UTI Caused by Staphylococcus saprophyticus

Abstract

Coagulase-negative Staphylococci (CoNS) are one of the most frequently isolated bacteria in the clinical microbiology laboratory. These bacteria are normal inhabitants of human skin and mucous membranes; also, they have emerged as significant nosocomial pathogens. Staphylococcus saprophyticus is a Gram-positive bacterium well known for causing uncomplicated urinary tract infections in young sexually active females, responsible for complications including urinary tract infections, epididymitis, prostatitis, and acute pyelonephritis. CoNS can be divided into two groups based on susceptibility to novobiocin. The novobiocin-susceptible species include S. epidermidis, S. haemolyticus, S. hominins, S. lugdunensis, S. schleiferi, and the novobiocin-resistance species, including S. saprophyticus and S. xylosus. The acute uncomplicated UTI, including cystitis and pyelonephritis, is frequent in an immunocompetent nonpregnant female population, the second most common cause of community-acquired urinary tract bacterial infection in women after the Escherichia coli. S. saprophyticus is a part of the normal human flora which colonizes the rectum, urethra, cervix, and gastrointestinal tract. Bacterial colonization of the bladder and ureter epithelium occurs via several types of adhesin, including hemagglutinins with autolytic properties. Also, some strains can create and produce biofilms to increase their pathogenicity.

1. Introduction

Staphylococcus organisms can be coagulase-positive or negative, and Coagulase-negative Staphylococcus microorganisms are associated with human infections. S. saprophyticus is a clustering Gram-positive Commensal CoNS (Coagulase-negative Staphylococci), non-motile, non-spore, non-hemolytic coccus and Novobiocin-resistant which is a common urinary tract pathogen accounting for 10–20% of cases in young women, rarely associated with urinary tract infections in male populations, with the cell membrane that’s made up of the typical lipid-protein bilayer made of phospholipids and the cell wall which is composed of peptidoglycan and teichoic acid that function to maintain the shape of the cell associated with adhesions, unique adhesion protein which allows it to attach to human uroepithelial cells and abundant transporter systems to adapt to changing pH and osmolarity [1]. S. saprophyticus is a common cause of urinary tract infections in the young, sexually active female population. There are multiple chances of developing prostatitis and urethritis in immunocompetent hosts. S. saprophyticus can be differentiated from other coagulase-negative Staphylococcus by its resistance to Novobiocin, and like other uropathogens, S. saprophyticus can produce ammonia by utilizing urease [2]. Coagulase-negative Staphylococcus can be found on the skin, rectum, urethra, and cervix as a microbiome [3, 4, 5]. S. saprophyticus is the second most common cause of UTI after E. coli. Over 40% of all sexually active females contain S. saprophyticus as part of their normal genitourinary flora [3, 4, 5]. General risk factors for UTIs are recent sexual intercourse, benign prostatic, pregnancy, and female sex [6]. This bacterium can encode different transport proteins, enabling it to adjust to environmental pH changes and proliferate urine.

2. Definition of UTI

Urinary tract infection, also called UTI, is one of the most common bacterial infections; it is characterized into different groups: young women with uncomplicated cystitis, female with recurrent cystitis, women with acute uncomplicated pyelonephritis, asymptomatic bacteriuria, and adults with cystitis complications. A complicated UTI is a condition that increases the risk of developing severe complications like treatment failure (Figure 1) [7].

Figure 1.

Classification of UTIs in young women.

UTI is a term to explain any urinary tract infection that concludes with asymptomatic bacteriuria, pyelonephritis, and cystitis. Acute complicated UTIs are typically between 27 to 44% of the healthy female with normal urinary tracts. The incidence of symptomatic UTI in men younger than 50 years is much lower than in women [8]. Asymptomatic bacteriuria is found in 5% of young women and rarely in men younger than 50 [9]. Most uncomplicated UTIs in the healthy female population has resulted from uropathogenic, found in rectal flora in men; colonizing uropathogens may also come from the partner’s vagina or rectum [10]. Factors predisposing patients to develop complicated UTIs are generally caused by urine flow which facilitates the entry of uropathogenic into the urinary tract by bypassing the host defense system [11]. Recurrent types of cystitis in healthy female is triggered when an infection is repeated during different period, which is caused by the persistence of the infected strain in the fecal flora [12]. Asymptomatic bacteriuria occurs in patients without any urinary infections [13]. Both pyelonephritis and cystitis are UTIs involving the bladder and kidneys; based on the risk factors such as gender and having sexual intercourse, other complications can be classified into complicated or uncomplicated UTIs [14]. These classifications are made to help patients in need of diagnostic tests or even more extended periods of antimicrobial treatments. On the other hand, an uncomplicated UTI can occur in a healthy nonpregnant woman with beneficial flora and no history of bladder compilations such as bladder catheterization [15]. Diabetic women are classified as a group having complicated infections. As mentioned before, cystitis and pyelonephritis are depended on the patient’s risk factors, such as UTI history, diabetes, age, e, and gender. Although cystitis can progress to hostile stages and cause acute pyelonephritis, the occurrence is rare [16]. Acute pyelonephritis includes sepsis, kidney infection, and perinephric abscess [17]. Recurrent UTIs are commonly defined as infections within 12 months or predisposition to two disorders within 6 months [18]. Females diagnosed with UTI will develop a recurrence within 3 months [19]. A summary of risk factors for common UTIs is shown in Table 1 [20, 21, 22, 23].

Type of Infection	Risk Factors
Premenopausal women	Having recently had sexual intercourse, Previous UTI history.
Postmenopausal women	History of previous UTI, Incomplete bladder emptying
Recurrent UTI	Recent sexual intercourse, Spermicide use, Diabetes
Pyelonephritis	Sexual intercourse, Mother with UTIs.

Table 1.

Risk factors for common UTIs.

For different reasons, postmenopausal women with the risk of developing UTIs, such as lower levels of systemic estrogen, play essential roles in adjusting the vaginal pH and maintaining the normal vaginal flora. The lower estrogen level in postmenopausal women is a crucial factor contributing to UTIs in the community. Based on a Cochrane review, vaginal estrogen, cranberries, Hyaluronic acid, and Chondroitin sulfate have a big part in decreasing recurrent UTIs [24]. Probiotics are thought to contribute to preventing UTIs by restoring the normal vaginal microbiome [25].

3. Pathogenicity and virulence factors

In the 1990s, Kloos and Bannerman [26] shed light on the clinical importance of CoNS. Today, CoNS represent one of the most virulent nosocomial pathogens which had a crucial impact on human health [27]. Staphylococci colonize and develop complications by owning the strain-specific virulence strategies for the aggression, invasion, and adherence factors essential for pathogenicity and evading the host immunity mechanisms. Once the periurethral region contaminated with S. saprophyticus from the gut, the microorganisms will colonize the urethra before traveling up to the bladder. To attach to the uroepithelial cells, S. saprophyticus expresses adhesins: extracellular slime and fibronectin binding proteins [27]. S. saprophyticus strains can also produce urease which hydrolyzes the ammonia to ammonia and carbon dioxide, ammonia will support the bacteria’s survival with the pH increasing [28]. As soon as the host immune system cells sense the bacterial infection, phagocytes, macrophages and neutrophils are being called to engulf the bacteria, then the bacteria are trapped inside a phagosome, which occurs when the phagosome fuses with a specialized vesicle that has degradative agents. However, S. saprophyticus bacteria can eventually escape the digestion pocket in coating themselves with the hosts proteins in order to disguise themselves to prevent from being identified by antibodies or blood proteins [27].

3.1 Adherence to surface and biofilm formation

Biofilm production has a significant role in infection. It’s an accumulation of microorganisms (primarily endogenous) and their self-developed polymeric matrix extracellular products which form on the surface. (e.g., the ureteral stents) The first moment of Staphylococci colony formation is adherence to host epithelium cells which increases its virulence and also its antibiotic tolerance in comparison with isolates without biofilm production. Adherence is critical in initiating UTI pathogenesis [28]. The colonization of the multilayered biofilm is considered an essential step in the pathogenesis of a foreign host [29]. In the biofilm, bacterial cell agglomerates, extracellular DNA (eDNA), pili, flagella, and extracellular polymeric substances are encased in an extracellular material composed of teichoic acids to protect the microorganism from the host immune system [30]. After insertion into the host, ions, polysaccharides, and other components diffuse toward the host cells and provide a receptor site for bacterial adhesins, enhancing the adherence rate. In the next step, bacterial cells release protons as signaling molecules to develop a concentration on the surface, which can lead to the formation of a biofilm format. Members of Staphylococcus produce various adhesins, such as proteinaceous ones, grouped into surface-anchored proteins, also termed cell wall-anchored (CWA) proteins [31].

In many developing countries the UTIs caused by S. saprophyticus and the structure of biofilm are not that well studied but the phases of biofilm formation by CoNS can be divided into initial attachment, Accumulation, Maturation, Detachment, and dispersal. The initial extension of CoNS is followed by the accumulation phase, which includes cell proliferation, intracellular adhesion, and maturation. A developed biofilm is built up of three layers: linking film, which cattachtch to the surface of the tissue, forming a base layer of compact microorganisms, and surface film, where free-floating bacterial cells are spread over the surface [32]. Some Staphylococci strains have been associated with a 240-kDa protein called biofilm-associated protein (Bap), which mediates the attachment and biofilm accumulation and plays a role in developing bacterial inflammation, recurrent cystitis, and chronic prostatitis [33]. The surface virulence factors include proteins such as Aas (Binds to the fibronectin), UafA (Binds to bladder epithelia cells), UafB (Binds to fibronectin and bladder epithelial cells), Srdl (Binds to collagen) [32]. The chosen antibiotic in uncomplicated S. saprophyticus UTIs is nitrofurantoin 100 mg orally twice daily for five to seven days in more complicated cases [30]. Also the prescribing of Trimethoprim-sulfamethoxazole (TMP-SMX) may be given alternatively in uncomplicated cases [30]. The general steps of biofilm formation in S. saprophyticus [31].

3.2 Teichoic acids

Teichoic acids are involved in the adherence of S. saprophyticus to host epithelium cells, which dose-dependently is promoted by the attachment of these microorganisms, which act as a bridge between fibronectin polymer material and bacteria [34]. Teichoic acids have been shown to exert binding functions for matrix molecules in Gram-positive, including Staphylococci. Wall teichoic acid (WTA) is linked to the peptidoglycan (PG), composed of glycerol phosphate units, substituted at the positions of glycerol with alpha-glu-cocaine, alpha-glucose, alpha-6-D-alanyl-glucose [35].

3.3 Aggressive virulence factor

Coagulase-positive staphylococci have been isolated from more than 95% of cases of toxic shock syndrome (TSS). Toxic shock syndrome toxin-1 (TSST-1) is produced in more than 92% of cases. Compared to S. aureus, CoNS have much lower levels of aggressiveness and mostly are not producers of super toxin antigens. The capability of CoNS to produce exfoliate toxins has been doubted since the late 1980s [36]. TSST-1-producing coagulase-negative staphylococci were also isolated from different cases, but the illness episodes were mild recurrences of TSS since they did not meet all the TSS criteria. The strains of presumed positive toxic shock syndrome toxin 1 (TSST-1) cannot produce and exert TSST-1 [37].

3.4 Production of Lantibiotics

Lantibiotics are a group of post-translationally modified peptides that contain unusual amino acids such as lanthionine residues. Commensal staphylococci produce Lantibiotics like Nisin A (act against a wide variety of bacteria, including strains of Lactococcus, Streptococcus, and Staphylococcus), Epidermin, and Mersacidin [38]. These groups of bacteriocins are classified into cationic antimicrobial peptides (CAMPs), which are classified into two types, including Type A (e.g. Nisin, Bisin, Subtilisin, and Epidermin) and Type B (e.g. Mersacidin, Duraycin, and Cinnamycin). The production plays a role in bacterial interference, creating an ecological niche for Staphylococci [39]. These antibiotic peptides also include methyl xanthine amino acids, which can bind to bacterial cell wall precursor lipid components and disrupt cell wall production. Type A kills rapidly by pore-forming mechanisms, and Type B inhibits peptidoglycan biosynthesis [40].

4. Identification and grouping of CoNS by novobiocin testing

Novobiocin is an antibiotic that interferes with DNA replication and binds to DNA gyrase, leading to the blocking of adenosine triphosphates (ATPase) activity. If a CoNS isolate is recovered from urinary tract specimens, testing for resistance to novobiocin will distinguish S. saprophyticus from other clinical CoNS [41]. This method is based on the disc diffusion test using 5-μg novobiocin discs on Hinton agar or blood agar medium [41]. As the microorganism multiplies during incubation to produce a surface of confluent growth, cells are exposed to the antibiotic that diffuses into the agar from the paper disk. If the bacteria are susceptible to novobiocin, there will be a formation of a zone of inhibition around the disk representing an area where the bacterial growth has been prevented [42]. A zone of inhibition less than 16 mm is indicative of novobiocin resistance. The CoNS have been classified into two groups based on this particular pattern. The ones demonstrating novobiocin susceptibility include epidermidis, S. capitis, S. haemolyticus, S. hominis, S. lugdunensis, S. warneri and S. saccharolyticus. The novobiocin-resistant group consists of: S. kloosii, S. saprophyticus, and S. xylosus [42].

5. Antimicrobial susceptibility

UTIs are individually becoming challenging to treat due to the incorrectly widespread antibiotic use and bacterial resistance mechanism. Regarding antimicrobial resistance, CoNS have been divided into two groups: 1-Susceptible to antimicrobial agents and 2-those exposed to antibiotics in the hospital. CoNS are thought to show an exquisite reservoir of genetic elements that led to resistance to β-lactam antibiotics and other antimicrobial classes [43]. In Staphylococci, including CoNS species, penicillin-binding protein (PBP) expression can lead to β-lactam resistance, such as cephalosporins and carbapenem [44].

6. Preventing recurrent UTI/probiotics

Nonantimicrobial and antimicrobial prophylaxis regimens have been studied in the female population with recurrent UTIs. Probiotics can prevent UTIs by helping to restore the normal vaginal microbiome. Studies investing in Lactobacillus spp. to prevent recurrent UTIs in women have found a link between recurrent symptomatic UTIs and probiotics. Still, additional studies are needed for final decisions to be made [45].

6.1 Preventing recurrent UTI/cranberries

The mechanism of cranberries preventing UTI is yet to be discovered. Although, studies show that the daily drinking of 300 mL of cranberry juice plays a role in preventing this complication due to the function of proanthocyanidins found in cranberry, which inhibit the microorganisms from adhering to the bladder walls and the epithelium cells and make tissues damages [46].

6.2 Preventing recurrent UTI/hyaluronic acid and chondroitin sulfate

The glycosaminoglycan layer has been found in the bladder wall, made of Hyaluronic acid and Chondroitin sulfate, which plays a role in preventing the adherence of microorganisms to the urothelial cells [47]. A damaged glycosaminoglycan layer could lead to an increased rate of recurrent UTIs in both the male and female populations (Table 2) [48].

Medication	Dose
Vaginal estrogen	Estradiol ring 2 mg
Probiotics	Vaginal suppositories two times a week
Cranberries	300 mL juice
Hyaluronic acid and Chondroitin sulfate	800 mg and 1 g in 50-mL solution
Antibiotics	Nitrofurantoin 50 mg daily
	TMP-SMX daily
	Cephalexin 125 mg daily
	Norfloxacin 200 mg daily

Table 2.

Prophylaxis for recurrent UTI.

7. Treatment and resistance

Treatment with antibiotics has been indicated in complicated UTIs and pyelonephritis. There is no indication for routine susceptibility tests for UTI due to S. saprophyticus because it’s usually susceptible to empirical therapy for uncomplicated UTI [49]. The antibiotics for uncomplicated UTI are sulfonamides, ampicillin, and nitrofurantoin 100 mg twice daily for five days or trimethoprim/sulfamethoxazole 160/800 twice daily for three days. In acute uncomplicated UTIs, NSAIDs are a preferred analgesic [50, 51]. resistance to trimethoprim/sulfamethoxazole can lead to failure in empirical therapy, so an antimicrobial susceptibility test is necessary in these cases [52]. Baicalin can be used in UTI treatment because of its inhibitory effects on more efflux gene expression, which encode the msrA efflux pump, which is essential in multidrug resistance in staphylococcus strains [52]. Nalidixic acid has no rule in treating S. saprophyticus UTI due to bacterial resistance. In some studies, the terms methicillin resistance and Oxacillin resistance is being used and recording to CLSI guideline the cefoxitin disc is also being used [54]. Oxacillin resistance occurs due to the production of pB2a in the microbe [52]. Pivmecillinam is another acceptable antibiotic in pregnant patients, while mecillinam is not practical [54] (Table 3).

Antibiotic	Dose
Nitrofurantoin monohydrate	100 mg
TMP-SMX	160/800 mg
Fosfomycin	3 g once
Pivmecillinam	400 mg
Fluoroquinolones	Ciprofloxacin 250 mg
	Ofloxacin 200 mg
Amoxicillin-clavulanate	500/125 mg
Cephalosporins	Cefdinir 100 mg
	Cefaclor 250 mg
Cefpodoxime
Ciprofloxacin	500 mg

Table 3.

Treatment with antibiotics.

A single dose of fosfomycin trometamol also is a good choice in treating uncomplicated UTI and pregnant patients with lower UTI as a first-line empirical therapy (Figure 2) [53].

Figure 2.

Antibiotic-resistance profile [54].

Some S. saprophyticus species are resistant to Cefixime and fosfomycin trometamol naturally, so it does not recommend to use these drugs in treating acute pyelonephritis. Ceftriaxone can be used instead of Cefixime and ciprofloxacin for treating acute pyelonephritis [55].

8. Conclusion

CoNS are versatile Gram-positive bacteria, either coagulase-positive or coagulase-negative, with mucous membranes and skin niches. Coagulase-negative organisms should not always be thought of as contaminants in tissue infection. CoNS rarely get hostile because most of them lack virulence factors. Based on the rise of weak and susceptible patients, CoNS consequently have become major nosocomial pathogens, and their virulence functions have led to complications such as urinary tract infections (UTI). Urinary tract infections are among the most frequent types of hospital and community infections especially in women than man because of their anatomical differences. Pyelonephritis and cystitis are the most common UTIs based on the factors affecting patients and are classified as complicated or uncomplicated. Uncomplicated infections are those in nonpregnant healthy women with normal genitourinary tract and medical history without any recent UTIs. S. saprophyticus is one of the major pathogens causing UTIs. It is a Coagulase-negative Staphylococci (CoNS), colonizing the ureter epithelium via adhesins with the ability to produce biofilms to increase their pathogenicity, however little has being discovered about antibiotic resistant patterns and biofilm functions in this topic. We must know that the treatment of UTIs depends on the S. saprophyticus growing resistance to antibiotics. The big part of S. saprophyticus infections can be treated with antibiotics as said before but if left untreated, can progress to complications. A great deal of knowledge of antimicrobial resistance patterns is essential when choosing an antibiotic agent. So many questions about the ecology, pathogenesis, and phylogeny of CoNS have not been answered yet, but hopefully, following the development of new methodology tools, further research can be approached.