Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Author: Dr. R.K. Shimpi
M.S.( Gen. Surg.), M.Ch. (Urology), FAIS, FICS (Uro), Consultant Uro-Surgeon, Andrologist, Robotic Surgeon, Ruby Hall Clinic, Inamdar Hospital, Asian Institute of Men’s Health & Urology, Pune
download ArticleAbstract
Urinary tract infections (UTIs) are the most globally prevalent disease affecting all age groups. The recent emergence of resistant pathogens has led to the increased cause of morbidity and healthcare expenditure. Limited options of novel antibiotic agents and broad spectrum effectiveness of fosfomycin against the bacterial species has re-evaluated its position as potential therapy. With the advances in technology, the technically superior multilayer packaging of fosfomycin granules helps to preserve its stability and effectiveness to treat the resistant infections.
Keywords: Fosfomycin, Urinary tract infection, Multilayer sachet packaging
Introduction
Urinary tract infections (UTI) are the most common type of infection found in outdoor patients. It is most prevalent in women than men with lifetime incidence rate of 50-60% [1]. The prevalence increases with age with approximately 20% over 65 years of age. It is the leading cause of morbidity and healthcare expenditures in persons of all ages globally.
UTI is the infection of urinary tract affecting both lower and upper tract. It may be community acquired or hospital acquired [2]. The causative agent behind infections are the bacteria. Different measures can be employed to treat and prevent the infections, but due to high pervasiveness of resistant bacterial strains the complete elimination of infection becomes difficult and the incidence of recurrence increases.
Urinary Tract Infection (UTI)
Urinary system constitutes the urethra, urinary bladder, ureter and the kidney. UTI is an infection that can affect any of these parts. If the part of lower tract consisting urinary bladder is affected, it is termed as bladder infection or cystitis. If the part of upper tract consisting of kidney is affected, it is termed as kidney infection or pyelonephritis [3].
The most common symptom of UTI is fever. Other symptoms of lower urinary tract infection include pain with urination, frequent urination, and feeling the need to urinate despite having an empty bladder [4]. Usually in addition to the symptoms of a lower UTI, kidney infection includes fever and flanking pain [3]. Clinically the UTI is diagnosed by the presence of cloudy urine with foul smell; and further confirmation can be done by urine culture identifying the bacterial strain in urine [5]. If infection in upper tract is suspected, complete blood count and blood cultures are required for confirming the source of infection via blood.
Risk factors include female anatomy, sexual intercourse, diabetes, obesity, and family history [6]. Kidney infection is usually followed by a bladder infection, but may also result from a blood-borne infection. Females are more susceptible due to the short length of urethra, pregnancy, absence of prostatic secretion and feasible contamination of the tract with faecal flora due to nearby vicinity [7]. During infection, bacteria typically enter the bladder through the urethra and attach to bladder wall to form biofilm (figure 1), that can resist the body’s immune response [8].
E. coli is most common organism causing UTI which accounts for up to 90% of cases. P. mirabilis, Klebsiella species, P. aeruginosa and Enterobacter species are less frequent offenders. Gram-positive organisms are less common which includes Group B Streptococcus, S. aureus, S. saprophyticus and S. haemolyticus [9].
Figure 1: Showing bladder infection of lower urinary tract
UTIs, Treatment and Resistance to Antibiotics
Clinically UTI is divided into two categories – uncomplicated UTI and complicated UTI. These categories can be further sub divided into – asymptomatic bacteriuria, acute uncomplicated cystitis, acute uncomplicated pyelonephritis and recurrent uncomplicated UTIs.
Uncomplicated UTI mostly affects healthy individuals, who does not have any structural or neurological urinary tract abnormalities; which includes cystitis and pyelonephritis. Complicated UTI happens to individual due to the factors that compromise the urinary tract; which include pregnancy, neurological disease causing urinary retention, renal failure, urinary obstruction, renal transplantation and the presence of foreign bodies such as calculi, indwelling catheters or other drainage devices [10].
Treatment of UTIs mainly include antibiotics, as UTI is commonly caused due to bacterial infections. The form of antibiotic used to treat a bacterial UTI usually depends on part of the urinary tract involved. Lower tract UTIs can usually be treated with oral antibiotics. Upper tract UTIs require intravenous antibiotics, which are directly inserted into veins. At times the patient does not respond to the course of antibiotic treatments going on, for this the specific strain of bacteria which has infected the patient needs to be determined for choosing the right type of antibiotic treatment. Besides this, bacteria may develop resistance to antibiotics. To reduce the risk of antibiotic resistance, it is essential to choose the shortest treatment course possible, and should typically last not more than 1 week.
Commonly used antibiotics, includes trimethoprim/sulfamethoxazole (TMP/SMX), nitrofurantoin, or fosfomycin; are typically first line therapy [11]. Cephalosporins, amoxicillin/clavulanic acid, ceftriaxone, or a fluoroquinolone, ciprofloxacin may also be used [12]. However, antibiotic resistance to fluoroquinolones among the bacteria causing urinary infections has been increasing. Phenazopyridine can occasionally be prescribed for managing the pain during the therapy, along with acetaminophen to control fever.
Currently UTI is mostly managed empirically without urine culture or susceptibility testing.This may lead to the frequent misuse of antibiotics. The overuse or misuse of antibiotics is often the reason for antibiotic resistance. Antibiotic resistance makes the treatment ineffective, increasing the severity of the disease and incidence of high mortality rate.
Antimicrobial resistance remains the major problem in the therapy for UTI throughout the world. Fundamental mechanism of antibiotic resistance may be due to enzymatic degradation of antibiotics, alteration of bacterial proteins or changes in the membrane permeability to antibiotics. Antibiotic resistance can appear spontaneous because of random mutation or more commonly following gradual build up over time [13].
Fosfomycin
Fosfomycin is an antibiotic primarily used to treat bladder infections, generally prescribed orally. It was first discovered in 1969 and approved for medical use in 1996. It is on the World Health Organization's List of Essential Medicines; classified under critically important for human medicine. It was originally produced by certain types of Streptomyces, although it is now made synthetically [14].
Fosfomycin is a broad spectrum antibiotic, derived from phosphonic acid. It is considerably active against both gram-negative and gram-positive bacteria. Specially, fosfomycin is considered active against Enterococcus spp. (irrespective of vancomycin resistance), Staphylococcus aureus (irrespective of methicillin resistance), and S. epidermidis [15]. Fosfomycin also exhibits considerable activity against Gram-negative pathogens, including E. coli, Salmonella spp., Shigella spp., Serratia spp., Citrobacter spp., Proteus mirabilis, Klebsiella and Enterobacter spp. [16]. It is effective in treating the UTI infection caused by Escherichia coli and Staphylococcus saprophyticus.
Fosfomycin, Bridging the Gap
In recent times, the emergence of resistance pathogens has complicated the therapeutic approach to serious infections. Also, resistant pathogens are frequently being encountered in easily treated infections, like that of acute cystitis due to ESBL E. coli isolates. Limited options of novel antibiotic agents have necessitated the re-evaluation of fosfomycin, as a potential therapeutic option for infections caused by contemporary isolates with advanced antimicrobial resistance [17].
Observations have been made in regards to few bacterial species of resisting the intracellular killing after phagocytosis from neutrophils and persisting inside the host cell. Therefore, they can cause relapse of infections after few days resulting into recurrent diseases [18]. Based on studies, fosfomycin was been observed to penetrate inside the cells and assist in bacterial clearance in cell line experiments. Compared to other antimicrobials, fosfomycin was more active than glycopeptides and daptomycin [19].
Fosfomycin, Mechanism of Action
Fosfomycin has bactericidal activity. It inhibits bacterial cell wall biogenesis by inactivating the enzyme UDP-N-acetylglucosamine-3-enolpyruvyltransferase, also known as MurA [20]. This enzyme catalyses the committed step in peptidoglycan biosynthesis, namely the ligation of phosphoenolpyruvate (PEP) to the 3'-hydroxyl group of UDP-N-acetylglucosamine. This pyruvate moiety provides the linker that bridges the glycan and peptide portion of peptidoglycan.
Fosfomycin enters the bacterial cell through the glycerophosphate transporter [21]. After entering the cell, fosfomycin (aPEP analog) inhibits MurA by alkylating an active site cysteine residue (Cys 115 in the Escherichia coli enzyme) [22]; which prevents the formation of N-acetylmuramic acid, an essential element of the peptidoglycan cell wall.
Fosfomycin, Pharmacokinetics
The concentration of fosfomycin in serum is higher when it is administered before intake of food. Pharmacokinetic parameters indicate that absorption is significantly reduced after food intake. 58% of the administered dose is found in the urine within 24 hours [23-25].
Urinary concentration is high and may exceed 2000mg/L after administration of a single dose. Urinary levels remain high for a prolonged period (over 24hours) constituting an argument in favour of its use in the treatment of common urinary tract infections [25, 26].
Fosfomycin, Pharmacodynamics
Fosfomycin has demonstrated concentration-dependent killing in two different in vitro models. Fosfomycin activity uses kill curves at concentrations from 1x MIC to 64x MIC for isolates of E. coli and P. mirabilis [27]. When bacterial growth was assessed from time 0 to 24 hours, bacterial inhibition was directly proportional to fosfomycin concentration [27]. For E. coli, complete eradication was observed at 6–8 hours at fosfomycin concentrations ≥4x MIC [28].
Improved Bioavailability of Fosfomycin with Trometamol
When Fosfomycin is administered orally, it is partially absorbed by the small intestine by two mechanisms- (i) a saturable carrier-mediated system associated with a phosphate transport system, and (ii) a non-saturable process with first-order kinetics [29]. Studies with fosfomycin calcium have shown that before reaching the small intestine, fosfomycin undergoes acid-catalyzed hydrolysis in the stomach, where intra-gastric acidity and gastric emptying rate can affect the extent of fosfomycin’s hydrolytic degradation and consequently its bioavailability [30].
Whereas, trometamol is a pH (i.e., alkaline) organic compound believed to slow acid-catalysed hydrolysis. As mentioned, fosfomycin trometamol is the most preferred oral formulation due to its improved properties compared to fosfomycin calcium, including higher bioavailability (F) which ranges from 33% to 44% [31] compared to 12–37% for the calcium salt [32]. It has been observed that when bioavailability was taken into account from urinary excretion data following oral and parenteral administration of fosfomycin trometamol, values as high as 58% have been calculated [33]. Despite the fact that the bioavailability of the two salts is diminished when taken orally, following food when taken under fasting conditions, serum concentrations of the trometamol salt are around 2–4 fold higher than the calcium formula of fosfomycin [34, 35].
Fosfona, Technological Advancement
The increased bioavailability of fosfomycin in granules form is considered for better treatment of urinary tract infections before the complicated UTI. It was taken into account that the improved bioavailability of fosfomycin has better patient compliance and will help in reducing the frequent hospital stays of patients for parenteral administration. Further, the complications with the granules were found with its stability and packaging of it. The hygroscopic granules of fosfomycin trometamol formed chunks and caking of the granules by absorbing moisture in different geographical conditions.
With further advancement of technology and studies, the outer and inner packaging is fused for a dual packaging of four layers. The packaging which comprises an inner layer having high water vapour permeability for packaging article, an outer layer having no or low water vapour permeability. The new advancement in packaging of the fosfomycin trometamol prevent the granules from caking into chunks and having a better stability in the long run, while the layers also serve as desiccants, while in storage. The technological advancement in the packaging led to the granules having caking properties which can be stored for a long term of over six months, especially over one year without accompanying occurrence of caking. The overall quality of the packaging helped the molecule reached to superiority in terms of quality for the reach to patients. The new sachet form with four layers has increased the shelf-life of the molecule in an unopened sachet for 3 years.
Dosage and Administration
The benefit of a single dose regimen and granule formulation with better bioavailability, fosfomycin has achieved an important place in the world of antibiotics. Fosfomycin trometamol is currently approved for use in several European countries and is approved as a single 3-g dose for treating uncomplicated UTIs in women, specifically UTIs due to E. coli infection [36]. The molecule has also been investigated as a potential therapy for surgical prophylaxis in order to prevent prostate infection and even as a treatment for prostatitis due to MDR Gram-negative bacteria [37]. The use of a multiple-dose regimen with fosfomycin trometamol has emerged as a potential strategy for treating of complicated and/or recurrent UTI, as well as infections due to MDR bacteria [38]. A study has suggested that a single dose of 3 g of fosfomycin trometamol in every 72 hours is sufficient to achieve the appropriate concentration to treat resistant pathogens causing recurrent UTI [39].
In premature infants, the recommendation is 100 mg/kg/day divided into 2 doses; for full-term new-borns, 200 mg/kg/day in 3 doses is recommended. Starting at 12 years of age or 40 kg of weight, the dosage is the same as for adults. In the case of infections by multidrug-resistant microorganisms, there are no specific recommendations for children, while for adults the recommendation is 8-12 g/day for Gram-positive microorganisms and 16-24 g/day for Gram-negative microorganisms [40].
Fosfomycin is recommended as the first-line treatment of uncomplicated lower urinary tract infection due to broad spectrum, low resistance of uropathogens, high safety profile and good compliancy [41].
Fosfomycin trometamol should be taken immediately after dissolving the 3 g of granules in a glass of water.
Conclusion
The World Health Organization currently perceives that antibiotic resistance is one of the significant dangers confronting worldwide general wellbeing, especially given the decrease in the number of powerful antibiotics. In this regard, rethinking and re-examining of old antibiotics, fosfomycin has been proposed as a potential molecule in treating resistant bacterial infection of urinary tract. The emerging multi-drug resistance strains of E. coli and ESBLs can be treated with fosfomycin trometamol, with its low resistance chance due to its unique mechanism of action. Oral fosfomycin in a multiple-dose regimen has emerged as a potential strategy for treating complicated UTIs and prostatitis. The convenient single dosage and administration of fosfomycin is also an added advantage to the women, who are at higher risk of getting infected by UTI once in a lifetime. Due to the resistance rate of antibiotics, fosfomycin is an old and unique antibiotic that can reduce the burden of hospital stays and recurrent UTI. In the meantime, using fosfomycin as a monotherapy should be avoided due to the rapid development of resistance in vitro.
References
