By Carol A. Kemper, MD, FACP, Section Editor: Updates, Clinical Associate Professor of Medicine, Stanford University, Division of Infectious Diseases; Santa Clara Valley Medical Center, is Associate Editor for Infectious Disease Alert.

The emerging NDM problem

NDM-1 Carrying Enterobateriaceae – USA: (Rhode Island) ex Viet Nam. A ProMED-mail post, June 21, 2012; http://www.promedmail.org.

This ProMED-mail alert describes the case of a young Rhode Island resident who traveled to Cambodia and Viet Nam, where she was hospitalized with spinal cord compression in December 2011. She returned to the United States in January 2012, with a chronic indwelling Foley catheter. She was initially found to have a urinary tract infection with an ESBL-containing E coli organism. Subsequent urine specimens obtained in February and March 2012 grew two strains of carbapenemase-producing Klebsiella pneumoniae, which was weakly positive on Hodge testing. The isolate was sent to the CDC, and was found to contain NDM producing carbapenemase, stricter isolation precautions were implemented, and no further cases were identified. The isolate was resistant to 24 different antimicrobials, and sensitive only to tigecycline (MIC = 2 micrograms/mL), colistin, and polymixin B. This case represents the 13th case of NDM identified in the United States.

It has been barely two years since the MMWR described the emergence of a novel resistance mechanism, called New Dehli metallo-beta lactamase (NDM-1), which was identified in 3 Enterobacteriaceae isolates in the U.S. between January and June 2010. These isolates, including an E. Coli, Klebsiella pneumoniae, and Enterobacter cloacae, all carried a plasmid-producing enzyme called "blaNDM-1", which confers resistance to all beta-lactams and carbapenems, with the exception of aztreonam. However many of these types of bacteria, including the 3 isolates above, harbor plasmids that encode for multiple resistance factors and are frequently broadly resistant to virtually all antibacterials. These plasmids are also easily transmitted to other Enterobacteteriaceae or other gram negatives. They can colonize the gastrointestinal tract for months and can spread through the environment through contaminated water sources or through surfaces. Nosocomial transmission is therefore of critical concern.

While initial reports suggested that many persons colonized or infected with these NDM isolates had recently received medical care in India or Pakistan, this is no longer an exclusive risk factor or identifier for these cases. NDM-containing isolates have been reported from every continent, with the exception of South America. In addition to the 13 isolates discovered in the United States, 29 cases have been identified in the United Kingdom, at least 17 of which were previously cared for or hospitalized in India or Pakistan. However, of the 77 cases identified in Europe up to 13 (17%) may have occurred as the result of nosocomial transmission.

It's only a matter of time before these isolates become more frequent, unless vigorous efforts are made to identify and isolate cases. The accompanying editorial argues for an increase in point prevalence studies in U.S. hospitals, including more vigorous screening of all ICU admissions or high risk cases using nucleic acid amplification methods. If NDM is identified, than surveillance should be extended to other persons in that unit (or skilled nursing facility). Only a rigorous active surveillance and infection control plan can limit the inevitable spread of these organisms.

When Pneumonia occurs with Flu: Think Influenza

Jain S, et al. Influenza-associated pneumonia among hospitalized patients with 2009 pandemic Influenza A (H1N1) virus – United States, 2009. Clin Infect Dis 2010;54: 1221-1228.

Cases of pandemic H1N1 requiring hospitalization were examined by reviewing two national case series from spring and fall 2009. During this period, a total of 451 patients with laboratory-confirmed H1N1 were hospitalized, 195 (43%) of whom were diagnosed with pneumonia based on chest radiographs. Not unexpectedly, those patients with pneumonia had higher rates of admission to ICU (52% vs 16%), were more likely to be diagnosed with ARDS (26% vs 2%), sepsis (18% vs 3%), and mortality (17% vs 2%), than those without pneumonia. More than half of those with pneumonia had bilateral infiltrates (67%); the others had multilobar infiltrates (7%), or unilobar involvement (31%). Bacterial infection, mostly bacteremia, was confirmed in 13 patients (7%) with pneumonia and 2 (< 1%) of those without.

What was not necessarily expected was the finding that patients with influenza-associated pneumonia were less likely to receive antivirals within 48 hours of admission compared with those admitted with influenza without pneumonia (28% vs 50%, p < .0001). Eventually during the hospitalization, a similar proportion of patients with or without influenza-associated pneumonia did receive antiviral therapy (78% vs 79%); 91% of this was oseltamivir.

The key to this paradox may be that the very presence of pneumonia or infiltrates on chest radiographs was more likely to prompt a diagnosis of bacterial infection and administration of antibacterials, rather than trigger a suspected diagnosis of influenza. "Sepsis" (which was based on clinical judgment) was diagnosed in 18% of these pneumonia cases, compared with only 2% of non-pneumonia cases, suggesting either bias in the suspicion of bacterial infection – or even more possibly, a more severe systemic inflammatory response from H1N1 infection in those with pneumonia.

During influenza season, Influenza (H1N1) should be included in the differential of patients admitted with severe illness and pneumonia, or "sepsis" and pneumonia, and presumptive antiviral treatment started as soon as possible, at least until additional information and the results of tests are available.

Voriconazole Safe in Renal Patients: To a limited degree

Neofytos D, et al. Administration of Voriconazole in patients with renal dysfunction. Clin Infect Dis 2012; 54:913-921.

Parenteral versions of voriconazole contain a cyclo-dextrin base, which acts as a solubilizing agent, that reportedly is inadequately renally cleared (by glomerular filtration) in patients with renal dysfunction. Animal studies have found that the administration of this cyclodextrin base to mice and rats can result in renal toxicity, and dose-related renal tubule vacuolization and obstruction in rats. Limited data in humans does not support this finding; adverse renal reactions to voriconazole are infrequent, and one report indicates that hemodialysis may result in clearance of the product.

These authors examined adults (greater than or equal to 18 years of age) with renal dysfunction (creatinine clearance < 50 mL/min) treated with voriconazole for a minimum of 3 days. Patients requiring hemodialysis or CVVH were excluded. The authors focused their investigation on 42 (25%) patients with CrCl < 50 mL/min receiving parenteral voriconazole; 77 (46%) patients with CrCl > 50 mL/min receiving parenteral voriconazole; and 47 (28%) patients with CrCl < 50 mL/min receiving orally administered voriconazole. Renal function was assessed at days 3 and 7 of treatment, and at the end of treatment, whenever that occurred. Changes in renal function were determined using pre-defined criteria (RIFLE).

The median duration of voriconazole treatment for each of the three groups, respectively, was 10 days (3 to 25 days), 10 days ( 3 to 59 days), and 9 days (2 to 86 days). Two-thirds (65.7%) of the patients received a loading dose at 6 mg/kg twice daily for one day. Thereafter, 47 patients received a standard dose of 200 mg twice daily; 35 (21%) received 2-3 mg/kg twice daily; 72 (43%) received 4 mg/kg twice daily, and 12 (7%) received 5-6 mg/kg twice daily. Voriconazole plasma levels were assessed in 27 patients. Eight patients had voriconazole levels > 5 micrograms/mL.

Changes in baseline renal function occurred in 19 (11.4%), 14 (8.4%), and 28 (16.9%) of patients at day 3, day 7, and end of treatment, respectively. In univariate analysis, voriconazole plasma levels > 5 micrograms/mL were associated with worsening renal function at the end of treatment. However, in multivariate analysis, significant predictors of renal dysfunction included the administration of immunosuppressant agents/chemotherapy, the co-administration of penicillin antibacterials, hematologic malignancy, and the administration of fluconazole within 30 days of voriconazole use. In contrast, the administration of voriconazole was actually associated with a protective renal affect (OR 0.19; P = .01). Liver impairment was the only predictor of renal dysfunction at day 7 of treatment. Some of this may reflect the overall disease severity of the patient. However, there was no good evidence that voriconazole had a significant adverse impact on renal function in any of these groups of patients, with the possible exception of those with plasma levels > 5 micrograms/mL.

The authors advocate for the cautious use of voriconazole, in either oral or parenteral formulation, for those patients with renal impairment where it is deemed medically necessary.