ICAAC/IDSA/ASTMH 2003

Conference Coverage

The following summary of selected abstracts from 3 meetings will be published in multiple parts. The 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) met in Chicago September 14-17, 2003. The Infectious Disease Society of America (IDSA) met in San Diego October 9-12, 2003. The American Society of Tropical Medicine and Hygiene met in Philadelphia December 3-7, 2003. — Stan Deresinski, MD, FACP

Gram-Negative Bacilli

Antibiotic Therapy

Monte Carlo simulations were performed to determine pharmacodynamic parameters in critically ill patients based on published pharmacokinetic data. For organisms at the NCCLS breakpoint, the probability of achieving an optimal pharmacodynamic parameter with standard dosing of either imipenem or cefepime was 64%, while it was 55% for ceftazidime and 14% for ciprofloxacin. With piperacillin/tazobactam, it was 70% for Enterobacteriaceae and 39% for other Gram negatives (IDSA 194).

The initial choice of antibiotic therapy is critical to a successful outcome in patients with life-threatening infections. A retrospective review of 133 episodes of multidrug-resistant Gram-negative bacteremia in ICU patients undergoing regular multisite surveillance cultures found that 80% of those bacteremias were preceded by detectable colonization. Of those with colonization, initial empiric antibiotic therapy was appropriate in 77%, while in those without prior detectable colonization, it was appropriate in only 56% (P = .037) (ICAAC K-699).

A meta-analysis of 17 studies of Gram-negative bacteremia (only 1 of which was a prospective, randomized trial) failed to find evidence of reduced mortality in patients given combination therapy as opposed to monotherapy (ICAAC K-700).

Polymyxin B, given intravenously for a mean duration of 15.8 days, produced a 54% microbiological and 96% clinical cure rate in 26 patients with multidrug-resistant Gram-negative infection. No nephrotoxicity was seen, but 1 patient had lower extremity weakness attributed to the drug. Eight patients with nosocomial infection caused by multidrug-resistant A baumannii and P aeruginosa, 5 of whom were bacteremic, were treated with intravenous colistin. Seven survived and did not develop renal toxicity. The death was due to sepsis on day 4 of therapy. Finally, polymyxin B was administered to 20 patients with resistant Gram-negative infections by intravenous (76%), intraventricular (10%), and inhalational (14%) routes. Infection was cleared in 80%. One patient had a doubling of serum creatinine, 1 had rash, and 1 had muscle weakness (ICAAC K-701s, K-712, K-702).

ESBL-Producing Organisms

Extended spectrum b-lactamases (ESBL) continue to expand in number and type, in bacterial host range, and in geographic extent. The prevalence of fecal carriage of ESBL-producing Enterobacteriaceae among outpatients in Madrid increased from 0.3% in 1991 to 2.6% in 2003. ESBL-producing Gram-negative isolates were detected in 3.2% of 6421 isolates from 42 ICUs and 21 non-ICU sites in the United States (ICAAC C2-38, C2-46).

In addition to infection control lapses and number of ventilator days, prior administration of third-generation cephalosporins, aminoglycosides, or trimethoprim-sulfamethoxazole were each associated with an increased risk of infection with ESBL-producing organisms. Ninety-five percent of isolates carried a mobile DNA element with a sulfonamide-resistance gene (ICAAC K-717).

In general, the most reliably effective antibiotics in the treatment of infection due to ESBL-producing Gram-negative bacilli are the fluoroquinolones and carbapenems. Thus, a retrospective analysis of 133 patients with bloodstream infection due to ESBL-producing E coli or K pneumoniae found that the 30-day mortality was 16% in those treated with either a carbapenem or ciprofloxacin, while it was 55% in those treated with a blood spectrum cephalosporin with or without an aminoglycoside. A separate retrospective study found that treatment of infections due to a ceftazidime-resistant K pneumoniae with another third-generation cephalosporin was associated with poor outcome. Combination therapy with a fluoroquinolone, but not an aminoglycoside, was associated with improved outcome (ICAAC K-720, K-716).

While third-generation cephalosporins are ineffective in the treatment of these infections, the role of cefepime, a putative fourth-generation cephalosporin, remains incompletely understood. Four papers dealt with this issue:

· A retrospective review of 8 patients who received cefepime for treatment of infections caused by ESBL-producing bacteria found that 6 experienced bacterial eradication and either clinical cure (5) or improvement (1). One patient experienced reinfection 2 weeks after completion of therapy. One of the 2 failures was infected at baseline with a cefepime-resistant organism (IDSA 295).

· Cefepime was used to treat 21 episodes of infection due to ESBL-producing E aerogenes, while a carbapenem was used in 23 episodes. Clinical improvement was observed in 62% and 70% (P < .05), respectively. Bacteriologic eradication was achieved in 14% of the cefepime and 22% (P = .437) of the carbapenem recipients (ICAAC K-718).

· A retrospective analysis of infections with an ESBL-producing E aerogenes found similar outcomes in 23 patients treated with a carbapenem and 21 who received cefepime (ICAAC K-718).

· Treatment of infection due to E cloacae with cefepime yielded good clinical results when the cefepime MIC was < 2 mcg/mL. ESBLs were, however, present in isolates with MICs as low as 4 mcg/mL (ICAAC K-719).

Cumulatively, these reports suggest that infections due to ESBL-producing Gram-negative bacilli may often be successfully treated with cefepime, provided that the MIC of the pathogen is < 2 mcg/mL. Since this value is well below the NCCLS breakpoint for susceptibility/resistance, most clinicians may not be able to make this distinction based on routine reports from their microbiology laboratory.

Acinetobacter

Risk factors for colonization by Acinetobacter baumannii were reported in separate studies to be associated with cephalosporin or carbapenem use. An important risk factor for infection due to carbapenem-resistant A baumannii was colonization density, defined as the mean number of culture-positive sites/total sites sampled (ICAAC K-707, 708, K-710).

Seven of 8 patients infected with multidrug-resistant A baumannii were successfully treated with IV colistin, although 6 had an increase in serum creatinine concentration of > 0.5 mg/dL (ICAAC K-712).

Enterobacter

In one case of E cloacae bacteremia, imipenem susceptibility did not predict diminished ertapenem susceptibility (IDSA 227).

Klebsiella

Transferable plasmid-mediated quinolone resistance associated with the qnr gene, associated with low-level ciprofloxacin resistance, was found to be widely distributed in clinical strains of K pneumoniae in the United States. The activities of gatifloxacin, levofloxacin, gemifloxacin, and moxifloxacin each have MICs similar to ciprofloxacin against qnr E coli transconjugants. Additional chromosomal resistance in donor strains was associated with higher-level resistance to all quinolones tested (ICAAC C1-605, C2-98).

P aeruginosa

The incidence of carbapenem resistance in P aeruginosa rose from 10% to 15% over 10 years at the University of Pennsylvania. This increase did not correlate with carbapenem use, suggesting that other agents may play a role in driving this resistance (ICAAC C2-1964).

Piperacillin/tazobactam and levofloxacin were synergistic or additive in vitro against 88% of 100 P aeruginosa isolates. Twenty-one of 42 (50%) isolates initially resistant to piperacillin/tazobactam became susceptible to it after addition of levofloxacin. The comparable result with 58 levofloxacin-resistant strains was 29% "conversion." In a result that I would have considered unexpected, in vitro synergy between gatifloxacin and ciprofloxacin was identified against 52% of 31 strains of ciprofloxacin-resistant P aeruginosa. It was speculated that gatifloxacin may inhibit efflux of ciprofloxacin (IDSA 230, 229).

Vibrio vulnificus

Between 1991 and 2001, 65 patients in California were reported to have Vibrio vulnificus infection, and 40 (62%) died. Ninety-one percent presented with primary septicemia, and 89% of those reported consumption of raw oysters, all of which originated in the Gulf of Mexico (when origin was known). The sale of raw oysters harvested from the Gulf of Mexico from April 1 to October 31 is now restricted in California unless the oysters are appropriately treated with a process validated to reduce V vulnificus to nondetectable levels (ICAAC L-181).

Urinary Tract Infection

In a randomized trial with prolonged follow-up involving 379 women with uncomplicated cystitis, ciprofloxacin 250 mg b.i.d. for 3 days was superior to amoxicillin/clavulanate 500 mg b.i.d. for 3 days. This was true even in women infected with bacterial strains susceptible to amoxicillin/clavulanate. Although the usual practice in the United States is to treat for only 3 days, a meta-analysis of randomized trials found that antibiotic treatment of uncomplicated urinary tract infection for 5-7 days achieves higher bacterial eradication rates (RR, 1.28; 95% CI, 1.05-1.56) at the cost of more adverse events. There was no difference with regard to symptom resolution (ICAAC L-264, ICAAC L-261).

Greater than 90% clinical and bacteriological cure was achieved in all treatment groups among 62 women with uncomplicated E coli cystitis randomized to treatment with either ciprofloxacin for 3 days, nitrofurantoin for 7 days, or a single dose of fosfomycin. Ciprofloxacin and fosfomycin, but not nitrofurantoin, each reduced vaginal and rectal E coli prevalence. Antibiotic resistance among rectal E coli arose only in 1 patient who had received ciprofloxacin, and in that case, it was transient (ICAAC L-265).

Antibiotic resistance is, nonetheless, increasing in frequency among urinary pathogens. A survey of 890 outpatient urinary E coli isolates from across the United States and Canada found that 38% were resistant to ampicillin, 23% to trimethoprim/sulfamethoxazole, 6.9% to levofloxacin, and 1.8% to nitrofurantoin. In a case-control study, risk factors for ciprofloxacin-resistant E coli urinary tract infection were found to be recurrent infections and, unsurprisingly, prior receipt of quinolones (IDSA 226, ICAAC C2-267, C2-94).

A cohort of 171 otherwise healthy nonpregnant patients with community-onset acute uncomplicated pyelonephritis was treated with orally administered ciprofloxacin for 7 days. Blood cultures were positive in 16.5%; 99% of all infections were due to E coli. Bacterial eradication and clinical cure were each 94%-95% when assessed 5-9 days post-treatment. The clinical success rate in bacteremic patients was 95% (ICAAC L-262).

Localization of the site of infection within the urinary tract is more complicated in males than in females because the prostate must be considered in the former. Thirty-three febrile adult males with urinary tract infection underwent scanning with radioactive indium-tagged leukocytes. Thirteen of 14 with clinical evidence of acute prostatitis had uptake in the prostate; 1 had it in the kidneys. Of the 6 with a clinical diagnosis of acute pyelonephritis, 3 had renal and 3 had prostatic uptake. Twelve of 13 with clinically undefined site of infection had prostatic uptake, and 1 had renal uptake. Rectal examination had 46% sensitivity, 80% specificity, 93% positive predictive value, and 21% negative predictive value for the diagnosis of acute prostatitis. The comparable figures for flank examination were 60%, 89%, 50%, and 92%, respectively. Half the patients with flank tenderness had acute prostatitis. These findings demonstrate the limited accuracy of physical examination in site localization of urinary infection in males (ICAAC L-259).

Mycobacterial Infections

Mycobacterium tuberculosis

The introduction of TNF-blocking agents in the treatment of rheumatoid arthritis, Crohn’s disease, and other inflammatory disorders has been associated with an increased risk of fungal and mycobacterial infections. Examination of the FDA Adverse Event database identified 574 reports of granulomatous infection associated with the use of etanercept or infliximab, occurring at frequencies of 494 out of 36,5000 vs 80 out of 150,000 (P < .001), respectively. Tuberculosis was most frequently reported, followed by histoplasmosis (ICAAC B-1521).

A single case of laryngeal tuberculosis resulted in transmission to 133 contacts, 5 of whom developed active tuberculosis. The apparent transmission rate to close contacts was 68%. In New York City, the mortality rate in patients with tuberculous meningitis decreased from 75% in 1992 to 42% in 2001. Among HIV-infected patients, mortality decreased from 86% to 67% (ICAAC l-957, L-955).

Routine monitoring of serum hepatic transaminases is not currently recommended in patients receiving INH for treatment of latent tuberculosis, except in patients at increased risk of hepatotoxicity. However, in patients with latent TB undergoing monthly evaluations, the incidence of INH-associated hepatitis (AST or ALT > 3 times normal) was 0.8% and was asymptomatic in 72 of 79 (91%). Twenty-seven of the 72 (38%), representing an overall incidence of 3 per 1000, had further increases in hepatic transaminases to > 5 times normal, with none ever developing symptoms. The only independent risk factor for hepatoxicity was increasing age. These results suggest that routine transaminase monitoring may be warranted in INH recipients (IDSA 407).

In a randomized trial involving patients with cervical tuberculous lymphadenitis, 12 months of therapy (2HERZ/10HRE) appeared to be superior to 6 months (2HERZ/4HRE) (ICAAC L-954).

Moxifloxacin was highly active in a murine model of tuberculosis, being more potent than isoniazid. In addition, in patients with active pulmonary tuberculosis, moxifloxacin and INH (each given alone) had comparable early bactericidal activity as defined as the decrease in CFU/mL of sputum at day 5 (ICAAC B-1035, IDSA 405).

Mycobacterial 16S rRNA was detected in 5 of 10 sarcoid tissue specimens and in none of 10 controls. In 3 of the 5, rpoB sequences were also identified. Sequencing suggested that the DNA detected was from a novel variant of M tuberculosis (IDSA 416).

Mycobacteria Other Than Tuberculosis (MOTT)

Linezolid, levofloxacin, and moxifloxacin were active in vitro against M kansasii (ICAAC E-1711).

Outbreaks of skin and soft-tissue infections due to M abscessus occurred in individuals who received cosmetic injections by unlicensed personnel, as well as in others who had undergone acupuncture (ICAAC K-1432, IDSA 845, 846).