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Urinary anti-infective agent

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Urinary anti-infective agent, also known as urinary antiseptic, is medication that can eliminate microorganisms causing urinary tract infections (UTIs). UTIs can be categorized into two primary types: cystitis, which refers to an infection in the lower urinary tract or bladder, and pyelonephritis, which indicates an infection in the upper urinary tract or kidney.[1]

 
Scanned electron photograph of E.Coli

Escherichia coli (E.Coli) is the most common microbial cause of UTIs, accounting for 75% to 95% of reported cases. Other species of Enterobacteriaceae, such as Klebsiella pneumoniae and Proteus mirabilis, as well as bacteria like Staphylococcus saprophyticus, can also cause UTIs.[2][3] Antibiotics are commonly used to treat UTIs by targeting and inhibiting bacterial growth in the urinary tract. These agents relieve UTI symptoms such as frequent urination, burning sensation, and discomfort.

The use of antimicrobial therapy to treat UTIs started in the 20th century. Nitrofurantoin, trimethoprim-sulfamethoxazole (TMP/SMX), fosfomycin, and pivmecillinam are currently the first-line agents for empiric therapy of simple cystitis.[4] On the other hand, the choice of empiric antimicrobial therapy for pyelonephritis depends on the severity of illness, the presence of resistant pathogens, and specific host factors. Ceftriaxone is often considered for parenteral treatment, while oral or parenteral fluoroquinolones, such as ciprofloxacin or levofloxacin, are reasonable alternatives for treating pyelonephritis.[5]

Antimicrobial therapy should be tailored to the individual, considering factors like the severity of illness, specific host factors, and pathogen resistance in the local community.[1] Choices of agents and dosages may need to be adjusted for individuals with renal dysfunction, during pregnancy, and in pediatrics to optimize therapeutic outcomes while minimizing potential risks and adverse effects.

Origin & Development

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The discovery of antimicrobial agents contributed significantly to UTI management during the 20th century. Nitrofurantoin emerged as the first practical and safe urinary antimicrobial agent, but it was with limited spectrum of activity.[6] Subsequently, in the 1970s, beta-lactam antibiotics and TMP/SMX became available for UTI therapy.[6] Antimicrobial resistance was developed to these agents due to their widespread and extensive usage, which restricted their clinical efficacy in UTI management. Fluoroquinolones emerged during the 1980s and were recommended as an alternative when resistance to TMP/SMX reaches 10% or higher.[6] The evolving landscape of drug resistance will continue to influence the development and application of antimicrobial agents in UTI therapy.[7]

Types of urinary anti-infective agents

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Urinary antiseptics are medications that target bacteria in the urinary tract.[8] They can be divided into two groups: bactericidal agents, and bacteriostatic agents. These antiseptics help prevent infections by effectively eliminating UTI symptoms through their action on microorganisms.[9][10]

Urinary bactericidal agents

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Urinary bactericidal agents are commonly used to treat UTIs by killing bacteria in the urinary tract. Nitrofurantoin, fosfomycin, beta-lactam antibiotics, and fluoroquinolones are the most commonly used drugs in clinical practice.

Nitrofurantoin

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Chemical structure of nitrofurantoin

Nitrofurantoin is commonly prescribed as the first-line treatment for uncomplicated cystitis, with an efficacy rate ranging from 88% to 92%.[11] It can also be a prophylactic agent to prevent long-term UTIs.[12] This antibacterial medication is effective against both gram-positive and gram-negative bacteria.[13] Nitrofurantoin exhibits its bactericidal activity through various mechanisms, including inhibiting ribosomal translation, causing bacterial DNA damage, and interfering with the citric acid cycle. However, the specific role of each mechanism remains to be further explored.[11][13]

When nitrofurantoin is metabolized, it converts into a reactive intermediate that attacks bacterial ribosomes, inhibiting bacterial protein synthesis.[11][13] This medication is typically taken orally and has minimal systemic absorption, reducing potential side effects.[14] Common adverse reactions associated with nitrofurantoin include brown urine discoloration, gastrointestinal (GI) intolerance, such as nausea and vomiting, loss of appetite, rash, and peripheral neuropathy.[15]

Fosfomycin

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Chemical structure of fosfomycin

Fosfomycin is a phosphonic acid bactericidal agent recommended as the first-line treatment for acute uncomplicated cystitis, boasting a cure rate of 91%.[4][11] It is administered orally as a single dose; In more complicated UTIs, the dose is adjusted to be repeated every three days to achieve successful eradication.[11]

The bactericidal effect of fosfomycin is attributed to its ability to inhibit bacterial wall synthesis by inactivating an enzyme called pyruvyl transferase, which is responsible for microbial cell wall synthesis.[11] Fosfomycin acts against gram-positive and gram-negative bacteria. Administration of fosfomycin may lead to side effects such as headache, dizziness, GI intolerance, and abdominal cramps.[15]

Beta-lactam antibiotics

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chemical structure of beta-lactam

Beta-lactam antibiotics are typically considered as a second-line option for treating UTIs due to their comparatively lower effectiveness and higher potential for adverse effects.[16][17] Commonly used beta-lactam antibiotics for UTIs include cephalosporins and penicillin. These antibiotics exert their bactericidal effects by binding to penicillin-binding proteins through their beta-lactam rings, which disrupts the normal function of these proteins, inhibiting bacterial cell wall synthesis and leading to cell death.[18]

Cephalosporins are a subclass of beta-lactam family with broad-spectrum activity against numerous gram-positive and gram-negative bacteria.[14] They are categorized into five generations.[18] First and third-generation cephalosporins, like cefalexin and ceftriaxone, are more commonly used in clinical practice. [19] Common adverse effects associated with cephalosporins include hypersensitivity, rash, anaphylaxis, and seizures.[14]

Penicillin is another widely used subclass that effectively targets various bacteria.[20] However, it is not recommended as a first-line treatment for uncomplicated cystitis due to the high prevalence of penicillin-resistant E. coli strains.[14] Within the penicillin class, pivmecillinam is considered the first-line empiric treatment for acute cystitis due to its wide spectrum of activity against gram-negative bacteria and its specific efficacy in the urinary tract. It has consistently demonstrated a high cure rate of over 85% for UTIs and a low resistance rate among E. coli strains.[4][21][22] Amoxicillin-clavulanate combination, which enhances the effectiveness of amoxicillin, is often used as an alternative for cystitis treatment when other options cannot be used.[23]

Fluoroquinolones

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Chemical structure of one of the most used fluoroquinolone - ciprofloxacin

Fluoroquinolones are a class of antimicrobial agents known for their high efficacy and broad spectrum activity against both aerobic gram-positive and gram-negative bacteria.[14][24] These potent antibiotics exert their bactericidal effects by selectively inhibiting the activity of type II DNA topoisomerases,[24] which effectively halt the replication of bacterial DNA, leading to bacterial death.[24]

Among the fluoroquinolones, ciprofloxacin and levofloxacin are commonly used for the treatment of UTIs. These agents are well-absorbed orally and achieve significant concentrations in urine and various tissues.[14] However, fluoroquinolones administration carries risk of GI symptoms, confusion, hypersensitivity, tendinopathy, and neuropathy.[25] Additionally, the broad use of fluoroquinolones has contributed to the development of antimicrobial resistance in some areas. As a result, fluoroquinolones are generally reserved for more serious UTIs or when there are no better anti urinary-infective agent options. [25]

Bacterial static agents

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Chemical structure of trimethoprim-sulfamethoxazole (TMP-SMX)

Urinary bacteriostatic agents are commonly used to treat UTIs by inhibiting bacterial growth. Sulfonamides are the most widely used drugs in this class in clinical practice.

Sulfonamides

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Sulfonamide is a bacteriostatic agent that competitively inhibits the bacterial enzyme dihydropteroate synthase, by acting as a substrate analog of para-aminobenzoic acid (PABA), to curb the production of folic acid.[26] TMP/SMX, also known as co-trimoxazole, is a combination of two antibacterial agents that work synergistically to combat a wide range of urinary tract pathogens.[27] TMP/SMX is commonly used due to its ability to achieve high concentrations in urinary tract tissues and urine and demonstrate notable efficacy for both treatment and prophylaxis against recurrent infections.[14] Common adverse effects include GI symptoms, rash, pruritus, and photosensitivity.[28]

Renal dysfunction

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Kidney disease can impact renal drug elimination and other pharmacokinetic processes involved in drug disposition, such as absorption and drug distribution. The impaired function of the kidneys can result in altered drug concentrations in the body, potentially leading to toxicity or suboptimal therapeutic effects. Therefore, drug dosages need to be adjusted for patients who fail to achieve the desired therapeutic serum drug levels.[29]

Management

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When initiating antimicrobial treatment, it is crucial to consider decreased renal excretion in patients. Most antimicrobials have a wide therapeutic index, no dose adjustment is initiated until glomerular filtration rate (GFR) falls below 20 mL/min, except for antimicrobials with nephrotoxic potential, like aminoglycosides.[30]

Medication Safety

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The choice of urinary anti-infective agents for patients with renal dysfunction is generally the same as for normal individuals. However, drug dosages may need to be adjusted. It is important to note that nitrofurantoin is contraindicated in patients with an estimated GFR of less than 30 mL/min/1.73m2 as drug accumulation can lead to increased side effects and reduced urinary tract recovery, increasing the risk of treatment failure.[31] TMP/SMX also raises concerns as the urine concentrations of sulfamethoxazole decrease to subtherapeutic levels in patients with creatinine clearances less than 50 mL/min; hence, reduced dosage of trimethoprim should be prescribed alone in patients with low creatinine clearance.[32]

Pregnancy

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Pregnant women who suffer from UTIs are more likely to experience recurrent bacteriuria and develop pyelonephritis compared to non-pregnant individuals.[33] Untreated UTIs during pregnancy have been associated with adverse outcomes, including preterm birth and low birth weight infants.[34][35]. Eradicating bacteriuria can reduce this risk by 70% to 80%, significantly decreasing complications from UTIs.

Management

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Antimicrobial treatment should be adjusted for UTIs in pregnant women to avoid potential side effects brought to fetus.[36] For acute cystitis and pyelonephritis in pregnant women, antibiotic treatment is often empiric. Commonly used antibiotics for uncomplicated cystitis include amoxicillin-clavulanate and fosfomycin, while parenteral beta-lactams are preferred for acute pyelonephritis. These options are chosen because they are considered safer in pregnancy and have a relatively broad spectrum of activity. Typically a course of five to seven days is given to minimize fetal exposure to antimicrobials and ensure optimal treatment outcomes.[33]

Medication Safety

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During pregnancy, the type of urinary anti-infective agents should be carefully chosen due to the potential impact on fetal development. Penicillins, cephalosporins, fosfomycin, and meropenem are safe options during pregnancy.[37] Nitrofurantoin is typically avoided during the first trimester due to uncertain associations with congenital anomalies.[38] TMP/SMX should also be avoided as it may be associated with impaired folate metabolism, which increases the risk of neural tube defects.[39] [40] However, when all alternative antibiotics are contraindicated, nitrofurantoin and TMP/SMX become the last resort at the expense of the fetus.[41] It is to know that fluoroquinolones should be avoided during pregnancy as they are associated with bone and cartilage toxicity in developing fetuses.[42][43][44]

Pediatrics

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Urinary tract infection is a significant clinical issue in childhood, affecting approximately 7 percent of febrile infants and young children.[45] If left untreated, the infection can ascend from the bladder to the kidneys, resulting in acute pyelonephritis, which leads to hypertension, kidney scarring, and end-stage kidney disease. In the acute UTI treatment in pediatrics, urinary antiseptics are administered to eliminate the infection, alleviate acute symptoms, and minimize the risks of recurrence and long-term complications.[46]

Management

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The choice of urinary anti-infective agents in pediatric patients is based on the suspicion of kidney involvement. It is important to note that the dosage of antibiotics used in children is typically weight-dependent.Generally, oral or parenteral cephalosporins are recommended as first-line agents for children older than two months.[47][48] Second-line therapy should be considered for patients who have poor response to first-line treatment. Alternative choices include amoxicillin-clavulanate, nitrofurantoin, TMP/SMX, and ciprofloxacin.[46]

In children with less suspected pyelonephritis, a five-day oral course of cephalexin is preferred. A 10-day treatment regimen should be initiated for children with suspected pyelonephritis, and a third-generation cephalosporin such as cefdinir is suggested. However, if second-line therapy is initiated in pediatric patients with suspected kidney involvement, ciprofloxacin should be the preferred option among the four alternatives. Nitrofurantoin may not be adequate in treating upper urinary tract infections, while amoxicillin-clavulanate and TMP/SMX should be used with caution due to the risk of kidney scarring in these patients.[46]

Medication Safety

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The choice of urinary anti-infective agents in pediatric patients may differ from that in adults due to the potential harm they can cause to children. For example, systemic fluoroquinolones should be excluded in pediatric patients due to the potential risk of musculoskeletal toxicity.[49]

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