Infection post transplantation- CPG

43. MANAGEMENT OF INFECTION POST KIDNEY TRANSPLANTATION

Infections related to transplantation procedure and opportunistic pathogens can adversely affect the outcome of kidney transplantation.

43.1 General guidelines for infection recognition1
The following factors may assist in the identification of the causative pathogen and initiation of therapy (Table 43.1)

43.1.1 The temporal occurrence of presumed infectious episode relative to the date of transplantation (see Figure 43.1)

43.1.2 Pretransplantation donor screening

43.1.3 Pretransplantation recipient screening

43.1.4 Acquisition of community and hospital acquired pathogens
e.g. pneumococcus, pseudomonas species, MRSA, VRE

43.1.5 Net state of immunosuppression
a. Prophylactic immunosuppressive protocol employed and treat-ment for acute rejections
b. Neutropaenia
c. Open wounds, foreign bodies (catheters, stents), fluid collections
and devitalised tissues
d. Metabolic abnormalities (malnutrition, hyperglycaemia, ureamia)
e. Infection with immunomodulatory viruses (CMV, EBV)

Table 43.1: Risk factors for infection post kidney transplantation1
Pretransplantation (Recipient) Perioperative Post-transplantation

Medical Condition
a. Immunosuppression for chronic conditions eg steroid, cytotoxics
b. Diabetes mellitus
c. Suboptimal nutritional status
d. Unrecognised or
inadequately treated
infection
Surgery
a. Prolonged procedure or anaesthesia
b. Graft injury or prolonged ischaemia
c. Bleeding or multiple blood transfusions
Post-op management
a. Catheters, stents, and intubation
b. Anastomotic breakdown or leak
c. Fluid collections or devitalized tissue
d. Early re-exploration or retransplantation
e. Leukopaenia
Pretransplantation (Recipient) Perioperative Post-transplantation
Altered bacterial colonisation
a. Pre-op antibiotic exposures
b. Duration of hospitalisation Graft ( donor)
a. Bacteraemia or sepsis
b. Unrecognised infection in allograft
c. Microbial contamination of preservation fluid
Nosocomial infection
a. Prolonged antibiotic therapy
b. Increased antibiotic resistance

Immunosuppression
a. Multiple agents
b. Antibody induction and treatment for acute rejection.
c. Steroid – pulse and maintenance dose


43.2 Diagnosis of infection
Diagnosis of infections post kidney transplantation can be difficult due to attenuation of the usual clinical signs and symptoms of infection by alterations in the immune response. Fever may be absent in the presence of infection due to immunosuppression.
In transplant recipients, fever also has a more expanded differential diagnosis which in addition to infections, may include:
43.2.1 Graft rejection

43.2.2 Adverse effect of medication
Treatment with antibodies (OKT3 and polyclonal antibodies) for acute rejection may cause fever and signs and symptoms suggestive of aseptic meningitis and pulmonary infiltrates.

43.2.3 Systemic inflammatory response
The presence of more than one causative agent must be considered e.g. CMV disease facilitating other opportunistic infections.


43.3 Diagnosis of pneumonia
Includes radiological examinations, culture of blood, sputum, tracheal aspirate, bronchoalveolar lavage (BAL), transthoracic fine needle aspirate, pleural fluid, and transbronchial lung biopsy.
Specific pathogens should be sought in addition to common bacteria,

43.4 Diagnosis of pneumonia
Includes radiological examinations, culture of blood, sputum, tracheal aspirate, bronchoalveolar lavage (BAL), transthoracic fine needle aspirate, pleural fluid, and transbronchial lung biopsy.
Specific pathogens should be sought in addition to common bacteria, such as:

43.4.1 Legionella pneumophila – direct fluorescent antibodies of antigens in respiratory specimens.

43.4.2 Pneumocystis carinii – fluorescein labeled antibody of BAL or sputum.

43.4.3 Nocardia – modified acid-fast staining.

43.4.4 Cytomegalovirus (CMV) – antigen detection using DEAFF from respiratory fluid and blood.

43.4.5 Mycobacterium tuberculosis
43.4.6 Fungi

43.5 Diagnosis of urinary tract infection
Clean catch mid-stream urine specimen for culture. If suspected, tips of ureteric stents should be cultured.

43.6 Diagnosis of wound and other infections
Wound infections, skin nodules or necrotic tissues should be swabbed and biopsied when appropriate. Aspiration and drainage of any collections, either percutaneously with ultrasound guidance or surgically should be performed.
Intravascular access and catheter tips should be cultured. Patients with diarrhoea should have stool examination done including detection for clostridium difficile.

43.7 Treatment of infection
In severe infection, immunosuppressive therapy may need to be reduced or stopped. A number of antibiotics interact with cyclosporin metabolism and the level has to be monitored and adjusted accordingly. Antibiotic dosage also needs to be adjusted for renal impairment.
The implementation of anti-microbial therapy can be considered under the categories of prophylaxis therapy, empirical therapy and definitive therapy.
43.7.1 Prophylaxis therapy
Peri-operative antibiotics prophylaxis may reduce the incidence of wound infection. However, prolonged course of antibiotics may promote emergence of resistance organisms and increase the risk for Clostridium difficile colitis. The choice of broad spectrum antibiotics should have good Gram negative coverage according to local bacteriological and susceptibility pattern. The duration of treatment should be minimised.

43.7.2 Empirical therapy
For patients with suspected bacterial infections, empirical therapy may be started while waiting for results of bacteriological studies. The choice of therapy should be guided by the available clinical information such as:
a. Suspected anatomical site of infection
b. Probable organism
c. Local antibiotic susceptibility pattern
d. Previous anti-microbial therapy
e. Time since transplantation (see fig 42.1)
f. Net state of immunosuppression
Initial empirical treatment for suspected severe bacterial infection should be broad spectrum, and effective against Gram positive and Gram negative bacteria. The duration of therapy is based on the resolution of clinical signs and symptoms of bacterial infections, usually of 10 to 14 days duration.
If a specific pathogen is isolated, and sensitivities are available, treatment is changed to appropriate narrow spectrum agent (see specific therapy). If patient deteriorates or did not improve, aggressive search for source of infection should be performed, including search for MRSA, ESBL producers, mycobacterium and fungal infections. At the same time consider changing antibiotics (e.g. Imipenem).

Table 43.2: Pathogens and recommended antibiotics.
Pathogens (suspected/proven) Antibiotics
Gram negative

Gram positive: Aerobic:
Staph aureus (MSSA)
Staph aureus (MRSA)
Staph epidermidis (MRSE)
Streptococcal
Listeria

Anaerobic:
Clostridium perfringens
Clostridium difficile


Legionella

Pneumocystis


Norcadia
3rd generation cephalosporins


Cloxacillin
Vancomycin
Vancomycin
Penicillin + Gentamicin
Ampicillin + Gentamicin


Penicillin
Oral Vancomycin or Metronidazole

Erythromycin* + Rifampicin*

Cotrimoxazole + Pentamidine
Dapsone+Trimethoprim

Cotrimoxazole , Minocycline, Amikacin, Ceftriazone, Imipenem
* cyclosporin dosage needs to be adjusted

43.7.3 Specific therapy
Therapy is focused on the specific organism isolated to avoid superinfection.

43.8 Mycobacterial infection3
Can occur as early as one month post-transplantation. Unusual presentation of mycobacterium tuberculosis and non tuberculous mycobacterial disease may delay diagnosis.
Patients with previous mycobacterial infection are at risk of reactivation. Patients may have disseminated disease, and may involve skin, joints and bones, and central nervous system.

Rifampicin (R)
Isoniazid (H)
Pyrazinamide (Z) daily for 2 months
Vitamin B6
*

Then if susceptible,
Rifampicin
Isoniazid daily# for 4 to 10 months

*In certain situations, ethambutol (E) or ciprofloxacin may be added.
#Daily dosing to avoid fluctuating cyclosporin level.

If intolerant of rifampicin, combination of daily isoniazid, pyrazinamide and ethambutol is given for 18 to 24 months, or 12 months after cultures are negative, whichever is longer.
If intolerant to isoniazid, combination of ERZ daily for 2 months then ER for 12 to 16 months, or 12 months after cultures are negative, whichever is longer.
Caution: With the use of rifampicin, the dose of cyclosporin should be doubled and the cyclosporin dose should be adjusted with close monitoring of cyclosporin level. The dose of cyclosporin may need to increase by 3 to 5 folds with the use of rifampicin.
Chemoprophylaxis for mycobacterial is currently not given routinely.

43.9 Pneumocystis carinii infection
Occurs from 1 month post-transplantation onward.

Presents with fever, non-productive cough, breathlessness, hypoxia and diffuse interstitial infiltration or focal consolidation on chest radiography. Bronchial alveolar lavage and transbronchial biopsy are good diagnostic methods.
43.9.1 Treatment
Treatment is intravenous cotrimoxazole (20 mg/kg/day trimethoprim and 100 mg/kg/day sulphamethoxazole) given 6 hourly for at least 2 weeks. If there is no improvement after 4 to 5 days, add in pentamidine infusion at 4 mg/kg/day.
Alternatively Dapsone (100 mg/day) and Trimethoprim (15 mg/kg/day) may be used but caution on the use of dapsone and cotrimoxazole combination which may cause haemolysis in G6PD deficiency.
Chemoprophylaxis with oral co trimoxazole 80/400 daily or inhaled pentamidine 300 mg/month may be required for at least 3 months post treatment.

43.9.2 Chemoprophylaxis
Chemoprophylaxis for pneumocystis carinii pneumonia with co trimoxazole 80/400 daily is recommended for the first 6 months after renal transplantation and during treatment for acute rejection.4 (Level A) However the duration of chemoprophylaxis is unclear.5 (Level B)

43.10 Fungal infection
43.10.1 Candidiasis
Oral nystatin may be helpful as prophylaxis during period of intensified immunosuppression (first 3 months after transplant).
Culture of candida from the mouth, urinary catheter and vaginal swab may be sufficient to justify local or topical treatment. Evidence of candida in the blood or disseminated infection of the lungs or other organs must be treated with intravenous amphotericin B or fluconazole.

43.10.2 Aspergillosis
Usually presents with pneumonia but may disseminate to gastrointestinal, skin and central nervous system. Treatment is with intravenous amphotericin B. Itraconazole is an alternative.

43.10.3 Cryptococcosis
May cause meningitis, pulmonary, dermatological, and other organ specific disease. Treatment of meningitis is with intravenous amphotericin B followed by fluconazole. Less severe disease can be treated with fluconazole alone

43.10.4 Histoplasmosis
Usually causes acute pulmonary syndrome. Treatment is with intravenous amphotericin B or itraconazole.

43.11 Hepatitis B virus (HBV) infection
The outcome of HBV hepatitis is unfavourable in renal transplant recipients as it may lead to progressive liver damage. This can be prevented by careful pre-transplant donor and recipient screening, and by vaccination of the recipient.6
The routine use of OKT3 and polyclonal antibodies for induction should be avoided in transplant recipients who are positive for hepatitis B surface antigen (HBsAg). Such patients should be monitored for raised liver enzymes and viral replication by HBV-DNA PCR.7 (Level D)
Azathioprine is omitted from HBV carriers undergoing kidney transplantation. (Level D) In HBV seroconverted recipients, azathioprine withdrawal had been shown to reduce the incidence of progression of viral hepatitis to cirrhosis in a small study.8 (Level D)
Treatment of active HBV hepatitis is limited. The biggest concern regarding the use of interferon-alpha is precipitation of acute rejection. Two small studies demonstrated clearance of HBV DNA in renal transplant recipients by Lamivudine 100mg daily. However, viral replication recurred when therapy was discontinued and one patient developed lamivudine resistant viral mutant.9,10 (Level D) Early referral to hepatologist is desirable.

43.12 Hepatitis C infection
HCV hepatitis may develop progressive liver disease in the long term but at a slower rate than HBV hepatitis.
In HCV positive recipients, the use of OKT3 and polyclonal antibodies should be avoided. Early reduction of immuno-suppression may be useful in preventing severe liver disease.

Azathioprine is omitted from HCV carriers undergoing kidney transplantation. (Level D) Azathioprine should be stopped in HCV seroconverted recipients and in those with hepatitis.8 (Level D)
Currently there is no effective treatment for HCV hepatitis. Interferon-alpha may precipitate acute rejection.

43.13 Cytomegalovirus (CMV) infection and disease
CMV infection occurs primarily after the first month of transplant-ation and the risk is dependent on the serological status of the donor and recipient.
CMV infection is the presence of CMV viraemia with mild fever without evidence of tissue invasion. It may be asymptomatic.
CMV disease refers to symptomatic or tissue-invasive acute CMV infection eg pneumonitis, hepatitis, haematological, nervous system and gastrointestinal involvement.
The risk of CMV infection is greatest in donor-positive, recipient-negative (D+R-) kidney transplant patients, particularly after the use of anti-lymphocyte antibodies.
CMV is associated with immunomodulatory derangements that can lead indirectly to opportunistic superinfections, allograft rejection, and development of post transplant lymphoproliferative disease.
43.13.1 Diagnosis
a. Direct early antigen fluorescent foci (monoclonal antibody against pp65, DEAFF), in urine, blood, throat washing
b. CMV DNA PCR
c. Upper and lower GI endoscopy and biopsy
d. Bronchio-alveolar lavage
e. Serology (IgM and IgG) is less helpful

43.13.2 Treatment of CMV disease11 (Level C)
a. Intravenous ganciclovir for at least 2 to 4 weeks, dosage according to renal function

Table 43.3: Dosing of ganciclovir
Serum Creatinine (umol/l) <130>400 On dialysis
GFR (ml/min) 70 50-69 25-49 10-24 <10
Dose (mg/kg/dose) 5 bd 2.5 bd 2.5 daily 1.25 daily 1.25
3x/wk after HD

b. Foscarnet 180mg/kg/day may be used instead of ganciclovir especially in ganciclovir resistant CMV
Note: Acyclovir has no role in treating CMV disease while CMV immunoglobulins and intravenous immunoglobulin have uncertain value.

43.13.3 Monitor during treatment
a. Daily full blood count, renal profile, liver enzymes
b. CMV DNA if available
c. Repeat cultures for CMV as necessary
Overall, given that life threatening disease is difficult to treat successfully once it is established, prevention by either prophylaxis or pre-emptive therapy is the most effective approach.

43.13.4 Prophylaxis therapy
Modalities of prophylaxis therapy (dose adjustment required for renal impairment)13
a. IV ganciclovir 5 mg/kg bd for at least 14 days, followed by oral
1000 mg tds for 2 to 12 weeks

b. Oral ganciclovir 1000 mg tds for 2 to 12 weeks
In children14,15: > 50 kg 1000 mg tds
37.5 – 50 kg 750 mg tds
25 – 37.5 kg 500 mg tds
c. Oral valacyclovir 2000 mg qds for 90 days
d. Oral acyclovir 800 mg qds for 12 weeks.

Table 43.4: Definitions of prophylaxis and pre-emptive therapy 11
Strategy Definition Advantages Disadvantages
Prophylaxis Treatment administered before and at transplantation to prevent CMV disease Easy to administer • Risk of unnecessary exposure of low risk individual to a drug.
• Prolonged exposure may result in development of resistance

Pre-emptive therapy Treatment administered for a brief period if laboratory tests indicate a high risk for CMV disease • Exposure of fewer individuals to drug
• Reduce duration of exposure
• Minimizes emergence of resistant CMV • Requires sensitive, predictive test to detect infection
• Depending on test sensitivity may not identify all individuals at risk of disease

Table 43.5: Prophylaxis therapy12
Donor (D) recipient (R) serological status Immunosuppression regime Recommendations
D-/R- +/-antilymphocyte therapy Not needed
D+/R- Conventional Prophylaxis (Level B)
D+/R- Antilymphocyte therapy Prophylaxis (Level A)
D+/R+ Conventional Discretionary (Level C)
D+/R+ Antilymphocyte therapy Prophylaxis (Level A)
D-/R+ Conventional Discretionary (Level C)
D-/R+ Antilymphocyte therapy Prophylaxis (Level A)

43.13.5 Pre-emptive
Currently there is insufficient data to recommend routine screening for CMV infection (presence of viraemia).11
Therefore, there is no guideline on pre-emptive therapy.

43.14 Varicella-zoster (Level C)
The most commonly seen manifestation in older paediatric transplant recipients is dermatome-restricted herpes zoster.
In younger children, primary varicella infection can result in rapidly progressive and overwhelming infection with encephalitis, pneumonitis, hepatic failure, pancreatitis and disseminated intravascular coagulation.
43.14.1 Prophylaxis on exposure
Prophylactic varicella-zoster immune globulin (VZIg) given to seronegative children within 72 hours of accidental exposure can modify the disease in 75% of cases.

43.14.2 Treatment
Chickenpox: intravenous acyclovir 500 mg/m2/dose tds should be instituted immediately.
Zoster: oral acyclovir 400 mg/dose 5x/day (< 2 yr) ,
800 mg/dose 5x/day (> 2 yr)
(dosage adjustment will be needed in renal impairment)
In chicken pox discontinue azathioprine until 2 days after the last new crop of vesicles has dried up.
The dose of other immunosuppressive agents will depend on the clinical situation and response to therapy.


References
1. Kubak BM, Pegues DA, Holt CD. Infectious complications of kidney transplantation and their management. In: Handbook of Kidney Transplantation (Danovitch GM) 3rd ed, Lippincott Williams & Wilkins. 2001;pp 221-262
2. Rubin RH, Young LS, eds, Clinical approach to infection in the compromised host. Plenum,1994.
3. Practice Guidelines for the Control and Management of Tuberculosis. 2nd edition. 2002
4. Ioannidis JPA, Cappelleri JC, Skolnik PR, Lau J, Sacks HS: A meta-analysis of the relative efficacy and toxicity of Pneumocystis carinii prophylactic regiments. Arch Intern Med 1996; 156: 177-188
5. Recommendations for the Outpatient Surveilance of Renal Transplant Recipients, in Clinical Practice Guidelines of the American Society of Transplantation, J Am Soc Nephrol 2000; 11 (supplement 15): S49-50
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7. The EBPG Expert Group on Renal Transplantation: European Best Practice Guidelines for Renal Transplantation (part 1), Nephrol Dial Transplant 2000; 15 (supplement 7): 75
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9. Rostaing L, Henry S et al. Efficacy and safety of lamivudine on replication of recurrent hepatitis B after cadaveric renal transplantation. Transplantation 1997; 64: 1624-1627
10. Goffin E, Horsman Y et al. Lamivudine inhibits hepatitis B virus replication in kidney graft recipients. Transplantation 1998; 66: 407-409
11. Recommendations from the IHMF Management Strategies Workshop: The Challenge of CMV Infection and Disease in Transplantation, 2000.
12. Recommendations for the Outpatient Surveilance of Renal Transplant Recipients, in Clinical Practice Guidelines of the American Society of Transplantation, J Am Soc Nephrol 2000; 11 (supplement 15); S45-46
13. The EBPG Expert Group on Renal Transplantation: European Best Practice Guidelines for Renal Transplantation (part 1), Nephrol Dial Transplant 2000; 15 (supplement 7); 71-74
14. CMV infections following renal transplantation – effects of antiviral prophylaxis : a report of NAPRTCS. Paedr Nephrol 1997; 11: 665-667
15. Guido Filler. Prophylactic oral ganciclovir after renal transplantation – dosing and pharmacokinetics. Paedr Nephrol 1998; 12: 6-9