved significant effects against the visible symptoms. Cranberry contains the active ingredient proanthocyanidins, which prevents the adhesion of microorganisms on the catheter surface. Cranberry was suggested as a supplemental therapy along with other strategies, which can assist in the reduction of the number of catheter days, providing a low chance of infection [
81]. Costa et al. (2020) developed anti-adhesive coating catheters with a natural polymer produced by cyanobacteria. These coatings were further tested in culture media and artificial urine biofilm-promoting conditions against primary contaminants of UTIs. The results proved excellent anti-adhesive properties, resulting in a reduced attachment of microorganisms to the catheter surface. This could be a novel alternative strategy to reduce the usage of antibiotics [
82].
The usage of nanoparticles in biomedical devices is a promising approach. Shalom et al. (2017) synthesized catheters coated with Zn-doped CuO nanoparticles. These catheters were tested in vivo in rabbits, and they provided excellent results in biofilm inhibition assays with no visible biofilm formation, even on the 7th day post-infection. Moreover, the biocompatibility tests proved the safety of the materials [
83]. Another highly prominent alternative to the antibiotic strategy is the usage of antimicrobial peptides. Yu et al. (2017) developed a surface with active antimicrobial peptides labelled with cysteine on polyurethane. This surface coating prevented bacterial adhesion by up to 99.9% for Gram-positive and Gram-negative bacteria. The in vivo experiments conducted on a mouse model showed a 4-log reduction. These catheters also proved to be safe in cytotoxic studies with fibroblast cells [
84]. Simple but effective techniques such as using chlorhexidine (0.1%) for cleaning prior to the catheter insertion can reduce the risk of infection. Switching to chlorhexidine from saline has saved AUD 387,909 per 100,000 for Australian hospitals [
85]. The use of silver alloy in urinary catheter coatings to reduce CAUTI is being tried, but no clear significant benefit has been observed [
86,
87]. The usage of fosfomycin trometamol is possible for the treatment of CAUTI patients as it possesses a low rate of bacterial resistance, and no cross- or parallel-resistance with other frequently used antibiotics has been identified [
88].
2.3. Ventilator-Associated Pneumoniae
VAP is the predominant infection of pulmonary parenchyma that develops in patients being supported by mechanical ventilators. Approximately one-third of nosocomial pneumonia cases, with the majority being VAPs, are acquired in the ICUs [
89]. Patients are often in bad condition, and the invasive procedure of intubation may contribute to the patient’s risk of colonization by exogenous microbes. They can come from contaminated bronchoscopes, water supply, respiratory equipment, humidifiers, ventilator temperature sensors, respiratory nebulizers, or a contaminated environment [
90]. The majority of infections occur within 48–72 h of subjecting the patient to a mechanical ventilator [
91,
92]. In previously healthy patients, normal oropharyngeal microbiota are usually involved in early-onset VAP (less than 4 days of hospitalization), whereas late-onset VAP (after at least 5 days of hospitalization) is more likely caused by nosocomial, often MDR pathogens [
93].
VAPs cause high infection rates and have demonstrated a high morbidity and increase in healthcare costs, leading to a financial burden on patients. Epidemiological studies reviewed by Bassi et al. (2014) pointed to the development of VAPs in approximately 10 to 40% of the patients on mechanical ventilation for more than 2 days [
90]. The estimated attributable mortality of VAPs is around 10%, with higher mortality rates in surgical ICU patients [
94]. Incidence rates vary among countries, while discrepancies may be caused by different interpretations of definitions, the selected type of microbiological sampling method, or the studied population [
92]. In addition, important differences between approaches in Europe and the USA have become apparent. International recommendations for hospital-acquired pneumonia (HAP)/VAP diagnosis, treatment and prevention (Guidelines for the management of HAP and VAP) were published under the auspices of a group of organizations (European Respiratory Society, European Society of Intensive Care Medicine, European Society of Clinical Microbiology, and Infectious Diseases and Asociación Latinoamericana del Tórax) [
89]. In America, the CDC American Thoracic Society and Infectious Diseases Society of America established the clinical pulmonary infection score criteria, which are even used by many studies in Europe [
95].
According to Torres et al. (2017), the incidence of VAPs is still very high (50%), despite the decreasing trend compared to the previous 10 years [
96]. In EU countries (nine EU countries included, study conducted in 2006), an incidence density of 18.3 VAP episodes per 1000 ventilator days was noted [
97]. The European study of ICU-acquired infections (data collected in 2007) showed that the overall incidence density was 7.9 pneumonia episodes per 1000 patient days. The mean device-adjusted pneumonia rate was 13.2 intubation-associated pneumonia per 1000 intubation days [
98]. From recent national studies, Wałaszek et al. (2018) monitored VAPs in Polish ICUs from 2013 to 2015. The incidence of VAP was 8.0%, and the incidence density was 12.3/1000 ventilator days [
99].
VAP risk factors include oropharyngeal and gastric colonization; thermal injuries; posttraumatic, postsurgical intervention factors such as emergency intubation, reintubation, tracheostomy, bronchoscopy, and inserting a nasogastric tube; patients’ body positioning; level of consciousness; stress ulcer prophylaxis; and the use of medications, including sedative agents, immunosuppression, and antibiotics [
100]. There is still confusion in the epidemiology and diagnostic criteria of VAPs, despite major advances in microbiological tools and antimicrobial treatment regimens [
92]. Modification of the oropharyngeal flora and trans-colonization plays a central role in the risk of infection. A better understanding of its physiopathology must be a priority in the context of the prevention of this infectious risk [
101].
Microorganisms such as
P. aeruginosa, members of the family
Enterobacteriaceae,
A. baumannii,
Stenotrophomonas maltophilia, and MRSA have been regarded as culprits in these infections [
102,
103]. These microorganisms often form biofilm. In one of the above-mentioned studies, the predominant etiologic agents causing VAP were
Enterobacteriaceae (32.6%), non-fermenting Gram-negative bacteria (27.6%),
S. aureus (21.3%), and
K. pneumoniae (12.5%). Using substandard methods, such as the cultivation of endotracheal aspirate or positive blood culture,
A. baumannii (23.8%) was also commonly observed [
99]. Similar microorganisms have been described in the work of Thorarinsdottir et al. (2020), who monitored the microbial composition (biofilm) colonizing mechanical ventilators [
104].
According to a prospective observational study on intensive care nosocomial pneumonia in Europe, data on VAP incidence showed variability between the countries involved. In Spain, France, Belgium, and Ireland, the predominant isolate was
S. aureus;
P. aeruginosa was observed in Italy and Portugal;
Acinetobacter was predominant in Greece and Turkey; and
E. coli was the most frequently isolated in Germany [
97]. Besides bacteria,
Candida spp. are frequently found in bronchial samples in mechanically ventilated patients. The study of Timsit et al. (2019) showed that 68.5% of patients receiving mechanical ventilation had a tracheal colonization with
Candida spp. Interaction between fungi and bacteria could lead to several complications (increase in bacterial toxin production or inflammation); however, the study did not find an association with a higher risk of bacterial VAP [
105]. Another fungal pathogen such as
Aspergillus fumigatus can be involved in VAP, particularly in patients with a recent history of influenza [
106]. Recently, there have been studies showing that SARS-CoV-2 infection can also be associated with VAP. The incidence of ventilator-associated lower respiratory tract infections is significantly higher in patients with SARS-CoV-2 pneumonia compared to patients with influenza pneumonia or no viral infection upon ICU admission [
107,
108].
Minimal ventilator usage is considered a good strategy, and the treatment should be limited to 7 days in the vast majority of cases [
92]. However, ventilator support is frequently necessary and critical for patients in the ICU. Several strategies have been in place against VAP. The administration of available antibiotics, for example, tobramycin inhalation solution, has reduced the recurrence of
P. aeruginosa among ICU patients compared to the control group treated with systemic antibiotics in Japanese hospitals [
109]. Sahuquillo et al. (2015) studied the effectivity of treatment by systemic antibiotics compared to their inhalation (tobramycin or colistin) in patients with microbiologically proved biofilms associated with VAP. Microbial infection was not influenced by the selected way of treatment [
110].
Selective digestive decontamination (SDD) as well as oral hygiene care (OHC) seems to be important for reducing infections in critically ill patients with mechanical ventilation. Janssen et al. (2021) in their study showed that patients with SDD treated with a paste and suspension composed of amphotericin B, tobramycin, and colistin, administered orally, had a better prognosis in developing postoperative pneumonia, with 20.1% cases compared to 36.9% once without SDD [
111]. Van Hout et al. (2019) treated patients four times a day with an oropharyngeal paste containing polymyxin E/colistin, tobramycin, and amphotericin B (2% concentration). Another group, in addition to the oropharyngeal paste, was treated four times per day with 10 mL of non-absorbable suspension of polymyxin E or colistin (100 mg), tobramycin (80 mg), and amphotericin B (500 mg) through a nasogastric tube. Additionally, a third-generation cephalosporin (cefotaxime, 1000 mg four times per day or ceftriaxone 2000 mg once per day) was administered intravenously during the first four days in ICU admission. The results showed that SDD significantly reduced mortality [
112].
The link between VAP and dental plaque/biofilm has also been intensively studied. It was shown that brushing teeth with 0.12% chlorhexidine is also effective in inhibiting oral biofilms, reducing the incidence of VAP in patients [
113]. Hua et al. (2016) tested chlorhexidine mouthwash on VAP-associated critically ill patients in the ICU and proved a reduction in VAP from 26% to approximately 18%. However, no evidence in mortality difference and duration of ventilation was obtained comparing patients with and without OHC [
114].
The use of an endotracheal tube with an ultrathin and tapered cuff and coated with antimicrobial agents, such as hexetidine, silver, silver-sulfadiazine, and chlorhexidine, has also shown promising results [
115]. An alternative strategy conducted by Prazak et al. (2019) showed the effectiveness of bacteriophages against resistant
S. aureus. Animal experiments proved that curing infection was not absolute, but a significant reduction was observed [
116]. A study by Homeyer et al. (2020) introduced the idea of functionalizing antibactericidal agents such as nitric oxide into the endotracheal tubes. This proved its efficacy by significantly reducing
P. aeruginosa among ICU patients [
117]. Using photodynamic inactivation to decrease biofilm formation on endotracheal tubes gave excellent results. Zangirolami et al. (2020) functionalized endotracheal tubes with the photosensitizer curcumin and then irradiated them with an external light source. This assay proved to be effective against both Gram-positive (
S. aureus) and Gram-negative bacteria (
P. aeruginosa,
E. coli). Moreover, the application of this technique reduced biofilm thickness accompanied by a disruption of biofilm cells [
118]. İbiş and Ercan (2020) used an interdisciplinary approach of using dielectric barrier discharge plasma and air plasma afterglow against biofilms formed by
P. aeruginosa,
A. baumannii,
S. aureus, and
C. albicans. In these protocols, the biofilms were significantly reduced without any significant damage to the endotracheal tube [
119].
These studies show that various new alternative methods for the treatment of VAPs are constantly being developed. However, the priority is continuous patient monitoring to prevent chronic infections, and antibiotics should be given to the patient as soon as VAP is suspected.