Urinary Tract Infections in Transplant Recipients
Authors: Francisco López-Medrano and José María Aguado
EPIDEMIOLOGY
Urinary tract infection (UTI) is the most prevalent infection in adults for which antimicrobials are used. UTI is the most common bacterial infection affecting renal transplant recipients and its incidence is much higher than in the general population. In the case of solid organ transplant (SOT) recipients, there is an important difference between renal transplant and the rest of solid organ transplant recipients. In the cohort of patients with bacteremia of the Spanish Network for the Study of Infections in Transplantation (RESITRA), UTI was the origin of bacteremia in 39% of renal transplant recipients as opposed to 3% in liver, 3% in cardiac and 0% in lung transplant recipients. In 2,405 SOT recipients followed up for 3 years in the RESITRA cohort, the incidence of cystitis per 100 subjects and year was as follows: 2.41 for cardiac, 3.09 for liver, 1.36 for lung and 13.84 for renal transplant recipients. The incidence of pyelonephritis per 100 subjects and year was 0.3 for cardiac, 0.8 for liver, 0.6 for lung and 3.66 for renal transplant recipients.
Some risk factors have been described for UTI in renal transplant recipients and are outlined in Table 1. As in the general population, UTI is more frequent in female than in male patients. Most of the infections (> 75%) occur in the first year after renal transplantation, especially in the first 3 months. The earliest possible removal of the bladder catheter has been advocated as an important measure for curtailing UTI rates. UTI in particular pyelonephritis has been proposed to adversely impact long-term graft function in renal transplantation, but most authors conclude that mortality is not affected.
Etiologic Agents
Gram negative bacteria account for >70% of UTI and, as in the general population, Escherichia coli is the most common clinical isolate in solid organ transplant recipients. The incidence of Pseudomonas aeruginosa infection tends to be higher than in the general population, especially in the case of pyelonephritis. Some reports have documented an increase in the prevalence of Pseudomonas aeruginosa, coagulase-negative Staphylococci and Enterobacter cloacae in the first 3-5 weeks after renal transplantation, followed by a preponderance of infections by Escherichia coli and Enterococcus spp. from weeks 6 to 12. Frequency of bacteria causing lower and upper UTI in renal transplant recipients is outlined in Table 2.
CLINICAL MANIFESTATIONS
UTI can be due to lower (cystitis) and upper (pyelonephritis) urinary tract infections. Cystitis is characterized a combination of any of the following symptoms: frequency, urgency, dysuria (pain with micturition), hematuria and suprapubic pain. Concurrent prostate disease must be ruled out in males with lower UTI symptoms; perineal or low back pain may, on occasion, be the only manifestations. The development of fever should be considered as a sign that probably indicates upper UTI. Fever may be the most reliable clinical sign in differentiating between upper and lower UTI. Pyelonephritis of the native kidney may manifest as rigors and pyrexia, hematuria and flank pain over the affected kidney that might irradiate to the genital area. Symptoms of cystitis may also be present, but their absence does not rule out pyelonephritis. Pyelonephritis may also manifest initially as symptoms attributable to the gastrointestinal tract such as nausea, vomiting and diarrhea or constipation.
Renal transplant recipients may also develop pyelonephritis of the kidney graft. This entity warrants prompt recognition as the outcome of both the infection and the allograft depends upon early employment of appropriate therapy. As the allograft is usually placed in the right or left iliac fossa, renal graft pyelonephritis must be considered if lower right or left abdominal quadrant pain plus fever develops in the recipient and should be differentiated from appendicitis, diverticulitis and other abdominal conditions. In female patients, ectopic pregnancy, pelvic inflammatory disease and ovarian cyst torsion should also be considered. Additionally, graft rejection can produce fever and pain over the transplanted kidney. An abscess or other space-occupying lesion should be considered in the patient with UTI when fever persists beyond 48 to 72 hours despite appropriate antimicrobial therapy.
APPROACH TO DIAGNOSIS
Laboratory diagnosis of the solid organ transplant recipient with suspected UTI should begin with microscopic examination of urine sediment. Pyuria is considered an indicator of UTI and its absence should suggest an alternative diagnosis. A white blood cell count of 10 cells/mm3 of unspun urine by a chamber method is usually considered the best cutoff. The leukocyte esterase dipstick has sensitivity that ranges from 75-95%. The absence of pyuria in a symptomatic patient suggests that urethritis or vaginitis should be considered as alternatives diagnoses to cystitis. Gram stain of freshly-voided unspun urine is another useful technique for the diagnosis of UTI. The finding of one bacterium or more in each oil-immersion field suggests the presence of at least 105 colony-forming units (CFU)/mL. If the Gram stain shows Gram-positive cocci, empirical therapy should be directed against enterococci. If it shows Gram-negative bacilli, empirical therapy aimed at enterococci is not necessary.
Urine culture is mandatory in any suspected UTI of solid organ transplant recipients. A careful clean-catch urine specimen must be collected for culture. In acutely dysuric women with confirmed pyuria, the threshold for significant bacteriuria should be 102 CFU/mL or more of a single or predominant pathogen. In dysuric men a growth of 103 CFU/mL or more is considered significant. For asymptomatic bacteriuria, the isolation of 105 CFU/mL in a single specimen for men and in two consecutive specimens for women is necessary for diagnosis. For suprapubic aspiration specimens and samples collected during nephrostomy tube insertion, colony counts are considered to be significant if greater than 102 CFU/mL. Up to 30-40% of the patients with pyelonephritis may have bacteremia and therefore blood cultures must be collected in febrile solid organ transplant recipients with suspected UTI.
The goal of performing imaging studies is to rule out correctable anatomical abnormalities, mainly obstruction that may predispose to recurrence. They are indicated when nephrolithiasis is suspected or proven and to evaluate persistent hematuria. Some authors recommend imaging studies for every solid organ transplant recipient developing pyelonephritis, especially for renal transplant recipients and for those with recurrent infections. While renal ultrasound is a noninvasive means for assessing obstructive uropathy, computerized tomography (CT) is more sensitive for the detection of nephrolithiasis as well as for renal and perirenal abscesses.
APPROACH TO THERAPY
Antibiotic treatment is different for those solid organ transplant recipients who develop cystitis as opposed to pyelonephritis. Cystitis can be treated with oral antibiotic on most occasions. Empiric antibiotic treatment should be initiated pending results of urine culture. Options for oral therapy in this clinical situation are listed in Table 3. Local pattern of resistance of the most frequent urinary pathogens must be taken into consideration when choosing empiric treatment. Cotrimoxazole is not an adequate empirical treatment for those solid organ transplant recipients receiving prophylaxis with this antibiotic. A β-lactam antibiotic should not be used for those patients reporting a previous allergic reaction to this group of antibiotics. Drugs frequently used for cystitis are quinolones, oral cephalosporins and fosfomycin that do not interact with immunosuppressive drugs. Short-course or single-course regimens are not recommended for solid organ transplant recipients. Most experts recommend therapy for10-14 days. Eradication of the organism should be confirmed by a follow-up culture of an after-treatment urine sample.
Pyelonephritis unless another source of fever is readily apparent, in febrile renal transplant patient with abrupt deterioration of renal function, consideration should be given to treatment with empirical parenteral antibiotic therapy aimed at Gram negative bacilli, including Pseudomonas aeruginosa, and enterococci after blood and urine samples have been collected. Hospitalization may be considered in solid organ transplant recipient with pyelonephritis. Previous microbiological results of UTI should be taken into consideration. Active antibiotics against Pseudomonas aeruginosa include piperacillin-tazobactam, ticarcillin-clavulanate, ceftazidime, cefepime, imipenem, meropenem and doripenem. Carbapenems should be used if extended-spectrum beta-lactamase enterobacteriaceae (Escherichia coli or Klebsiella pneumoniae) infection is a consideration. Addition of an aminoglycoside may be considered in patients with multiresistant Gram negative bacteria.
Alternative antibiotics for those patients reporting an allergic phenomenon to β-lactams are fluoroquinolones and aztreonam for Gram negative bacteria, and vancomycin for enterococci. For those patients in whom vancomycin-resistant enterococci is a concern, linezolid, daptomycin and quinupristin/dalfopristin can be an alternative.
Surviving Sepsis Campaign recommendations should be applied to patients with pyelonephritis developing severe sepsis or septic shock. This implies early initiation of broad-spectrum antibiotics, aggressive fluid replacement in the first hours after shock, early resolution of obstruction of the urinary tract and drainage of purulent collections.
Solid organ transplant recipients with pyelonephritis should receive therapy for 14 days. Step-down from intravenous to oral therapy is appropriate when the infection is microbiologically controlled, the patient has clinically improved and is afebrile for at least 48 hours. Longer treatments may be necessary for those with renal or perirenal abscesses.
Recurrent UTI
Repeated episodes of UTI can be either reinfection by a new microorganism (either a new bacterial species or a new serologic type of E coli) or relapse (a recrudescence by the same organism of a prior partially treated infection). The distinction is relevant as the clinical approach is different for the two situations. Relapse tends to occur within two weeks of completion of therapy of a previous UTI while reinfection is likely occur more than two weeks after completion of therapy for the initial episode. Options for prophylaxis in solid organ transplant recipients with reinfections are discussed below. Relapse is likely to occur if there is persistent infection in the renal parenchyma or prostate gland, if the proper antibiotic was not used or if there a renal pathological process (most frequently renal calculi) is present. If previous antibiotic treatment was adequate according to susceptibility data, urological evaluation is mandatory in patients with relapsing infection. When non-correctable urological defects are found and the patient has failed to respond to after therapy for 10-14 days, the presence of a deep-seated tissue infection must be presumed. In this context, prolonged therapy (4-8 weeks) may eradicate the infection. If this strategy also fails, chronic suppressive antibiotic therapy may be considered. In vitro susceptibility pattern should be used for choosing the appropriate antibiotic. The major use of this approach is for patients with urological abnormalities that cannot be surgically corrected.
Less Frequent Agents of UTI in Solid Organ Transplant Recipients
A high degree of clinical suspicion must be kept for the diagnosis of urinary tract tuberculosis in solid organ transplant recipients. Presence of lower or upper urinary tract infection with pyuria and hematuria in the absence of isolation of bacteria in routine cultures (or sterile pyuria) should prompt urine cultures in specific selective media for the isolation of Mycobacterium tuberculosis. A negative tuberculin skin test nor the absence of thorax radiographic abnormalities suggestive of pulmonary tuberculosis exclude tuberculosis in this context. Presence of granulomatous infiltrates in bladder or kidney biopsy are helpful clues for the diagnosis of this infection. Urine smears for acid-fast bacilli may have false-positive results due to the presence of saprophytic mycobacteria in the urine of healthy individuals. Three first-morning clean-catch specimens of urine should be sent for mycobacteria culture (this type of sample is preferred over 24-hour collections). Polymerase chain reaction (PCR) is a sensitive and specific test that could be useful in this circumstance. Treatment of urinary tract tuberculosis does not differ from other forms of tuberculosis (see specific chapter). Some authors recommend extending antituberculous treatment to 9 months in this form of tuberculosis. Currently, surgery is reserved for complications such as hemorrhage, pain, inability to sterilize the urine or ureteral stricture.
This bacterium is a Gram-positive bacillus that, due to its strong urease activity, is able to synthesize struvite stones (ammonium magnesium phosphate) and develop incrusting cystitis and pyelitis. This bacterial infection is frequently overlooked because its isolation in urine culture requires incubation for more than 48-72 hours in a standard media or incubation in special media for the isolation of the bacteria. This infection should be suspected in renal transplant recipients with symptoms consistent with urinary infections for more than 1 month, presence of struvite stones or incrusted cystitis and/or pyelitis, alkaline urine (pH > 7) and pyuria in urine sediment with negative conventional urine culture (it should be considered in the differential diagnosis of “sterile” pyuria). Nephrostomy has been identified as a risk factor for this type of infection. One of the keys for the treatment of this infection is to remove any catheter in the urinary tract (mainly nephrostomy tube or ureteral catheter). This bacterium can be considered a multi-resistant microorganism. Clinically significant infections have been treated with vancomycin or teicoplanin. Sensitivity to linezolid has been demonstrated in vitro, but no clinical experience exists with its use.
The presence of Candida spp. in urine is most often due to colonization of the urinary tract. Urinary colonization is asymptomatic and usually associated with an indwelling urinary catheter. Asymptomatic candiduria can be controlled in many cases with catheter removal, without specific antifungal therapy. Persistent asymptomatic candiduria and symptomatic infection, with or without candidemia should be treated in renal transplant recipients. Recommended treatment depends on the antifungal susceptibility of the species of Candida isolated in the urine and does not differ from that in non-transplant setting. Persistence of candiduria in an immunocompromised host despite antifungal treatment should prompt abdominal CT or ultrasound to rule out an abscess or a renal pelvis fungus ball.
This trematode is endemic in most parts of Africa and some parts of the Middle-East. It mainly involves the urinary tract and the kidney and the diagnosis is based on the visualization of parasite ova in urine specimens. The urine should be collected close to noon, when egg excretion is maximal. Reactivation of a prior infection due to immunosuppression has been described in solid organ transplant recipients. Infection should be sought in the pretransplant work-up of candidates for transplantation originals from areas of endemicity, especially if peripheral blood eosinophilia is detected. This infection is not considered a contraindication for transplantation. Any solid organ transplant recipient from an at risk-area developing hematuria (with or without eosinophilia) should have urine examined to rule out the infection. S haematobium should be treated with praziquantel both in the pre and postransplant period, as chronic infection can lead to squamous carcinoma of the bladder.
Refer to the BK Virus chapter
PROPHYLAXIS
Unless considered to be harboring a persistent nidus of infection, the removal of native kidneys is not usually necessary. Even in patients with polycystic kidney disease, a conservative approach with regards to pretransplant nephrectomy is recommended.
Antibiotic prophylaxis of UTI has been advocated for renal transplant recipients. Percentage of resistance of bacteria to trimethoprim-sulfamethoxazole has been described as high as 84% for E coli, 67% for Enterobacter cloacae, 86% for coagulase-negative Staphylococci and 46% for Enterococcus species. Nevertheless, recent guidelines by KDIGO (Kidney Disease: Improving global outcomes) recommend the use of this antibiotic as prophylaxis for UTI and Pneumocystis jiroveci pneumonia during, at least, the first 6 months after renal transplantation.
There are controversies about the necessity of monitoring and treatment of asymptomatic bacteriuria in renal transplant recipients. Some authors have reported the association between repeated episodes of asymptomatic bacteriuria and the development of pyelonephritis, but without impairment of long-term renal-graft function when appropriately treated. Guidelines by KDIGO published in 2009 do not make any specific recommendations for the monitoring or treatment of asymptomatic bacteriuria. Some authors have recommended its treatment for the first three months after renal transplantation.
As in the general population, any solid organ transplant recipients with recurrent UTI due to reinfection should undergo urologic evaluation for prostate hyperplasia, urinary stones or other causes of urinary tract obstruction. Complete bladder emptying is one of the most important defense mechanisms against UTI. For renal transplant recipients without anatomical abnormality who suffer more than three recurrences per year, a prolonged antibiotic prophylaxis can be considered. Antibiotics that have proved to be useful in this setting are bactrim (trimetoprim 80 mg plus sulfamethoxazole 400 mg) or a quinolone (200-250 mg) every other day. The sensitivity of the last bacterium isolated from urine culture should be taken into consideration for the choice of the antibiotic for prophylaxis. Cephalexin, fosfomycin or nitrofurantoin could be alternative options. Evidence based data for the practice of administering a single-dose of antibiotic just before removal of a urethral catheter is lacking, including in solid organ transplant recipients.
Pancreas transplant recipients with bladder drainage of the exocrine secretions have a higher risk of UTI than those with enteric drainage (48% vs. 0% in a recent series; p < 0.001). In the case of relapsing or chronic UTI, conversion from bladder drainage to enteric drainage has been practiced with good results.
REFERENCES
1. Chung BH, Chang SY, Kim SI, Choi HS. Successfully treated renal fungal ball with continuous irrigation of fluconazole. J Urol 2001; 166: 1835-6. [PubMed]
2. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL. Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 2008; 36: 296-327. [PubMed]
3. de Souza RM, Olsburgh J. Urinary tract infection in the renal transplant patient. Nat Clin Pract Nephrol 2008; 4: 252-64. [PubMed]
4. Fiorante S, López-Medrano F, Lizasoain M, Lalueza A, San Juan R, Andrés A, Otero JR, Morales JM, Aguado JM. Systematic screening and treatment of asymptomatic bacteriuria in renal transplant recipients. Relationship with graft outcome. 2010 (in press). [PubMed]
5. Jiménez-Romero C, Manrique A, Morales JM, López RM, Morales E, Cambra F, Calvo J, García-Sesma A, Praga M, Moreno E. Conversion from bladder to enteric drainage for complications after pancreas transplantation. Transplant Proc 2009; 41: 2469-71. [PubMed]
6. Jiménez-Romero C, Manrique A, Meneu JC, Cambra F, Andrés A, Morales JM, González E, Hernández E, Morales E, Praga M, Gutierrez E, Moreno E. Compative study of bladder versus enteric drainage in pancreas transplantation. Transplant Proc 2009; 41: 2466-8. [PubMed]
7. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. American Journal of Transplantation 2009; 9(Suppl 3): S1–S157. [PubMed]
8. López-Medrano F, García-Bravo M, Morales JM, Andrés A, San Juan R, Lizasoain M, Aguado JM. Urinary tract infection due to Corynebacterium urealyticum in kidney transplant recipients: an underdiagnosed etiology for obstructive uropathy and graft dysfunction-results of a prospective cohort study. Clin Infect Dis 2008; 46: 825-30. [PubMed]
9. Muñoz P. Management of urinary tract infections and lymphocele in renal transplant recipients. Clin Infect Dis 2001; 33 Suppl 1: S53-7. [PubMed]
10. Pellé G, Vimont S, Levy PP, Hertig A, Ouali N, Chassin C, Arlet G, Rondeau E, Vandewalle A. Acute pyelonephritis represents a risk factor impairing long-term kidney graft function. Am J Transplant 2007; 7: 899-907. [PubMed]
11. Säemann M, Hörl WH. Urinary tract infection in renal transplant recipients. Eur J Clin Invest 2008; 38 Suppl 2: 58-65. [PubMed]
12. Ward TT, Jones SR. Genitourinary tract infections. In: Betts RF, Champman SW, Penn RL, eds. Reese abd Betts´ A practical approach to infectious diseases, 5th ed. Philadelphia: Lippincott Williams&Wilkins, 2003: 493-540. [PubMed]
Table 1: Risk Factors for UTI in Renal Transplant Recipients
|
Table 2 : Causal Pathogens and the Frequency of Bacteria in Lower and Upper UTI in Renal Transplant Recipients
| Etiology of cystitis | Prevalence | Etiology of pyelonephritis | Prevalence |
|---|---|---|---|
| Escherichia coli | 57% | Escherichia coli | 52% |
| Enterococcus faecalis | 13% | Pseudomonas aeruginosa | 12% |
| Klebsiella pneumoniae | 10% | Klebsiella pneumoniae | 8% |
| Streptococcus agalactiae | 6% | Morganella morgagni | 8% |
| Proteus mirabilis | 4% | Enterococcus faecalis | 8% |
| Klebsiella oxytoca | 2% | Coagulase negative Staphylococcus | 4% |
| Morganella morgagni | 2% | Enterococcus faecium | 4% |
| Pseudomonas aeruginosa | 2% | Others | 4% |
| Coagulase negative Staphylococcus | 1% | ||
| Enterococcus faecium | 1% | ||
| Others | 2% |
Table 3: Empirical Oral Antibiotic Treatment for SOT Recipients with Lower UTI Infection (Cystitis)a,b,c
| Antibiotic | Dose (mg) | Interval |
|---|---|---|
| Trimethoprim-sulfamethoxazoled,e | 160/800 | q12h |
| Norfloxacinf | 400 | q12h |
| Ciprofloxacinf | 500 | q12h |
| Levofloxacinf | 500 | q24h |
| Cefixime | 400 | q24h |
| Nitrofurantoin | 100 | q6h |
| Amoxicillin plus clavulanate | 500 | q12h |
aDose modification is necessary in renal failure
bRegimens of 10-14 days are preferred for SOT recipients
c Previous microbiological results of the patients should be considered. Susceptibility of the pathogen to selected antibiotic must be confirmed with in vitro susceptibility testing of the urine sample
dNot appropriate as empirical treatment for SOT under prophylaxis with this antibiotic
eEmpirical use limited to those geographical areas where frequency of resistance is less than 20%
fFluorquinolones should be avoided in pregnancy, nursing mothers and adolescents younger than 17 years-old
Hsueh PR. et al. Consensus review of the epidemiology and appropriate antimicrobial therapy of complicated urinary tract infections in Asia-Pacific region. J Infect. 2011 Aug;63(2):114-23.
Gupta K, Hooton TM, Naber KG, Wult B, Colgan R International Clinical Practice Guidelines for the Treatment of Acute Uncomplicated Cystitis and Pyelonephritis in Women: A 2010 Update by the Infectious Diseases Society of American and the European Society for Microbiology and Infectious Diseases
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Wagenlehner FME and Naber KG. Urinary Tract Infections