Medication Summary
The goals of pharmacotherapy are to eradicate the infection, prevent complications, and provide symptomatic relief to patients. Early treatment is recommended to reduce the risk for progression to pyelonephritis.
It is important to identify antimicrobial resistance patterns when considering empiric antimicrobial selection. Oral therapy with an empirically chosen antibiotic that is effective against gram-negative aerobic coliform bacteria, such as Escherichia coli, is the principal treatment intervention in patients with lower urinary tract infections. Appropriate antimicrobials for the treatment of cystitis include trimethoprim-sulfamethoxazole (TMP-SMX), nitrofurantoin, fluoroquinolones, or cephalosporins. Some patients may require a urinary analgesic such as oral phenazopyridine, which is useful to relieve discomfort due to severe dysuria.
Sulfonamides
Class Summary
Sulfonamides inhibit bacterial dihydropteroate synthase by competing with para-aminobenzoic acid (PABA). This action interferes with the uptake of PABA into folic acid, an essential component of bacterial development.
Trimethoprim-sulfamethoxazole (Bactrim, Bactrim DS, Septra, Septra DS)
Trimethoprim-sulfamethoxazole (TMP-SMX) is designed to take advantage of the synergy between trimethoprim and sulfonamides. TMP-SMX activity includes common urinary tract pathogens, both aerobic gram-positive and gram-negative bacteria, except Pseudomonas aeruginosa. Empiric therapy with TMP-SMX should be avoided if the prevalence of resistance is greater than 20%. This agent has been given an A-I rating in the 2010 Infectious Disease Society of America (IDSA) guidelines for treating cystitis. [1] General dosing recommendations include administering 1 tablet (160 mg/800 mg) twice a day for 3 days in patients with uncomplicated cystitis.
Antibiotics, Other
Class Summary
Empiric antimicrobial therapy should cover all likely pathogens in the context of this clinical setting. Antibiotics that have been used include nitrofurantoin, fosfomycin, or trimethoprim.
Nitrofurantoin (Furadantin, Macrobid, Macrodantin)
Nitrofurantoin is bactericidal in urine at therapeutic doses. It is indicated for the treatment of cystitis when caused by susceptible strains of E coli, enterococci, Staphylococcus aureus, and certain strains of Klebsiella and Enterobacter species. It is a good treatment option because of minimal resistance and propensity for collateral damage.
This agent has been given an A-I rating in the 2010 Infectious Disease Society of America (IDSA) guidelines for treating cystitis. [1] Nitrofurantoin should be avoided if there is suspicion for early pyelonephritis, and it is contraindicated when creatinine clearance is less than 60 mL/min.
Nitrofurantoin is manufactured in different forms to facilitate durable concentrations in the urine: macrocrystals (Macrodantin) and microcrystal suspension (Furadantin). A combined preparation of monohydrate/monocrystals (Macrobid) is indicated only for the treatment of acute cystitis caused by susceptible strains of E coli or S saprophyticus in patients 12 years of age and older.
General dosing recommendations for patients with uncomplicated cystitis include nitrofurantoin monohydrate/macrocrystals, 100 mg twice a day for 5-7 days, or
nitrofurantoin macrocrystals, 50-100 mg 4 times a day for 7 days.
Fosfomycin (Monurol)
Fosfomycin is a bactericidal agent that is used for the treatment of uncomplicated cystitis in susceptible strains of E coli and Enterococcus faecalis. Little cross-resistance between fosfomycin and other antibacterial agents exists. It is primarily excreted unchanged in the urine, and concentrations remain high for 24-48 hours after a single dose. This agent has been given an A-I rating in the 2010 IDSA guidelines for treating cystitis. [1] Fosfomycin can be administered at a dose of 3 g as a single dose with 3-4 oz of water for uncomplicated cystitis.
Trimethoprim (Primsol)
Trimethoprim inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid. It is active in vitro against a broad range of gram-positive and gram-negative bacteria, including uropathogens, such as Enterobacteriaceae and S saprophyticus. Resistance usually is mediated by decreased cell permeability or alterations in the amount or structure of dihydrofolate reductase. It demonstrates synergy with the sulfonamides, potentiating the inhibition of bacterial tetrahydrofolate production.
Fluoroquinolones
Class Summary
Fluoroquinolones are highly effective against gram-negative and gram-positive bacteria. A major concern with fluoroquinolones is the development of resistance among uropathogens and other organisms. [49] For that reason, these agents should be reserved as alternative therapies for acute cystitis. Fluoroquinolones are effective in 3-day regimens. In the 2010 IDSA guidelines, quinolones have an A-III rating for treating cystitis. [2]
Ciprofloxacin (Cipro. Proquin XR)
Ciprofloxacin is used to treat cystitis that is caused by E coli or S saprophyticus. For acute uncomplicated cystitis, the recommended dosage is 250 mg twice daily for 3 days. As the severity of the condition worsens, the duration of therapy is extended.
Ofloxacin
Ofloxacin is indicated for the treatment of both uncomplicated and complicated cystitis. Like other fluoroquinolones, it is most effective against gram-negative organisms such as E coli, Citrobacter diversus, C freundii, Enterobacter cloacae, Klebsiella species, Proteus species, and Shigella species. The usual regimen for uncomplicated cystitis is 200 mg given twice daily for 3 days. Complicated cystitis can be treated for 10 days.
Levofloxacin (Levaquin)
Levofloxacin is indicated for the treatment of uncomplicated and complicated cystitis. It is used to treat cystitis caused by E coli, S saprophyticus, or Klebsiella species. Levofloxacin can be given for uncomplicated cystitis at a dose of 250 mg every 24 hours for 3 days. It also can be given for complicated cystitis at a dose of 750 mg daily for 5 days or a dose of 250 mg daily for 10 days.
Penicillins, Amino
Class Summary
Penicillins such as amoxicillin and ampicillin are not recommended as empiric therapy for uncomplicated cystitis. However, amoxicillin-clavulanate may be used in uncomplicated cystitis as an alternative therapy.
Amoxicillin-clavulanate (Augmentin, Augmentin XR)
A beta-lactam antibiotic such as amoxicillin-clavulanate in 3-7 day regimens is recommended for the treatment of uncomplicated cystitis when other agents are not appropriate. In the 2010 IDSA guidelines, amoxicillin-clavulanate has a B-I rating for treating cystitis. [1]
Ampicillin
Ampicillin has activity against anaerobes and gram-negative aerobes. Ampicillin can be given intravenously or intramuscularly and generally is used in combination with an aminoglycoside (gentamicin) for empiric or directed activity against E faecalis in patients with complicated cystitis who cannot tolerate oral therapy or in patients in whom infection with resistant organisms is suspected.
Cephalosporins, Second Generation
Class Summary
Cephalosporins represent the majority of antibiotics known as beta-lactam antibiotics. The 2010 IDSA guidelines for treating cystitis give beta-lactams, in general, a B-I rating, listing them as second-line agents. [2] Cephalosporin antibiotics are classified into “generations” that somewhat correspond to their spectrum of action.
Cefaclor
Cefaclor is indicated for the treatment of cystitis and pyelonephritis that is caused by E coli, Proteus mirabilis, Klebsiella species, and coagulase-negative staphylococci. Cefaclor has been used at a dose of 500 mg 3 times a day for 7 days in patients with uncomplicated cystitis.
Cefuroxime (Ceftin, Zinacef)
Cefuroxime is indicated for the treatment of uncomplicated cystitis that is caused by E coli or Klebsiella pneumoniae. The general dosing recommendation is 250 mg given twice daily for 7-10 days.
Cephalosporins, Third Generation
Class Summary
Third-generation cephalosporins are broad-spectrum and have bactericidal activity. These drugs are the most active against serious gram-negative pathogens but have some activity against gram-positive pathogens. The 2010 IDSA guidelines for treating cystitis give beta-lactams, in general, a B-I rating, listing them as second-line agents. [2]
Cefpodoxime
Cefpodoxime is approved for the treatment of uncomplicated cystitis. It is an extended-spectrum oral cephalosporin with bactericidal activity against a wide spectrum of gram-positive and gram-negative bacteria, including E coli, S saprophyticus, and K pneumoniae. Patients with uncomplicated cystitis can be treated with cefpodoxime, 100 mg twice a day for 7 days.
Cefdinir
Cefdinir has been used an alternative therapy for uncomplicated cystitis when other therapies cannot be used. Dosing recommendations include 300 mg twice daily given for 7 days.
Ceftazidime (Fortaz, Tazicef)
Ceftazidime has broad-spectrum gram-negative activity and lower efficacy against gram-positive organisms. It is approved for both complicated and uncomplicated cystitis caused by Pseudomonas aeruginosa; Enterobacter species; Proteus species, including P mirabilis and indole-positive Proteus; Klebsiella species; and E coli. Ceftazidime, 500 mg IV or IM every 8-12 hours for 7-14 days, can be administered to patients with complicated cystitis. For patients with uncomplicated cystitis, a dose of 250 mg IV or IM can be given every 12 hours.
Cephalosporins, Other
Class Summary
Cefepime is a fourth-generation drug that has the gram-negative activity of the third-generation agents and the gram-positive activity of the first-generation drugs.
Cefepime (Maxipime)
Cefepime is a zwitterion; this property is thought to enhance the ability of this agent to penetrate porin channels in the cell walls of gram-negative bacteria. Cefepime is ideal for intramuscular administration.
Cefepime is indicated for the treatment of complicated and uncomplicated cystitis caused by E coli or K pneumoniae when the infection is severe or caused by E coli, K pneumoniae, or P mirabilis when the infection is mild to moderate, including cases associated with concurrent bacteremia with these microorganisms. Cefepime can be administered at a dose of 2 g IV every 12 hours for 10 days for patients with severe complicated cystitis.
Cefiderocol (Fetroja)
Cephalosporin antibiotic with a novel mechanism for penetrating the outer cell membrane of gram-negative pathogens by acting as a siderophore by binding to extracellular free ferric iron. Elicits bactericidal action by inhibiting cell wall biosynthesis through binding to penicillin-binding proteins. It is indicated for complicated UTIs, including pyelonephritis, caused by susceptible gram-negative microorganisms in adults who have limited or no alternative treatment options.
Penicillins, Extended-Spectrum
Class Summary
Extended-spectrum penicillins have a broad spectrum of bactericidal activity. They are used mainly in the treatment of infections suspected or known to be caused by gram-negative aerobes.
Piperacillin-tazobactam (Zosyn)
Piperacillin-tazobactam is useful because of its broad spectrum of bactericidal activity against gram-positive and gram-negative aerobic and anaerobic organisms. Piperacillin is a beta-lactam antibiotic and is mainly bactericidal. Tazobactam is an irreversible inhibitor of bacterial beta-lactamases.
Aminoglycosides
Class Summary
Aminoglycosides are bactericidal antibiotics used primarily in the treatment of gram-negative infections. They irreversibly bind to the 30S subunit of bacterial ribosomes, blocking the recognition step in protein synthesis and causing misreading of the genetic code. The ribosomes separate from the messenger RNA; cell death ensues.
The FDA approved a new aminoglycoside, plazomicin, in June 2018. Approval was based on the Phase 3 Evaluating Plazomicin in cUTI (EPIC) clinical trial (n=388). Plazomicin was noninferior to meropenem in terms of clinical cure and microbiological eradication at Day 5 and test-of-cure at about Day 17. [50]
Gentamicin
Gentamicin has activity against various aerobic gram-negative bacteria, as well as E faecalis and staphylococcal species. It is the only aminoglycoside with appreciable activity against gram-positive organisms. Gentamicin is used with ampicillin to treat patients with complicated cystitis who cannot tolerate oral therapy or patients in whom infection with resistant organisms is suspected.
Plazomicin (Zemdri)
Semisynthetic aminoglycoside antibacterial derived from sisomicin. Plazomicin has been engineered to overcome aminoglycoside-modifying enzymes (AMEs), the most common aminoglycoside-resistance mechanism in Enterobacteriaceae, and has in vitro activity against extended-spectrum beta-lactamase–producing, aminoglycoside-resistant, and carbapenem-resistant isolates. It is indicated for complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible microorganism(s): E coli, K pneumoniae, P mirabilis, and E cloacae. Limited clinical safety and efficacy data are available; therefore, the prescribing information recommends to reserve treatment for use in patients with cUTI who have limited or no alternative treatment options.
Analgesics, Urinary
Class Summary
These agents relieve pain, discomfort, and spasms of the bladder.
Phenazopyridine (Azo Standard, Azo Standard Maximum Strength, Baridium, Pyridium, UTI Relief)
Phenazopyridine is an azo dye excreted in urine, where it exerts a topical analgesic effect on urinary tract mucosa. It is compatible with antibacterial therapy and can help relieve pain and discomfort before antibacterial therapy controls infection. Its analgesic action may reduce or eliminate the need for systemic analgesics or narcotics.
Carbapenems
Class Summary
Carbapenem antibiotics are broad-spectrum antibiotics that are structurally related to beta-lactam antibiotics. The bactericidal activity of carbapenems results from the inhibition of cell wall synthesis and is mediated through the binding to penicillin-binding proteins (PBPs). Parenteral therapy may be warranted for treatment of patients with complicated cystitis who cannot tolerate oral therapy. Parenteral regimens that can be used include carbapenem antibiotics.
Doripenem (Doribax)
Doripenem is indicated as a single agent for the treatment of complicated cystitis and pyelonephritis caused by E coli (including cases with concurrent bacteremia), K pneumoniae, P mirabilis, P aeruginosa, and Acinetobacter baumannii. The general dosing recommendation is 500 mg IV every 8 hours for 10 days.
Imipenem/cilastatin (Primaxin)
Imipenem is a carbapenem antimicrobial agent. It is mainly bactericidal, and it inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific PBPs that are located inside the bacterial cell wall.
Cilastatin is a reversible, competitive inhibitor of dehydropeptidase-1 (DHP-1), an enzyme found in the brush border of the proximal tubular cells of the kidneys that breaks down imipenem to inactive metabolites. Cilastatin prevents the renal metabolism of imipenem, which results in an increase in urinary concentrations of imipenem and minimizes the nephrotoxicity observed when imipenem is administered alone. Imipenem can be administered at a dose of 500 mg IV every 6 hours for 7-14 days.
Imipenem/cilastatin/relebactam (Recarbrio)
Three-drug combination containing previously approved imipenem/cilastatin and relebactam, a beta-lactamase inhibitor. It is indicated for complicated urinary tract infections, including pyelonephritis, and complicated intra-abdominal infections in adults with limited or no other treatment options. Dosage modifications are necessary for patients who have renal impairment.
Meropenem (Merrem)
Meropenem is indicated for the treatment of bacterial meningitis, complicated skin and skin-structure infections, and intra-abdominal infections. However, it can also be used for the treatment of complicated cystitis. It inhibits cell wall formation, facilitates bacterial cell lysis, and is primarily a bactericidal agent. It inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific PBPs that are located inside the bacterial cell wall.
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Nonobstructing distal left ureteral calculus 2 X 1 X 2 cm.
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Multiple abscesses, upper pole of left kidney.
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Bilateral hydronephrosis.
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Plain radiograph in a 63-year-old patient with poorly controlled type 2 diabetes mellitus shows emphysematous cystitis.
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Lactobacilli and a squamous epithelial cell are evident on this vaginal smear. The presence of squamous cells and lactobacilli on urinalysis suggests contamination or colonization. Source: Centers for Disease Control and Prevention, Dr. Mike Miller
Tables
First-line therapy |
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Second-line therapy |
|
Alternative therapy |
*Should generally be avoided in elderly patients because of the risk of affecting renal function. |
First-line therapy |
Oral: Patients with complicated cystitis who can tolerate oral therapy may be treated with the following options:
Parenteral: Patients who cannot tolerate oral therapy as outlined above or patients with infection that is suspected to be due to resistant organisms should be treated with parenteral therapy, as follows:
Duration of therapy: Shorter courses (7d) are reasonable if patient improves rapidly; longer courses (10-14d) are reasonable if patient has a delayed response or is hospitalized.
Parenteral therapy can be switched to oral therapy once clinical improvement is observed. |
Second-line therapy |
Duration of therapy: Shorter courses (7d) are reasonable if patient improves rapidly; longer courses (10-14d) are reasonable if patient has a delayed response or is hospitalized.
Parenteral therapy can be switched to oral therapy once clinical improvement is observed. |
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