Infections are major cause of hospitalization and death in the dialysis and transplant populations, and treatment of these infections could be made more challenging by the emergence of pathogens resistant to multiple antimicrobial agents.

“We have observed trends of increasing antimicrobial resistance among Gram-negative bloodstream isolates, particularly Escherichia coli isolates, in kidney and other solid organ transplant recipients,” said Majdi N. Al-Hasan, MD, an infectious disease specialist now with the Division of Infectious Diseases at the University of Kentucky in Lexington.

He and his colleagues studied the incidence and outcomes of Gram-negative bloodstream infections among solid organ transplant recipients receiving care at Mayo Clinic in Rochester, Minn. From 1996 to 2007, antimicrobial resistance rates among E. coli bloodstream isolates in solid organ transplant recipients increased from 50% to 75% for ampicillin and 0% to 44% for ciprofloxacin. “In kidney transplant recipients, antimicrobial resistance rates of E. coli bloodstream isolates increased from 40% to 74% for ampicillin and from 0% to 53% for ciprofloxacin during the same period,” Dr. Al-Hasan said.

From 2000 to 2007, the prevalence of E. coli bloodstream isolates producing extended spectrum beta-lactamases increased from 0 to 11% in kidney transplant recipients, he said.

The results appear in the American Journal of Transplantation (2009;9:835-843).

In a separate study of Pseudomonas aeruginosa bloodstream infections conducted at the University of Pittsburgh Medical Center, researchers found that transplant recipients are at greater risk for multidrug-resistant P. aeruginosa bloodstream infections than non-transplant patients, according to paper published in Transplant Infectious Disease (2009;11:227-234). Over a 10-year period, researchers studied 503 subjects, 149 of them transplant recipients. Of the P.  aeruginosa blood culture isolates from transplant recipients, 43% were multidrug resistant compared with 18% of isolates from non-transplant recipients.

MRSA

In the dialysis population, researchers have observed an emerging problem with methicillin-resistant Staphylococcus aureus (MRSA). From 1995 to 2002, the percentage of dialysis centers treating one or more patients with MRSA rose from 40% to 76%, according to a report in Seminars in Dialysis (2005;18:52-61). The incidence of invasive MRSA infections among dialysis patients in 2005 was 45.2 cases per 1,000 population, indicating a 100-fold greater risk for these infections compared with the general population, according to the Centers for Disease Control and Prevention (CDC). Of 5,287 cases of invasive MRSA reported to the CDC by the Active Bacterial Core surveillance system during 2005, 813 (15.4%) were in dialysis patients.

Furthermore, in a study by investigators at St. John Hospital and Medical Center in Detroit, 40 (33%) of 120 hospitalized dialysis patients had S. aureus nasal colonization. Of these 40, 26 (65%) were colonized with MRSA, according to data published in Infection Control and Hospital Epidemiology (2009;30:4-8). Infections developed in eight of these 26 patients, whereas only one infection developed in 14 patients colonized with methicillin-susceptible S. aureus, which the researchers said underscores the significance of MRSA nasal colonization.

Vancomycin resistance

One of the major concerns regarding MRSA is the possible development of strains that also are resistant to vancomycin, an antibiotic widely used in dialysis centers, said Loren G. Miller, MD, MPH, Associate Professor of Medicine at the David Geffen School of Medicine at the University of California in Los Angeles (UCLA) and Director of Infection Control at Harbor-UCLA Medical Center in Torrance, Calif. Few good therapeutic options are available for vancomycin-resistant S. aureus (VRSA). Possible alternatives include linezolid, daptomycin, and telavancin (which recently received FDA approval), he said. He added that there is no evidence showing that these agents would be any more effective than vancomycin. In addition, the dosing of these agents for dialysis patients have not been fully worked out, he said.

So far, only a handful of VRSA cases have been reported, “but there are probably a lot more that haven't been recognized because VRSA is frequently not picked up by routine microbiology laboratory methods,” said Dr. Miller, an investigator at Los Angeles BioMedical Research Institute.

For reasons that are not clear, most VRSA cases have been detected only in the Detroit area, “and they don't seem to be epidemiologically linked to each other,” Dr. Miller said.

Nephrologists also should be alert for vancomycin intermediate resistant S. aureus (VISA) infections, he said. They should suspect VISA or VRSA infections in patients who are not responding as expected to vancomycin treatment, Dr. Miller said.

In addition, vancomycin-resistant enterococcal infections could be on the increase in dialysis patients, he said. “This can be a challenge to treat because the number of drugs that can treat these infections is limited.”

The possibility of drug-resistant infections in dialysis patients has implications for empiric treatment, Dr. Miller noted. Most infections in HD patients are caused by Gram-positive organisms (mostly S. aureus), Dr. Miller explained. Clinicians should consider the possible presence of Gram-negative pathogens in patients who are not responding to empiric treatment with drugs (such as vancomycin) that are only active against Gram-positive organisms. At Harbor-UCLA, typical empiric therapy for bloodstream infections in HD patients is vancomycin plus a drug active against Gram-negative bacteria, such as ceftazidime, he said.

Meanwhile, bloodstream infections and cellulitis seem to be on the rise among dialysis patients, mostly likely because of prolonged use of vascular-access catheters. Having a catheter is very large risk factor for having a bloodstream infection,” Dr. Miller said.

More Gram-negative infections

MRSA is not the only drug-resistant microbe with the potential to cause problems. In a prospective study conducted at an outpatient hemodialysis (HD) unit affiliated with Caritas St. Elizabeth Medical Center in Boston, researchers demonstrated that multidrug-resistant Gram-negative bacteria are an emerging threat among HD patients. Of 67 patients in the study, 19 (28%) were colonized with one or more antimicrobial-resistant bacteria at enrollment, according to a report in the Clinical Journal of the American Society of Nephrology (2008;3:752-758). Eleven (16%) were colonized with multidrug-resistant gram-negative bacteria, nine (13%) were colonized with vancomycin-resistant enterococci (VRE), and three (5%) were colonized with MRSA. Of 55 patients who had follow-up cultures, 22 (40%) had acquired at least one antimicrobial-resistant bacterium: 20%, 15%, and 13% acquired multidrug-resistant gram-negative bacteria, VRE, and MRSA, respectively. Antibiotic exposure was the only independent risk factor for multidrug-resistant gram-negative bacteria acquisition.

“These findings have important implications, because current measures aimed at preventing the spread of antimicrobial-resistant bacteria have focused on VRE and MRSA,” the authors observed.

Despite reports showing a growing problem with drug-resistant infections, David Van Wyck, MD, Vice President of DaVita Clinical Support Services, observed: “We have actually not seen a trend towards increasing antimicrobial resistance. Credit likely goes to intensive infection control efforts within facilities and great work by physicians.”

Decreased use of central venous catheters, high vaccination rates for influenza and pneumonia, and careful selection of antibiotics have helped to prevent infections and the development of drug-resistant pathogens, he said.

“The changing spectrum of pandemic and seasonal influenza will likely be the most challenging infectious risks in the coming year or two,” Dr. Van Wyck said.

According to the U.S. Renal Data System, pneumonia has been an increasing cause of death for dialysis patients, he noted.

Fluoroquinolone resistance

With respect to infections in renal transplant recipients, Dr. Al-Hasan said he is most concerned about increasing resistance to ciprofloxacin and other fluoroquinolone antibiotics. “Fluoroquinolones, especially the newer ones, have excellent bioavailability when taken orally,” he said. “This makes them a very attractive choice for ‘switch therapy' in patients with Gram-negative bloodstream infections (BSI). Unfortunately, over 50% of E. coli bloodstream isolates in kidney transplant recipients are now resistant to fluoroquinolones. This means that more than one half of kidney transplant recipients will require intravenous antibiotics for the entire course of treatment of Gram-negative BSI, which may substantially increase the cost of health care and may also increase the risk of complications related to placement of peripherally inserted central venous catheters for the administration of the intravenous antibiotics.”

“I believe that Gram-negative BSI as well as many complicated and non-complicated urinary tract infections in kidney transplant recipients will become much more difficult to treat in the future,” Dr. Al-Hasan told Renal & Urology News. “The urinary tract is, predominantly, the most common primary source of Gram-negative BSI in kidney transplant recipients.” In the study conducted at Mayo Clinic, the urinary tract was the primary source of infection in nearly three quarters of kidney transplant recipients.

Trimethoprim-sulfamethoxazole often is used for prophylaxis against opportunistic infections in solid organ transplant recipients, antimicrobial resistance rates to this drug combination have been unacceptably high to be considered for empiric treatment of UTI in this population, he said. The same goes for ampicillin and amoxicillin-clavulanate. This has left fluoroquinolones as the most popular option for the empiric treatment of UTI for many years. Unfortunately, the increase use of fluoroquinolones in kidney transplant recipients has likely resulted in increasing resistance rates among Gram-negative isolates to fluoroquinolones in this population. This leaves even fewer available oral options for physicians to treat UTIs.

“What is even more bothersome is that there are not any new oral antimicrobial agents with Gram-negative activity that appear to be coming through the pipeline anytime soon,” he said.

In terms of prevention, Dr. Miller and Dr. Van Wyck recommended such basic infection control techniques as washing hands and limiting the use of broad-spectrum antibiotics. Dr. Miller urged decreased reliance on catheters for hemodialysis vascular access. Dr. Van Wyck advised avoiding and removing central venous catheters whenever possible.

Curbing Antimicrobial Resistance

Clinicians should be aware of the antimicrobial resistance rates at their local institutions, said Majdi N. Al-Hasan, MD, an infectious disease specialist now with the Division of Infectious Diseases at the University of Kentucky in Lexington. This knowledge will enable them to make a more educated empiric decision when treating bloodstream infections, urinary tract infections, or other Gram-negative infections. In a recent study of solid organ transplant recipients conducted by him and his colleagues, they found that 20% of Pseudomonas aeruginosa bloodstream isolates were resistant to either piperacillin-tazobactam, cefepime, or imipenem, three of the most commonly prescribed intravenous antimicrobial agents for Gram-negative infections. Moreover, resistance rates were as high as 25% and 30% for gentamicin and ciprofloxacin, respectively.

This empiric decision may need to be adjusted based on the bacterial culture and in vitro antimicrobial susceptibility results. Given the high antimicrobial resistance rates reported nationally, “there is no longer one antimicrobial option that is guaranteed to be effective,” Dr. Al-Hasan said.

“In moderately or severely ill patients, always start with a broad-spectrum antimicrobial regimen that is likely to be effective against the potential causative pathogens based on the antimicrobial resistance patterns at your local institution,” Dr. Al-Hasan advised. “Then step down antimicrobial therapy based on the bacterial culture and in vitro antimicrobial susceptibility results.”