|Year : 2022 | Volume
| Issue : 3 | Page : 311-318
Pseudomonas Aeruginosa a tenacious uropathogen: Increasing challenges and few solutions
Falah Hasan Obayes AL-Khikani, Aalae Salman Ayit
Department of Medical Technique, College of Medical Technique, The Islamic University; Department of Medical Microbiology, AL-Shomali General Hospital, Babylon, Iraq
|Date of Submission||05-Oct-2021|
|Date of Acceptance||24-Nov-2021|
|Date of Web Publication||17-Sep-2022|
Falah Hasan Obayes AL-Khikani
Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf
Source of Support: None, Conflict of Interest: None
No population in the world can be cleared from urinary tract infections (UTIs) that considered the most common bacterial infection globally, every year more than 150 million people suffering from acute or chronic UTI caused by various bacteria. It is among the most frequent health care-associated diseases. In patients with UTI, Pseudomonas aeruginosa deserves special attention since it can affect patients with serious underlying conditions. P. aeruginosa is a multidrug-resistant pathogen causing numerous chronic infections including urinary tract disorders. Infection caused by this organism is difficult to treat because of the presence of its innate resistance to many antibiotics and its ability to acquire further resistance mechanism to multiple classes of antibiotics, including beta-lactams, aminoglycosides, and fluoroquinolones; thus, the treatment option for these drug resistance pseudomonas are very limited. P. aeruginosa-induced UTIs continue to be linked with substantial mortality and morbidity. This adverse consequence is owing to our failure to create effective disease-prevention treatment methods, which is related to a lack of knowledge of resistance mechanisms. This study alerts researchers to the need to better understand the mechanisms of resistance in P. aeruginosa-caused UTIs to develop viable treatment options. The microbiological perspectives, virulence factors, epidemiology, mechanisms beyond antibiotic resistance, and antimicrobial sensitivity of P. aeruginosa in UTI are discussed in this review as well as future strategies to build basic information and clear vision to other researchers for more studies regarding this tenacious bacterium.
Keywords: Antibiotic resistance, Pseudomonas aeruginosa, urinary tract infection, uropathogen
|How to cite this article:|
AL-Khikani FH, Ayit AS. Pseudomonas Aeruginosa a tenacious uropathogen: Increasing challenges and few solutions. Biomed Biotechnol Res J 2022;6:311-8
|How to cite this URL:|
AL-Khikani FH, Ayit AS. Pseudomonas Aeruginosa a tenacious uropathogen: Increasing challenges and few solutions. Biomed Biotechnol Res J [serial online] 2022 [cited 2022 Oct 5];6:311-8. Available from: https://www.bmbtrj.org/text.asp?2022/6/3/311/356156
| Introduction|| |
Because of rising antimicrobial resistance in the healthcare system, one of the most significant difficulties for clinicians is providing sufficient therapy for infections caused by Gram-negative bacteria. Pseudomonas aeruginosa is the most common Gram-negative rod infection, especially in severely sick and vulnerable individuals. Treatment options for P. aeruginosa infections have been severely limited due to antimicrobial resistance.,
P. aeruginosa is a Gram-negative, motile bacillus that can grow at 42°C as well as 37°C in aerobic circumstances. It also tests positive for oxidase and catalase enzymes., The bacteria may be found in a variety of habitats, including water and soil., It also considers an opportunistic human pathogen which has the capacity to causes infection, especially in individuals with immunocompromised system, and also can presence in hospital climate.
P. aeruginosa has the ability to secret several virulence factors that can use in their pathogenicity leading to invade and damage cells. Pigments production could be considers one of these virulence factors.,, Pyocyanin (PCN) is one of the most important pigments produced by P. aeruginosa.,, About 90% of P. aeruginosa isolated from patients found to produce PCN, especially during stationary phase of the growth curve. PCN as one toxin is usually secreted from this organism to kill other competitor microorganisms and to help it to colonize tissues as found in immune deficiency individuals with cystic fibrosis (CF) or acquired immune deficiency syndrome.,
The purpose of this review is to highlight some of the most recent developments in the field of P. aeruginosa-induced UTIs and to urge researchers to conduct more basic research at the pathogenesis level to find innovative therapies.
| Microbiological Perspective of Pseudomonas aeruginosa|| |
P. aeruginosa is a Gram-negative rod-shaped bacterium that produces oxidase. On blood agar, it can generate beta-hemolysis but not lactose fermentation on MacConkey agar medium. Other characteristics include the capacity to grow at 42°C with the formation of blue–green phenazine pigment and the creation of a grape-like odor due to secretion of 2-aminoacetophenone. P. aeruginosa, like other members of the pseudomonas genus, is a free-living bacteria that causes nosocomial infectious disease and is also found in intensive care units. P. aeruginosa is most frequently associated with various human infections such as urinary tract infection (UTI).,
Pseudomonas genus is found in hospitalized patients and CF through its ability to permanent resident in the airways of the patients. It is also a prevalent cause of hospital-acquired pneumonia, particularly in immunocompromised people,,, and it is mainly isolated from serious burns and wound infections. Multidrug-resistant P. aeruginosa wound infections have been linked to high rates of morbidity and death across the world., Furthermore, P. aeruginosa infection can induce tissue necrosis and necrotizing sinonasal infections by causing rapidly progressing pseudomonal acute rhinosinusitis.
Chemical signals have been found to be used by Gram-negative and Gram-positive bacteria to assess cell density and virulence factor expression. P. aeruginosa has been shown to detect and respond to a variety of environmental stimuli on a continuous basis. The presence of urine, which is a complex media, exposes invading organisms to circumstances such as varying osmolarity, pH, and Tamm–Horsfall protein, as well as variety of ions such as iron, when establishing in the urinary tract.
As a result, existing research suggests that iron levels influence P. aeruginosa virulence and are hence important for pathogenicity. Extrapolation of existing data might aid in the development of a new UTI prevention strategy based on iron supplementation, with far-reaching implications.,
Another key characteristic that has been linked to P. aeruginosa proliferation and virulence is osmolarity. P. aeruginosa must adjust to changes in urine osmolarity to develop and cause UTI. When the osmolarity was increased from 200 to 300 mOsmol/l, the production of virulence factors increased significantly. Increased osmolarity, on the other hand, resulted in a significant decrease in the generation of virulence factors. Organisms grown in medium with an osmolality of 300 mOsmol/l were resistant to phagocytosis and more virulent in a mouse model of ascending UTI, as evidenced by significantly higher neutrophil recruitment, bacterial load, malondialdehyde production, a marker of tissue damage, and renal and bladder pathology.,
In addition to environmental variables, the host plays a critical role in the initiation of an infectious process. As evidenced by the pathogenicity of virulent microorganisms in immunocompromised hosts and the absence of pathogenicity of virulent pathogens in immune hosts, microbial virulence is reliant on host characteristics. Innate immunity serves as a first line of defense in this regard, with macrophages and neutrophils playing a key role. Macrophages, which are mostly derived from the bloodstream, are one of the first lines of defense in the urinary tract and provide resistance to infection. When macrophages engage with an invading pathogen, biochemical compounds known as macrophage secretory products are produced (MSPs). The utilization of MSPs by P. aeruginosa can have far-reaching consequences, such as increased chronicity and recurrence of P. aeruginosa infections. Because MSPs are made up of a diverse group of biomolecules that can interact in complex ways, further study is needed to better understand their role in UTIs.
| Urinary Tract Infection|| |
UTIs are infections of the genitourinary tract, which extends from the renal cortex of the kidney to the urethral meatus. UTIs are one of the most common bacterial infections that affect people of all ages and stages of life. UTIs result in more than eight million visits to clinicians and more than two million hospitalizations in emergency rooms in the United States each year. UTI caused by P. aeruginosa is a serious public health problem that affects millions of people each year, and catheterization of the urinary system is one of the most common predisposing factors to such infections.
In both the outpatient and inpatient settings, UTIs are among the most common illnesses. UTIs were assessed to be the third most frequent illness after surgical site infections and pneumonia in the latest European point-prevalence study of health care-associated infections in acute care hospitals from 2011 to 2012, accounting for 19% of cases. Despite the implementation of particular preventive initiatives, it appears that rates are rising. In the United States, 93,300 UTIs were reported in hospitalized patients over the course of a year.
| Virulence Factors of Pseudomonas aeruginosa in Urinary Tract Infection|| |
P. aeruginosa has a number of virulence factors that play a role in pathogenesis in the host, including flagella,, and Type IV pili, which are found near the cell pole. It also released exopolysaccharide alginate,, which is utilized to build biofilm,, as well as exoenzymes S, T, U, and Y. P. aeruginosa also produces extracellular virulence factors such as elastase, toxin A, rhamnolipids, lipopolysaccharide, and protease. Lipases and phospholipases, which target lipids in the surfactant and host cell membranes, are further pathogenic agents of the bacteria.
Another virulence factor produced by P. aeruginosa is PCN, a blue water-soluble pigment. P. aeruginosa may also produce pigments such as yellow-green fluorescent pigments (pyoverdin), reddish pigment (pyorubin), and dark brown pigment (pyomelanin).
Pseudomonads, as a category, have modest nutritional requirements for development and may feed on a range of environmental substances; P. aeruginosa, for example, only needs acetate and ammonia as carbon and nitrogen sources. Furthermore, P. aeruginosa may grow anaerobically and does not ferment, instead receiving energy from sugar oxidation. This low nutritional requirement allows it to thrive in harsh environments such as hospital operating rooms, hospital rooms, clinics, and medical equipment, as well as sinks, showers, and even contaminated distilled water and has thus been identified as a significant source of nosocomial infection.
P. aeruginosa has a potential to develop biofilms on the surface of urinary catheters in addition to elaborating virulence factors. As a result, the most significant pathogenic characteristic of P. aeruginosa is the development of biofilms, which allows this bacterium to cause recurrent and chronic UTIs by evading host immune defense systems [Figure 1].
| Epidemiology of Pseudomonas aeruginosa in Urinary Tract Infection|| |
Gessard isolated P. aeruginosa from green pus for the first time in 1882. P. aeruginosa's widespread lifestyle permits it to contribute to human illnesses on a regular basis. It is present in normal intestinal flora, however, it does not adhere well to normal intact epithelium.
UTIs are one of the most frequent nosocomial infections, accounting for 20%–49% of all nosocomial infections, with P. aeruginosa accounting for about 10% of all UTIs.
These infections produced by P. aeruginosa generally develop as a result of catheterization, urinary system instrumentation, or surgery. Patient pain, pyelonephritis, morbidity, and, in rare circumstances, death are all possible outcomes of UTI. Because the insertion of the catheter may induce disruption of mucosal epithelial layers, encouraging bacterial colonization, pathogens exploit catheters as a route of host entrance. P. aeruginosa is a major uropathogen in UTIs, having a significant frequency in reported cases all over the world. According to the study, P. aeruginosa was responsible for 97 (9.6%) of the 1007 cUTI episodes.
After Escherichia coli was discovered to be the most often isolated uropathogen 35 (70%) and Klebsiella pneumoniae 8 (16%), Pseudomona aeruginosa 2 (4%) was found to be the third most common causative agent of UTI [61,62] another study mentioned that the prevalence of P. aeruginosa is 5.43%. A mixed infection of P. aeruginosa and other bacteria is conceivable. In another research, E. coli and pseudomonas were found in 2.2% of urine samples.
P. aeruginosa infections caused by XDR-PA accounted for roughly a quarter of all P. aeruginosa hospital infections, with a higher mortality rate. When an XDR-PA infection is suspected, an appropriate empirical antibiotic should be used very away. XDR-PA was found in 56 (22%) of the 255 people who had PA infections, 32 (12.5%) had Multidrug resistance P. aeruginosa (MDR-PA), and 167 (65.5%) had non-MDR PA.
P. aeruginosa was found in eight of the 250 urine samples tested (3.2%). P. aeruginosa was found in 2.7% of male patients and 3.5% of female patients (P = 0.035). It was 4.2% in patients <10 years old and 4.2% in patients older than 55 years old. These were the groups that were most often affected.
| Mechanisms of Antibiotic Resistance in Pseudomonas aeruginosa|| |
Antimicrobial resistance is defined as an organism's capacity to withstand the action of an antimicrobial agent to which it was previously susceptible., The emergence of MDR strains has increased, nosocomial infection caused by antibiotic-resistant P. aeruginosa has become a serious problem in clinical care settings (i.e., resistance to at least three antibiotics).
Other virulence factors generated by P. aeruginosa might be the source of resistance to most antibacterial drugs. Restricted uptake, efflux, drug inactivation, and changes in targets are three fundamental processes that render bacteria resistant to the action of antimicrobial drugs.,,,
The restricted uptake represented by the innate resistance of P. aeruginosa to all classes of antibiotics by lowering the permeability of such agents through bacterial cell wall. Efflux systems of bacteria are composed of three protein components working by eliminating the antibiotic molecules outside the bacterial cell. Third mechanism of drug inactivation and changes in targets is mainly resulted from mutational changes in target bacterial enzymes to become resistance to the action of selective inhibition of antibiotic [Figure 2].
|Figure 2: Some mechanisms of antibiotic resistance in Pseudomonas aeruginosa|
Click here to view
The formation of biofilm by P. aeruginosa can potentially contribute to bacterial protection by increasing antibiotic resistance., Reduced permeability, development of efflux systems, creation of antibiotic inactivating enzymes, and target modifications are all examples of antibiotic resistance mechanisms in bacteria. Most known resistance mechanisms in P. aeruginosa are exhibited by intrinsic chromosomally encoded or genetically imported resistance determinants that influence the major classes of antibiotics such as lactams, aminoglycosides, quinolones, and polymyxins.
Antibiotics that are often used to treat P. aeruginosa infections include aminoglycosides (gentamicin, tobramycin, amikacin, netilmicin), carbapenems (imipenem, meropenem), cephalosporins (ceftazidime, cefepime), fluoroquinolones (ciprofloxacin, levofloxacin), penicillin with-lac (colistin, polymyxin B).
P. aeruginosa strains are classified as MDR when resistance is observed in one of three antimicrobial agents; (2) extensively drug-resistant (XDR) when resistance is observed in all but one of three antimicrobial agents; and (3) pandrug-resistant (PDR) when the strain is nonsusceptible to all antimicrobial agents.
MDR, XDR, and PDR strains emerge in a timely manner as a result of changes in regulatory mechanisms that control the expression of resistance determinants, mutations, changes in membrane permeability, and horizontal acquisition of antibiotic-inactivating enzymes or enzymes that induce target modifications. The simultaneous development of these mechanisms confers multi-resistance to multiple strains, which is noteworthy.,,
Although efflux systems are known to impart a low degree of resistance, they frequently work in tandem with other resistance mechanisms, contributing to the high-level resistance seen in P. aeruginosa. Because of its poor permeability outer membrane (1/100 that of E. coli), P. aeruginosa has intrinsic resistance to a variety of antimicrobial drugs (b-lactam and penem group of antibiotics).
The frequent use of antimicrobial drugs is another factor linked to the rise in MDR-P. aeruginosa. This acquired resistance can occur during antibiotic therapy as a result of a mutational event or the acquisition of a resistance gene through horizontal gene transfer. A mutational event can result in overexpression of endogenous beta-lactamases or efflux pumps, as well as the expression of specific porins.
P. aeruginosa can import additional resistance mechanisms by horizontal gene transfer, making it resistant to a variety of anti-pseudomonal drugs. As a result, there are limited choices for treating severe nosocomial pseudomonas infection. The ever-changing microbial genome poses a greater hazard than infection itself. Horizontal gene transfer, transposon-mediated genomic changes, and the promiscuous nature of gene and genomic products are some of the mechanisms bacteria use to change their genome.
Most resistant bacteria species, including P. aeruginosa, encode enzymes that preferentially target beta-lactam medicines such as penicillin and cephalosporins. Because of the accumulating evidence of beta lactamase's promiscuous nature, the enzyme will acquire affinity for new generation beta lactum antibiotics, eliminating the need for bacteria to have extra genes for new generation antibiotics.,
| Antibiotic Sensitivity of Pseudomonas aeruginosa in Urinary Tract Infection|| |
Despite advances in antibiotic treatment, the mortality and morbidity associated with P. aeruginosa-induced UTIs remain significant. P. aeruginosa is a common infection in hospitals, particularly in intensive care units, due to its inherent resistance to several antibiotics and antiseptics, as well as its propensity to develop additional resistance mechanisms to numerous classes of antibiotics.
P. aeruginosa infections have become a major issue in hospital-acquired infections, particularly in severely sick and immunocompromised patients. The emergence of drug-resistant pathogens is the primary cause of increased mortality.
Ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin, ertapenem, ceftriaxone, gentamicin, and tobramycin antibacterial activity against P. aeruginosa as single antibiotics and in combination with zinc sulfate (2.5 mM). The P. aeruginosa CCIN34519 biofilm responded differently to the antibiotic-zinc sulfate combinations examined, with possible synergism in the instances of fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin, and norfloxacin) and carbapenem (ertapenem), as shown by reduced MIC and MPC values. Cephalosporins (ceftriaxone) and aminoglycosides (gentamicin and tobramycin) showed substantial antagonisms, as demonstrated by considerably increased MICs and MPCs.
Antibiotics that are used to treat P. aeruginosa infections include fluoroquinolones, beta-lactams, and aminoglycosides. Unfortunately, the multidrug-resistant P. aeruginosa isolates that patients are often exposed to in hospitals are resistant to one or more of these antibiotic groups.
According to a 2016 eCDC research, 33.9% of P. aeruginosa bacteria in Europe were resistant to at least one antibiotic category under surveillance (piperacillin tazobactam, floroquinolones, ceftazidime, aminoglycosides, and carbapenems). For all antimicrobial classes, there were substantial inter-country variations, with southern and eastern Europe having a higher prevalence of resistance than northern Europe. For example, 25%–50% of invasive isolates are resistant to carbapenems in Latvia, Poland, Slovakia, Hungary, Croatia, Serbia, Bulgaria, or Greece, while more than 50% of strains are resistant in Romania. 25%–50% of the invasive strains found in Slovakia, Romania, Croatia, Bulgaria, and Greece exhibited combined resistance to three or more of the antimicrobials previously listed.
Antipseudomonal cephalosporins 35 of 97 (36.1%), aminoglycosides 30 of 97 (30.9%), piperacillin–tazobactam 21 of 97 (21.6%), floroquinolones 43 of 97 (44.3%), and carbapenems 28 of 97 (28.1%) were all resistant to P. aeruginosa (28.8%). MDR was found in 28 of 97 (28.8%) cases, while substantially drug-resistant P. aeruginosa was found in 12 of 97 cases (12.3%).
Ampicillin (87.5%), norfloxacin (62.5%), gentamycin (62.5%), amikacin (62.5%), and aztreonam (62.5%) had the highest levels of resistance, whereas meropenem (0%), imipenem (12.5%), and polymyxin B had the lowest (12.5%). Because P. aeruginosa has been linked to a significant death rate in patients with XDR-PA infections, early and adequate empirical colistin therapy should be explored for critically ill patients who have an XDR-PA infection.
| Future Vision Strategies for Uro-pathogenic Pseudomonas aeruginosa|| |
The researchers in the field of antimicrobial agent may give more attention by highlight P. aeruginosa as a major health threat and strongly urged the research and development of alternate and new antimicrobial therapies due to the high rates of antibiotic resistance.
We have barely scratched the surface to begin to understand both the immensely complex bacterial factors that influence biofilm development, maturation, and dispersal, as well as the host factors that influence the immune response to biofilm infections. However, a more thorough understanding of biofilm biology and host immune response to biofilms is urgently needed given the recalcitrance of P. aeruginosa infections.
Combination therapy has several advantages over mono-therapy, including a higher likelihood that the infecting pathogen will be susceptible to at least one of the antimicrobials, the ability to use multiple mechanisms of bacterial killing, the prevention of resistance, and the additive or even synergistic effect of the combination,, especially when medicines target distinct bacteria and have various routes of entrance into the bacterial cell, resulting in increased antibacterial action.
Understanding how P. aeruginosa uses a variety of strategies to overrun critical host cell pathways may aid in understanding the pathophysiology of UTIs caused by this infection. This understanding must progress to the point where it can be converted into a real comprehension of the disease. This is still the most important difficulty for everyone working in this sector. All of this knowledge might aid in the development of successful P. aeruginosa biofilm prevention methods.
Improved antimicrobial susceptibility testing methods should be used to detect medication resistance in P. aeruginosa as soon as possible. It is also critical to comprehend the pattern of drug resistance and the mechanisms that underpin it. Because of the physiological similarities across animal models, more in vivo research is critical. Clinical research is needed to identify MDR risk factors and determine the best effective antibiotic regimens and treatment durations for treating severe infections caused by drug-resistant P. aeruginosa.
| Conclusions|| |
P. aeruginosa is an important infection in all populations, and it has been linked to an increase in morbidity and death among patients. P. aeruginosa is most commonly linked to a variety of human diseases, including UTIs. Multidrug resistance (MDR) has skyrocketed in recent years, and it is now regarded as a serious global issue. P. aeruginosa MDR strains have spread throughout the world. They are now posing a significant problem for doctors, as few secondary therapy alternatives are still accessible, and those that are have negative side effects. MDR is becoming more frequent, therefore, we need to figure out what's causing it in P. aeruginosa. Because these drug-resistant strains are resistant to virtually all dependable anti-pseudomonal medicines, their presence in clinical care settings makes them difficult and expensive to treat.
Hospitals and health-care settings have been shown to be reservoirs for large numbers of pathogenic strains of P. aeruginosa, which has been identified as a significant nosocomial pathogen due to the presence of intrinsic mechanisms of resistance to a wide range of antibiotics, as well as its ability to acquire resistance to all relevant treatments (via mutations).
Antibiotic resistance has a therapeutic treatment that is now available. Infections caused by P. aeruginosa necessitate an accurate diagnosis and antibiotic therapy based on that diagnosis. Furthermore, the role of bacterial and host variables in the progression of P. aeruginosa-caused UTI must be studied, as these infections can persist and become chronic, posing a risk to the treating physician. P. aeruginosa is one of the most aggressive opportunistic bacteria, and it continues to be a major cause of infection in immunocompromised persons, including those with UTI.
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Conflicts of interest
The authors declare that none of the authors have any competing interests.
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