Among other challenges, clinicians have to deal with new multidrug-resistant bacterial infections.

CLEVELAND—The three-part paradigm of infection following organ transplantation should guide the nephrologist in assessing the risk and instituting appropriate prophylaxis and treatment of infection following kidney transplant, Robin Avery, MD, said at the Nephrology Update 2008 here.

Complicating the management of these infections, however, is the emergence of unusual organisms and resistant organisms that are susceptible to fewer antimicrobials, necessitating more frequent use of drugs of last resort.

The classic timetable of infection following organ transplantation, as articulated by Dr. Robert Rubin over two decades ago, can be divided into three main periods: first month post-transplant, months 1 to 6, and after month 6. At any time, the risk can be deduced from knowing the time post-transplant, the prophylaxis administered, environmental exposures, and the net state of immunosuppression, said Dr. Avery, section head, Transplant Infectious Disease, Cleveland Clinic.

Rare but dangerous

“In recent years, we've had a number of very high-profile transmissions in the news,” she said. These include seronegative HIV transmission, seronegative hepatitis C transmission, West Nile virus, and lymphocytic choriomeningitis (LCM) virus.

“Thankfully these are rare. Unfortunately when they do occur, they are often associated with high morbidity and mortality,” she said. Therefore, they prompt discussion about the appropriate level of screening for pathogens in donors.

The answers are not always clear, Dr. Avery said. “For example, [in] the lymphocytic choriomeningitis situation…the donor's family member, hamster, and recipient all tested positive for LCM virus, but the donor's serology itself was negative,” she said. Additions to the current screening panel of pathogens in donors would be costly, and false positives may exclude some individuals who otherwise are appropriate donors.

First month post-transplant

In the first month post-transplant, the usual standard postoperative infections are the rule rather than opportunistic infections. These consist of line, lung, and wound infections. “Some are related to technical issues with the surgery itself, and some have to do with early reactivation of herpes simplex virus (HSV) or yeast. [Occasionally they involve] bacteremia or other unsuspected pathogens in the donor,” she said.

The rise of multidrug-resistant bacteria has complicated the management of post-transplant infection. “Methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, traditionally bad bugs, seem tame compared [with] some of the ones we're dealing with now,” she said.

Infection with quinolone-resistant Escherichia coli or other gram-negative bacteria is becoming more common, and “therefore it's important to get microbiologic confirmation and susceptibilities when treating urinary tract infection. Otherwise the patient may come back uroseptic, and it turns out [to be] ciprofloxacin-resistant,” she said.

ICUs are encountering carbapenem-resistant Acinetobacter and carbapenem-resistant Klebsiella (also known as carbapenemase-producing Klebsiella [KPC]), “which means resistance to imipenem and all standard antibiotics.” This means that these pathogens would respond only to amikacin, if that, or IV colistin or tigecycline, and some of these are nephrotoxic.

Imipenem has traditionally been a fallback to treat extended-spectrum beta-lactamase-producing E. coli and Klebsiella, but these organisms are now becoming resistant to imipenem. “We're also seeing more fluconazole resistance in yeast; Candida krusei and Candida glabrata are on the rise, and these often require other azoles or echinocandins; we try not to use amphotericin if we can help it, but sometimes we are still forced to use amphotericin preparations,” she said.

Increasing resistance of influenza to traditional drugs (amantadine/rimantadine) has occurred over the past year, leaving oseltamivir and zanamivir as the most effective options for the time being.

The virulent epidemic strain of Clostridium difficile that struck in 2005 remains a problem in 2008, she said.

Beyond one month

One to six months post transplant is the time when opportunistic infections associated with transplantation are a risk, including those with cytomegalovirus, HSV, varicella-zoster virus, Aspergillus and other molds, or Cryptococcus, as well as bacterial pneumonias.

After six months, patients can be divided into three groups for assessment of the risk of infection.

  • Group 1 patients are those with little rejection and good allograft function in whom immunosuppression can be tapered; this group remains susceptible to pneumococcal pneumonia, influenza, respiratory viruses, and UTI but not as much to Aspergillus and other opportunistic pathogens.
  • Group 2 comprises those with rejection, allograft dysfunction, and the need for high-dose immunosuppression; these patients often remain susceptible to infections commonly observed in months 1 through 6 and are candidates for extended prophylaxis.
  • Group 3 includes those who had an initially good course but who experience progressive infections with certain viruses (hepatitis B virus, hepatitis C virus, late CMV, human papillomavirus, and BK virus).

TMP-SMX remains valuable

Trimethoprim-sulfamethoxazole (TMP-SMX) continues to provide the best prophylaxis for Pneumocystis jiroveci, (formerly P. carinii) pneumonia. “In addition we get the side benefits of prophylaxis against Nocardia, Listeria, toxoplasmosis, and some respiratory pathogens, so I still call it the most cost-effective intervention in transplantation,” said Dr. Avery. Urinary tract pathogens, however, are frequently resistant to TMP-SMX in the current era.

CMV prevention

CMV infection may be linked to rejection and chronic allograft dysfunction. Also, CMV itself can be immunosuppressive and lead to secondary infections.

Historically, CMV prophylaxis has consisted of oral or IV ganciclovir. A three-month clinical trial found valganciclovir to be comparable to oral ganciclovir in preventing viremia, with less viremia breakthrough during the period of valganciclovir prophylaxis. However, valganciclovir did not eliminate viremia overall; by the end of one year, more than 40% of patients treated with either agent had CMV viremia.

Either prophylaxis or pre-emptive therapy has been used to prevent CMV infection. (Pre-emptive therapy refers to the administration of antiviral therapy only to those who have positive results on a sensitive early-detection test).

“Our center has chosen to do both,” Dr. Avery said. “A number of meta-analyses have shown that prophylaxis does make a difference in terms of indirect effects as well as preventing direct CMV syndromes. Pre-emptive therapy also appears to have a role in preventing indirect effects as well.”

Stopping prophylaxis will lead to late CMV infection in a certain number of patients; pre-emptive monitoring of the highest-risk patients, no longer than two weeks apart for the first year, “can pick up the CMV at an early stage, allowing for treatment [and] preventing the consequences of high viral load CMV infection,” she said.

BK virus

The BK virus is a polyomavirus that has a predilection for the urinary tract. Most of the population has been exposed, and the virus can reactivate after transplant. The risk of graft loss is high if BK virus is not treated.

A strategy of early blood or urine screening and early intervention is prudent. Therapy consists of reducing the intensity of immunosuppression and, if not successful, treating with leflunomide, cidofovir, IV immune globulin, or ciprofloxacin. Leflunomide is probably the most common therapy, but it may take months for a response, said Dr. Avery. “We've had some patients take 14 or 15 months to clear their BK,” she said.

When treating with leflunomide, watch for anemia, elevations in liver function tests, and thrombocytopenia; be aware that if leflunomide must be stopped for reasons of toxicity, the half-life of this agent is weeks or months.