The Emerging Role of Pseudomonas aeruginosa in Diarrhea: Where We Stand

Abstract

Although Pseudomonas aeruginosa (PA) hasn’t been considered as a recognized agent of diarrhea, this organism is able to cause community-acquired diarrhea accompanied by fever and sepsis, as well as antibiotic-associated diarrhea (AAD). Antibiotic resistance rates in stool isolates of PA are generally lower compared to other infection sites, but in patients with AAD, there are reports of resistance to most of the antibiotic classes in these isolates. PA, along with other opportunistic pathogens like Clostridioides difficile, can cause AAD. Therefore, it is suggested to examine stool samples of patients with predisposing factors such as intensive care unit (ICU) admission and long-time antibiotic treatment, especially with cephalosporins, for both C. difficile and PA.

Introduction

Diarrhea, a common gastrointestinal disorder is classically defined as the discharge of loose or watery stools, typically at least three times a day. People with diarrhea may exhibit symptoms such as nausea, abdominal pain, fecal incontinence and an urgent need to use the bathroom [1,2].

In between, bacterial diarrhea is responsible for a big part of diarrhea cases, which accounts for about 30% of all diarrheas [3,4]. Notably, several bacterial organisms like E. coli, Shigella, Salmonella, and Campylobacter are recognized as the main agents responsible for bacterial diarrhea [5,6,7].

Although some uncommon organisms are reported to cause diarrhea, not in recent years, but since the onset of the 20th century, Pseudomonas aeruginosa (PA) has been reported as the causative agent of diarrhea, mainly in case reports [8,9].

Although this organism is known as a common cause of nosocomial infections, presenting as pneumonia, surgical site infections, sepsis and urinary tract infections, for the first time, in 1918 and in Shanghai, China, occurrences of what was then named “Shanghai fever” were reported. These incidents of community-acquired diarrhea were accompanied with fever, sepsis and growth of PA from blood or other sterile body sites [10,11].

According to the classification proposed by Chuang et al., PA is causative agent of four distinct groups of gastrointestinal infections: Shanghai fever, enterocolitis, infectious diarrhea, and antibiotic-associated diarrhea [12].

Although there have been a number of case reports in this regard, the necessity of a review to connect current data about PA diarrhea is apparent. In this review, we aim to inspect our knowledge about the role of PA in the occurrence of diarrhea, clinical manifestations of patients, the underlying risk factors, and antibiotic resistance patterns of PA isolates and finally, prevention of PA diarrhea.

Colonization by PA in human gut

PA is an opportunistic pathogen and it is not usually considered as a normal member of the flora in the human body, and therefore the gut microbiota. Nonetheless, it is worth noting that this organism is an unusual colonizer of the human gut, affecting less than 10% of healthy individuals [13,14,15].

The remarkable aspect is how PA accomplishes this colonization. Previous studies suggest that PA exploits specific lectins such as PA-IL, and PA-IIL for binding to surface antigens on intestinal epithelium cells and facilitates its initial colonization [16,17]. Subsequently, the bacterium uses ExoS to bind to the FXYD3 factor and disrupt intracellular tight junctions, making PA able to penetrate through the intestinal epithelial barrier [18]. These isolates could potentially translocate to other body sites and cause bacteremia, pneumonia, urinary tract infection and skin involvement, so that the gut effectively serves as the reservoir for PA [19].

Past studies have shown that PA colonization is associated with various risk factors. One significant factor is gut microbiota dysbiosis, mainly due to exposure to antibiotics during hospitalization. This dysbiosis reduces the microbial population diversity and creates the opportunity for the growth of multidrug-resistant or MDR isolates, non-susceptible to at least one agent in at least 3 antibiotic classes, and extensively drug-resistant PA isolates or XDR, non-susceptible to at least one agent in all but 1 or 2 antibiotic classes [19,20,21,22].

For instance, piperacillin-tazobactam prescription is associated with a decreased population of commensal lactobacillus and Clostridiales taxa with a concomitant increase in carbapenem-resistant PA colonization acquisition among patients in the intensive care unit (ICU) [23].

Additionally, comparing to healthy people, cancer patients, individuals hospitalized in the ICU and those with hematological malignancies demonstrate a higher colonization rate, contributing to the development of PA infections [24,25].

Among ICU patients, a significant proportion are colonized with PA on admission, so that the gastrointestinal tract colonization rate among these individuals can reach up to 27%. Also, it has been shown that there is a higher risk of PA-related clinical infection in non-colonized patients, which can result in future infection with the same strain [26,27]. Since this colonization has significant consequences for the risk of infection in vulnerable patient populations, it is crucial to understand the factors that contribute to colonization.

The origin and clinical manifestations of PA diarrhea

According to the reviewed literature, PA diarrhea could be divided into two main groups: 1. hospital-acquired diarrhea (HAD) and 2. community-acquired diarrhea (CAD). HAD is defined as the occurrence of diarrhea after ≥3 days hospitalization, that was not present at the time of admission, while CAD is diarrhea with onset less than 3 days after admission [28,29,30].

Furthermore, the difference between PA carriage and PA causing diarrhea should be further clarified. In particular, some cases may yield pure or predominant growth of PA in their stool while diarrhea or other complications are not observed and the person is healthy [13,19,31,32].

As mentioned in

Table 1. Reviewed case reports and cases’ clinical characteristics.

CZL—cefazolin; CIP—ciprofloxacin; OFL—ofloxacin; GEN—gentamicin; MEM—meropenem; TOB—tobramycin; AMI—amikacin; AZT—aztreonam; AMK—amikacin; CTR—ceftriaxone; CTZ—ceftazidime; PIP—piperacillin; CTX—cefotaxime; CXT—cefoxitin; CTM—ceftizoxime; CRX—cefuroxime; CLT—cephalothin; IMI—imipenem; LEV—levofloxacin; COL—colistin; PTZ—piperacillin-tazobactam; VAN—vancomycin; DOX—doxycycline.

, a considerable number of cases are related to antibiotic associated diarrhea (AAD) that mainly occurs in HAD adult patients.

A long period of hospitalization and exposure to a variety of antibiotics may results in this phenomenon. We know under antibiotic pressure selection, population of opportunistic pathogens like Clostridioides difficile overcome the normal gut flora and proceed to gastroenteritis and diarrhea [33]. Similarly, evidences show other organism as well PA cause AAD, hence, it is proposed stool samples of these patients to be investigated for C. difficile and PA [34,35,36,37,38].

In a similar manner to AAD of adults, there are some reports of AAD in young children and infants. In this age group, AAD could be relevant to PA diarrhea incidence. For example, in the study by CH Chuang et al. about 56% of children with PA positive stool culture were dedicated to AAD cases that did not have underlying diseases [12]. Risk factors for AAD in children include the administration of cephalosporins and admission to ICU [39].

Another important aspect to consider is nonPA diarrhea despite of PA detection in stool culture, meaning the bacterium has colonized the host intestine, but another agent causes diarrhea. A variety of viruses, protozoa, or non-infectious situation agents like reactions to medicines and underlying diseases result in diarrhea [40,41].

Some researchers have explored other suspicious organisms in diarrhea cases. Concomitant detection of PA with Salmonella and Aeromonas species [42], rotavirus[12] and C. difficile[35] or a drug induced diarrhea in immunocompromised patients like leukemia patients [43]. Chemotherapy drugs are well known to cause diarrhea, which is a common side effect. Also, like antibiotics, they are considered to perturb gut normal flora and induce diarrhea, of course, there is little data about the role of PA in this case [43,44,45,46].

Conversely, CAD reports have predominantly been reported in infants and young children. Most of described cases had developed sepsis and ecthyma gangrenosum as the result of systemic infection with PA. In some patients, necrotizing enteritis and bowel perforation with the need for prompt surgical intervention were observed [47,48,49].

A considerable common point of these cases is that the patients have been previously healthy without underlying disease [8,42,43,47,49,50,51,52]. Considering all these, a probable explanation may go back to the deficient nature and low diversity of infants’ gut microbiota compared with adults, so that infants before age 1 are susceptible to develop diarrhea by different pathogens. About PA it is postulated that in the neonatal intestine, colonization and overgrowth of this organism will be followed by intestinal involvement and sepsis [49,52,53,54,55].

Regardless of which HAD or CAD groups the cases belong to, the mechanism by which PA causes diarrhea remains rather unclear. Unlike well-known bacteria that are specifically considered enteric pathogens and possess determined virulence factors to cause gastroenteritis in humans, this doesn’t apply to PA.

Previous studies have focused on various virulence factors of PA. Fakhkhari et al. compared intestinal PA isolates with environmental isolates and found that toxinrelated genes lasB, aprA, exoY, and exoS were significantly more frequent in diarrhea isolates [56].

Chuang et al. observed the isolates from Shanghai fever had a higher frequency of exoU and more rapidly penetrated through MDCK cell monolayers than respiratory and laboratory strains, probably explaining the mechanism by which PA crosses through intestinal cells and reaches the bloodstream [48].

In the study by Chowdhury et al., the wholegenome sequencing analysis of suspicious PA causing diarrhea revealed this isolate contained more than ten genes linked to toxin-associated factors (doc, phd, ratA, vapC, relE) and several key virulence factors such as mviM, bvgS, hudA, and pqsR, as well as the presence of the type 3 secretion system (T3SS) and the ability of in vivo fluid accumulation may be related to diarrheal infection [57].

An older study by Adlard et al. found that a considerable number of isolates indicated the ability to adhere to HEp-2 cells and showed twitching motility by type IV pili presumed to help PA gut colonization [58].

Considering the non-overlapping results of these studies, the limited number of conducted studies, and the high diversity of PA virulence factors, it could be concluded that there is still a gap in our knowledge of PA pathogenesis associated with diarrhea.

Antibiotic resistance in PA causing diarrhea

Another important aspect of these isolates not to be neglected is their resistance to antibiotic classes. According to Table 1 and other related studies, PA isolates from CAD cases were sensitive to most antibiotics, while HAD isolates showed a higher resistance rate, which is more noticeable in cases where patients received longterm antibiotic treatment and we defined them as AAD. Therefore, a variety of antibiotics were prescribed to cure the diarrhea, with ciprofloxacin being the most common choice. Interestingly, Chowdhury et al. reported an XDR PA isolate resistant to all antibiotics except for colistin. Despite such high resistance, however, the patient got intravenous ceftriaxone and doxycycline and recovered after 10 days. The authors noted that ceftriaxone possibly decreased the excretion levels of doxycycline from the body resulting in an elevation of its concentration in the serum [57].

In the study by Fakhkhari et al., 25.5% of stool isolates showed an MDR phenotype; all of them were sensitive to meropenem and had low resistance rates to ciprofloxacin, aztreonam and gentamicin [56].

Hu et al., in a group of hospitalized patients but without gastroenteritis, reported 41.3% resistance to carbapenems like meropenem [20]. Although we don’t have more data to give a comparison between these results and those from PA isolated from other infection sites, it could be concluded that the antibiotic resistance rate in stool isolates is generally lower [59,60,61].

The prevention of Pseudomonas aeruginosaassociated diarrhea and conclusion

Depending on the type of PA diarrhea, if it belongs to AAD diarrhea, the adjustment of prescribed antibiotics according to the isolate drug sensitivity pattern and cessation of antibiotic therapy with extended spectrum choices would be helpful [35,36,37]. In addition, high-risk patients like infants, immunocompromised and high-risk people need to be screened for the presence of PA in their stool samples. Despite the few reports of PA-associated diarrhea, it is not impossible to observe PA in the stool cultures of patients with diarrhea, especially those with special conditions reviewed in Table 1 and other studies [49,50,56]. Therefore, we recommend physicians and laboratory technicians should be more alert to the possibility of diarrhea by PA beside common fecal pathogens and perform antimicrobial susceptibility testing for suspicious non-fermenter colonies on XLD, MacConkey’s agar or other bacterial culture media [62].