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 meets in Philadelphia December 3-7, 2003. — Stan Deresinski, MD, FACP Antibacterials

Adverse Effects and Pharmacokinetics

Cefepime

Twenty-nine cefepime recipients developed encephalopathy that resolved on discontinuation of the antibiotic. Twenty-five of the 29 had impaired renal function. In a previously published report, the observed neurological abnormality was described as a "prolonged confusional state associated with diffuse rhythmic nonreactive triphasic sharp waves on the EEG," which resolved 24-48 hours after discontinuation of cefepime administration (Neurophysiol Clin. 2000;30:383; ICAAC A-525).

Daptomycin

The clinical development of daptomycin was slowed by the occurrence of myopathy associated with > 10-fold CPK elevations in several volunteers. Subsequent studies in dogs found that these problems were significantly reduced by changing from split dosing to once-daily administration of this lipopeptide (AAC 2003;47:1318). An analysis of clinical trials data found that 6.4% of recipients of once-daily daptomycin and 5% of recipients of comparator antibiotics developed musculoskeletal complaints. One daptomycin recipient (0.2%) developed elevated CK and muscle symptoms that reoccurred on rechallenge (ICAAC L-736).

Fluoroquinolones

Several prior studies have indicated that fluoroquinolone use is associated with an increased risk of Achilles tendon disorders, including rupture, especially in individuals older than 60 years of age and those receiving adrenal corticosteroid therapy (Infectious Disease Alert. 2002;22:25-28; BMJ. 2002;324:1306). In a case-control study involving a managed care population, fluoroquinolone use was again associated with increased risk of Achilles tendon rupture, with the magnitude of risk similar to that observed with oral corticosteroid exposure alone or with diabetes mellitus. The risk seen with fluoroquinolone use was less than that seen with other factors found to be associated with Achilles tendinopathies, including male gender, rheumatoid arthritis, skin or soft-tissue infection, obesity, and injected corticosteroid use. In contrast, however, examination of a large health insurance database found that the risk of Achilles tendon rupture associated with fluoroquinolone use did not significantly differ from the risk associated with the use of antibiotics of other classes. A comparison of 3 different fluoroquinolones—levofloxacin, ofloxacin, and ciprofloxacin—found no difference among them (ICAAC A-519, IDSA 195).

Previous studies have suggested that fluoroquinolones may cause tendon disorders as a consequence of chelation of magnesium and the production of local reduced levels of ionized magnesium. Some evidence, however, suggests an alternative or additional explanation. In in vitro studies, 2 fluoroquinolones caused alteration in matrix and signaling proteins, as well as causing tenocyte apoptosis (ICAAC A-520).

Fluoroquinolones, like macrolides, have been demonstrated to have a variety of anti-inflammatory effects in vitro. Moxifloxacin exerted anti-inflammatory effects on activated mononuclear and epithelial cells in vitro by inhibition of NFkB and ERK activation pathways. On the other hand, moxifloxacin upregulated Toll-like receptor expression on human neutrophils (ICAAC B-1504, B-1505).

Some macrolides and fluoroquinolones have been associated with prolongation of ventricular repolarization. Administration of doses of levofloxacin as high as 1500 mg was associated with an increase in heart rate but had no effect on the QTc interval (IDSA 196).

Administration of any fluoroquinolone together with magnesium, zinc, or iron is associated with reduced bioavailability of the antibiotic. In addition, levofloxacin Cmax was reduced by approximately 20% when administered with a mineral-fortified breakfast of juice and cereal when compared to administration in the fasting state. Gatifloxacin exposure is also significantly reduced when coadministered with Ensure (ICAAC A-1626, 1628).

Ketolides/Macrolides

Coadministration of either telithromycin or clarithromycin was associated with significantly increased exposure to simvastatin. A 12-hour dosing interval between telithromycin and simvastatin reduced the magnitude of this interaction by approximately one-half (ICAAC A-1623, 1624).

Linezolid

Linezolid has 100% oral bioavailability, and administration with continuous enteral feedings did not adversely affect the rate or extent of its absorption (ICAAC A-1614).

In a compilation of data from 2 phase-3 trials, the incidence of thrombocytopenia in patients with nosocomial pneumonia given linezolid for > 5 days was not greater than in those given vancomycin. However, linezolid administration beyond 14 days has been associated with an increased risk of the development of thrombocytopenia. Linezolid was administered for a mean of 43 days (range, 1-753 days) to 101 patients who received 119 courses of therapy with the drug. Sixteen percent developed anemia, and 20% developed thrombocytopenia. The subsequent mean time to recovery of a normal platelet count is 15.6 days (IDSA 198, 199).

Forty patients with chronic osteomyelitis, 22 of whom had orthopedic device infections, received IV linezolid for 7 days followed by oral administration for a mean duration of 26 weeks (range, 6-36). Therapy was discontinued because of the development of anemia with reticulocytopenia in 14 (35%) at a mean of 8 weeks (range, 4-19) and because of peripheral neuropathy, occurring at a mean of 24 weeks (range, 16-36) in 3. Thrombocytopenia occurred only once but may have been alcohol-related (IDSA 317).

Metronidazole

Despite a plasma half-life of approximately 8 hours, metronidazole is inexplicably routinely administered several times daily. Once-daily IV administration of 1500 mg metronidazole and 750 mg levofloxacin to healthy volunteers yielded acceptable pharmacokinetic results, with Cmin of 4.8 + 1.4 mcg/mL and 0.7 + 0.3 mcg/mL, respectively. This once-daily regimen is now being used in a clinical trial in the treatment of intraabdominal infections (IDSA 193).

Streptogramins

Approximately one-third of 56 patients given quinupristin/dalfopristin for treatment of VRE infection complained of myalgia and/or arthralgia. These complaints were significantly associated with increased serum alkaline phosphatase. This enzyme elevation was interpreted by the investigators as suggesting that biliary tract dysfunction is associated with musculoskeletal symptoms in recipients of this streptogramin combination (A-522).

Tigecycline

The investigational glycylglycine tigecycline appeared safe and effective in phase 2 trials involving hospitalized patients with complicated skin and skin-structure infections and with complicated intraabdominal infections (ICAAC L-738, 739).