Which antibiotic to use in simple cystitis and why.

Managing an OPD can be a daunting task for a young inexperienced doctor. In Pakistan, from where I am writing, one doctor may have to deal with 50 to a 100 patients in one session, all of them in a hurry, all upset by the heat, the wait in the OPD hall and the thought that the OPD will close before it is their turn to see the doctor. The doctor has to deal with their irateness, their hurry to get home and their illness. So let’s start with one of the commonest problems seen in an OPD.

Simple cystitis.

 The term acute simple cystitis refers to an acute urinary tract infection (UTI) that is presumed to be confined to the bladder.

CLINICAL MANIFESTATIONS — The classic clinical manifestations of cystitis consist of dysuria, urinary frequency, urinary urgency, and suprapubic pain. Hematuria is also often observed.

The symptoms of cystitis are usually difficult to obtain from women specially the elderly women who have a multitude of non-specific symptoms specially related to the digestive system which may not require attention other than the prescription of an antacid which they claim as their right. How ever do not ignore symptoms like dysphagia, loss of appetite and weight loss.

Older women can have a number of nonspecific urinary symptoms (such as chronic dysuria or urinary incontinence) that mimic symptoms of cystitis, even when there is no evidence of urinary tract infection (UTI).  In contrast, acute dysuria (less than one week duration), new or worsening urinary urgency, new incontinence, frequency, gross hematuria, and suprapubic pain or tenderness are more discriminating symptoms. Fever is also a discriminating feature. With fever be careful that you are not missing  a complicated UTI or acute pyelonephritis.

What should you do about this? A sensible action would be to do a urinalysis (in your hospital it may be called a urine R/E or urine D/R) and a urine culture. The problem is the hospital lab will probably not give you a report within an hour or two, the patient is not going to wait and wants instant relief. The culture report will take 48 hours and the patient will not come back so soon so what to do? Start empirical therapy or best guess therapy for 3-5 days.

When should you think of an infection extending beyond the bladder? Suspicion should be roused if there is/are:

  • Fever (>99.9°F/37.7°C) –  Take into account baseline temperature, other potential contributors to an elevated temperature, and the risk of poor outcomes should empiric antimicrobial therapy be inappropriate. You may need to admit the patient for a urine culture, blood culture, blood complete picture and other tests.
  • Other signs or symptoms of systemic illness (including chills or rigors, significant fatigue or malaise).
  • Flank pain.
  • Costovertebral angle tenderness i.e tenderness in the renal angle.

If any of these signs or symptoms are present in the setting of pyuria and bacteriuria, consider the patient to have acute complicated UTI and manage the patient differently.

Consider the patient to have complicated UTI if there is underlying urologic abnormalities (such as nephrolithiasis, strictures, stents, or urinary diversions), immunocompromising conditions (such as neutropenia or advanced HIV infection), or poorly controlled diabetes mellitus even if they have no or minor symptoms for upper urinary tract or symptoms of systemic infection. However, such patients can be at higher risk for more serious infection and have not traditionally been included in studies evaluating the antibiotic regimens we typically use for acute simple cystitis. Thus, such patients must be followed more closely and/or a low threshold should be set to manage them as complicated UTI (eg, if they have subtle signs or symptoms that could be suggestive of more extensive infection). Many patients with significant urologic abnormalities come to clinical attention for UTI because of signs or symptoms consistent with complicated UTI as defined here (rather than features of simple cystitis alone).

Certain populations, such as pregnant women and renal transplant recipients, have unique management considerations and thus are not included in the above categorization. These populations will be discussed elsewhere.

In debilated, elderly patients many mental changes such as  aggressive behavior, altered mental functions have been attributed to UTI. In most studies the symptoms correlating with acute cystitis in debilitated patient are  acute dysuria, change in the character of urine (gross hematuria, change in color or odor), and change in mental status if associated with the presence of both pyuria and bacteriuria. Among these patients with bacteriuria, there also appears to be no association between these nonspecific mental status changes and urinary markers of inflammation (ie, interleukin-6). Furthermore, treatment of bacteriuria in patients with acute delirium or nonspecific symptoms is not associated with improvement in mental or functional status (but is associated with Clostridium difficile).

EPIDEMIOLOGY — Cystitis among women is extremely common. The shorter distance from the anus to the urethra likely explains why women are at higher risk for urinary tract infections (UTIs) than men.Among otherwise healthy women, risk factors for cystitis include recent sexual intercourse and a history of UTI. Use of spermicide-coated condoms, diaphragms, and spermicides alone are also associated with an increased cystitis risk.

Other comorbidities, such as diabetes mellitus and structural or functional urinary tract abnormalities, can also increase the risk of cystitis or complicated UTI.

MICROBIOLOGY

Microbial spectrum — Escherichia coli is the most frequent microbial cause of simple cystitis (75 to 95 percent of cases), with occasional infections caused by other species of Enterobacteriaceae (such as Klebsiella pneumoniae and Proteus mirabilis) and other bacteria, such as Staphylococcus saprophyticus. Other gram-negative and gram-positive species are infrequently isolated in acute simple cystitis in the absence of antimicrobial or health care exposures.

If the patient has recently been admitted in a hospital or other health care facility or had a procedure done then think of other gram-negative bacilli (eg, Pseudomonas), enterococci, and staphylococci. Thus, culture and susceptibility testing are essential for management in patients who have such risk factors. Even in the absence of specific risk factors, resistance in E. coli can be a major issue.

Among otherwise healthy nonpregnant women, the isolation of organisms such as lactobacilli, enterococci, Group B streptococci, and coagulase-negative staphylococci other than S. saprophyticus from voided midstream urine most commonly represents contamination of the urine specimen. 

Treatment of simple cystitis.

First-line antimicrobial options — The preferred agents for empiric therapy of acute simple cystitis are nitrofurantoin monohydrate/macrocrystals, trimethoprim-sulfamethoxazole, fosfomycin, and, if available, pivmecillinam. In Pakistan think also of doxycycline, piperacillin, ciprofloxacillin and in pregnant women cephalexin.

  • Nitrofurantoin monohydrate/macrocrystals (Macrobid) – Dosed at 100 mg orally twice daily for five days. Can be effective in mild renal impairment even in the elderly.
  • Trimethoprim-sulfamethoxazole – Dosed as one double-strength tablet (160/800 mg) orally twice daily for three days. Randomized trials suggest a 79 to 100 percent clinical cure rate with a three- to seven-day regimen.
  • Fosfomycin – Dosed as 3 grams of powder mixed in water as a single oral dose. One randomized trial reported an early clinical cure rate of 91 percent and a bacterial cure rate similar to nitrofurantoin.
  • Pivmecillinam – Dosed as 400 mg orally twice daily for five to seven days. The clinical efficacy reported in randomized trials (55 to 82 percent) is lower than other first-line agents, but it has minimal propensity to select for resistant organisms. Pivmecillinam is an extended gram-negative spectrum penicillin used only for treatment of urinary tract infection (UTI). It is not available in the United States but is an agent of choice in many Nordic countries due to low resistance rates
  • Cephalexin. This drug is useful in asymptomatic bacteriuria specially in pregnancy as well as acute cystitis. It is safe in pregnancy. Dose is 500mg 6 hourly.
  • Amoxicillin-clavulanic acid. Resistance rates for first and second generation oral cephalosporins and amoxicillin-clavulanic acid are regionally variable but generally <10 percent. Dose is 625 mg 8 hourly or 1.2gm twice a day.
  • Pipamidic acid (Urixin).  400mg twicce a day for 5 days. Tell the patient to avoid exposure to the sun as it causes photosensitivity.
  • Quinolones. Ciprofloxacin 250 mg twice a day, Levofloxacin 250 mg once a day. Norfloxacin and Moxafloxacin may be used in women.Fluoroquinolone resistance rates have been <10 percent in most parts of North America and Europe, but there has been a clear trend of increasing resistance over time. In a study of E. coli urinary isolates from outpatients in the United States, resistance rates to ciprofloxacin increased from 3 to 17 percent between 2000 and 2010

Resistance trends in E. coli — Expected susceptibility patterns of E. coli should inform the empiric antimicrobial selection for cystitis. Increasing rates of resistance have been reported globally. Risk factors for urinary tract infection (UTI) with resistant organisms include recent broad-spectrum antimicrobial use, health care exposures, and travel to parts of the world where multidrug-resistant organisms are prevalent. In general, resistance rates >20 percent have been reported in all regions for ampicillin and in many regions for trimethoprim (with or without sulfamethoxazole).

Nevertheless, resistant infections are increasing in number, including those caused by extended-spectrum beta-lactamase (ESBL)-producing strains. An increase in ESBL-producing isolates has been described among patients with acute simple cystitis worldwide. In particular, a specific strain of E. coli, sequence type 131 (ST131), has emerged globally as a major cause of fluoroquinolone-resistant and ESBL-producing E. coli UTIs

Acute cystitis in women, non-pregnant and pregnant.

In women, the pathogenesis of UTIs begins with colonization of the vaginal introitus by uropathogens from the fecal flora, followed by ascension via the urethra into the bladder and, in the case of pyelonephritis, to the kidneys via the ureters. In pregnancy the weight and the increasing size of the uterus makes the entry of the bacteria into the ureter and kidney.

The clinical symptoms and evidence of complicated UTI have already been given  and are now repeated.   The classic clinical manifestations of cystitis consist of dysuria, urinary frequency, urinary urgency, and suprapubic pain. Hematuria is also often observed. Symptoms of cystitis can occasionally be subtle and more difficult to tease out, particularly in older women. Older women can have a number of nonspecific urinary symptoms (such as chronic dysuria or urinary incontinence) that mimic symptoms of cystitis, even when there is no evidence of urinary tract infection (UTI). Fever, chills, rigors, and other signs of systemic illness are not compatible with a diagnosis of acute simple cystitis.

Further tests may not be required if the patient has typical symptoms. a physical examination is required to ensure there is no tenderness in renal angle. A pregnancy test may be required if you need to use drugs that are not safe in pregnancy.

  • Urine analysis. Pus cells and RBCs may be seen. Casts if are seen it indicates upper UTI involvment.
  • Dipsticks are commercially available strips that detect the presence of leukocyte esterase (an enzyme released by leukocytes, reflecting pyuria) and nitrite (reflecting the presence of Enterobacteriaceae, which convert urinary nitrate to nitrite). The dipstick test is most accurate for predicting UTI when positive for either leukocyte esterase or nitrite, with a sensitivity of 75 percent and a specificity of 82 percent.
  • However, results of the dipstick test provide little useful information when the clinical history is strongly suggestive of UTI, since even negative results for both tests do not reliably rule out infection in such cases.

The differential diagnosis in of cystitis in a woman is as follows:

  • Vaginitis – In women with dysuria, the presence of vaginal discharge or odor, pruritus, dyspareunia, and absence of urinary frequency or urgency should prompt consideration of vaginitis. Causes of vaginitis include yeast infection, trichomoniasis, and bacterial vaginosis.
  • Urethritis – Evaluation for urethritis is warranted in sexually active women with dysuria, particularly those with pyuria on urinalysis but no bacteriuria. Causes of urethritis in women include chlamydia, gonorrhea, trichomoniasis, Candida species, herpes simplex virus, and noninfectious irritants, such as a contraceptive gel.
  • Painful bladder syndrome – This is a diagnosis of exclusion in women who have ongoing discomfort related to the bladder with symptoms of dysuria, frequency, and/or urgency but no evidence of infection or other identifiable cause.
  • Pelvic inflammatory disease – Lower abdominal or pelvic pain and fever are the most common clinical findings in patients with pelvic inflammatory disease (PID), although dysuria may also be present. The findings of mucopurulent endocervical discharge or cervical motion tenderness on pelvic examination are strongly suggestive of PID.

Consider patients to be higher risk for an MDR gram-negative organism if they have any of the following occurring in the prior three months:

  • An MDR gram-negative urinary isolate (ie, nonsusceptible to at least one agent in three or more antimicrobial classes; this includes extended-spectrum beta-lactamase [ESBL]-producing isolates)
  • Inpatient stay in a health care facility (eg, hospital, nursing home, long-term acute care facility)
  • Use of a fluoroquinolone, trimethoprim-sulfamethoxazole, or broad-spectrum beta-lactam (eg, third or later generation cephalosporin)
  • Travel to parts of the world with high rates of MDR organisms (eg, India, Israel, Spain, Mexico)

Otherwise treat women as outlined in this article at the start of the subject.

Simple cystitis in men.

The symptoms are the same as in women but are likely to be associated with abnormalities of the urinary tract, prostatitis and sexually transmitted diseases. be quick to do a urine culture and ultra sound of the urinary tract.

Urine culture — A midstream urine culture is recommended to confirm the diagnosis of UTI in men, using colony count criteria of ≥103 colony-forming units/mL of a predominant species. In women in whom coliform bacteria (eg, Escherichia coli) are isolated, lower colony counts are likely to represent infecting organisms. It is unknown if the same is true for men.

The spectrum of isolates causing simple cystitis in men is not well defined but is likely similar to that in women. E. coli (75 to 95 percent) is the predominant bacteria, with occasional other species of Enterobacteriaceae, such as Klebsiella pneumoniae and Proteus mirabilis

Underlying chronic prostatitis should be considered in men with cystitis, particularly in those men who have recurrent UTIs caused by the same strain of bacteria.

Urethritis must be considered in sexually active men; examination for penile ulcerations and urethral discharge, evaluation of a urethral swab specimen Gram stain, and diagnostic tests for Neisseria gonorrhoeae and Chlamydia trachomatis are warranted. A urethral Gram stain demonstrating leukocytes and predominant gram-negative rods suggests E. coli urethritis, which may precede or accompany urinary tract infection.

UTI after a renal transplant

Urinary tract infection (UTI) is the most common infection after kidney transplantation. UTI is associated with the development of acute T cell-mediated rejection, impaired allograft function, allograft loss, and death. Morbidity and mortality from UTI can be caused by recurrent and/or severe sepsis.

Definitions. 

  • Asymptomatic bacteriuria in the transplant population is defined by the presence of >105bacterial colony forming units per milliliter (CFU/mL) of urine on urine culture with no local or systemic symptoms of UTI.
  • Simple cystitis is the presence of >105 CFU/mL on urine culture with local urinary symptoms, such as dysuria, frequency, or urgency, but no systemic symptoms, such as fever or allograft pain.
  • Complicated UTI is the presence of >105 CFU/mL on urine culture with fever and either one of the following: allograft pain, chills, malaise or bacteremia with the same organism in urine, or biopsy with findings consistent with pyelonephritis.
  • Recurrent UTI is three or more episodes of UTI in one year.

Risk factors for UTIs after a renal transplant are:

Female sex, advanced age, recurrent UTI prior to transplant, vesicoureteral reflux, prolonged urethral catheterization, ureteral stent placement, cadaveric kidney transplant, history of polycystic kidney disease, delayed graft function.

MICROBIOLOGY — UTI after kidney transplantation is usually caused by gram-negative organisms (56 to 90 percent), with Escherichia coli as the dominant causative organism. Other commonly found gram-negative uropathogens include Pseudomonas aeruginosaEnterobacter cloacaeKlebsiella pneumoniae, and Klebsiella oxytoca.

Screening.

It is important to detect potential UTIs as early as possible among transplant recipients, particularly those who are within three months of transplantation. Untreated UTI that occurs within three months posttransplant is associated with an increased risk of allograft rejection.

You are advised to screen for asymptomatic bacteriuria until three months after transplantation. The rationale for screening is that asymptomatic bacteriuria needs to be treated in order to prevent symptomatic UTIs. Symptomatic UTIs have been associated with early graft dysfunction. However, there are no good data that have conclusively shown that either screening or treating asymptomatic UTIs prevents symptomatic UTIs.

In order to screen for asymptomatic bacteriuria, obtain a urine culture with an accompanying urinalysis with microscopy at 2, 4, 8, and 12 weeks posttransplant.

PREVENTION.  

UTIs are associated with significant morbidity among transplant recipients, especially if they occur early after transplantation. To prevent UTIs, administer prophylactic antibiotics. A meta-analysis of six randomized trials in 545 kidney transplant recipients demonstrated that trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis was associated with a reduced risk of sepsis and bloodstream infection (relative risk [RR] 0.13, 95% CI 0.02-0.7) and bacteriuria (RR 0.41, 95% CI 0.31-0.56). Prophylaxis did not reduce graft loss or mortality. For patients allergic to trimethoprim-sulfamethoxazole the use of cephalexin 250mg twice a day is recommended for three months.

Asymptomatic bacteriuria – Asymptomatic bacteriuria is diagnosed by screening urine culture and is defined by the presence of >105 colony forming units (CFU)/mL of bacteria.

UTI – Patients who present with signs or symptoms of UTI should undergo testing with a urine dipstick, urine microscopy, and urine culture. In addition, blood cultures should be obtained in those with symptoms suggestive of a complicated UTI (eg, fever or other systemic symptoms and/or allograft tenderness).

Patients with UTI typically have a urine dipstick that is positive for leukocyte esterase, nitrites, blood, and protein and urine microscopy that shows pyuria (ie, at least 10 white blood cells per high-power field of unspun urine). The diagnosis is established by a positive urine culture with >105 CFU/mL in the presence of associated clinical findings. Among patients with UTI, 9 percent have positive blood cultures. 

Patients who present with signs and symptoms of UTI and have a positive urinalysis but negative urine culture should be tested for C. urealyticum. C. urealyticum is a slow-growing organism with potent urease activity that requires selective media for isolation. This organism requires treatment with vancomycin.

Is imaging required in a renal transplant for further evaluation? Do an ultrasound if:  they are within one month of transplant (ie, the early postoperative period) or have a history of nephrolithiasis or have had two or more prior episodes within the same year. For patients with APKD (polycystic kidneys) an ultrasound may not be enough. Do a CT scan. A cystoscopy may be indicated.

The major differential diagnosis among patients who present with complicated UTI is acute allograft rejection. Fever and allograft tenderness are suggestive of UTI, whereas increased serum creatinine in the presence of new or worsening proteinuria and hypertension suggest acute rejection.If an acute rejection accompanies an acute UTI a renal biopsy is indicated.

Treatment.

  • Asymptomatic bacteriuria. Commonly used regimens for patients with normal renal function are ciprofloxacin 250 mg orally twice daily, amoxicillin 500 mg orally three times daily, and nitrofurantoin 100 mg orally twice daily (provided estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2). The dosing of
  • Simple cystitis.  Commonly prescribed empiric treatment includes ciprofloxacin 250 mg orally twice daily or levofloxacin 500 mg orally once daily, with dose adjustment based on eGFR. If Enterococcus species are suspected on the basis of past causative organisms, amoxicillin 500 mg orally three times daily or nitrofurantoin 100 mg orally twice daily (provided eGFR >60 mL/min/1.73 m2) should be added. Nitrofurantoin is contraindicated in patients with creatinine clearance <60 mL/min. ciprofloxacin and amoxicillin must be adjusted in patients with reduced renal function, and nitrofurantoin is contraindicated in patients with creatinine clearance <60ml/min.

The treatment of cystitis most often requires antibiotics, increased fluid intake and may be a day or two of rest in bed. Treatment regimes have been outlined above in different situations. I hope they will prove useful to my readers.

 

 

 

 

 

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Published by

shaheenmoin

I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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