Highlights from the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy
Chicago, IL, USA, December 1619, 2001

Introduction

Oral Levofloxacin As Successful as IVPO Ceftriaxone/Clarithromycin in Community-Acquired Pneumonia (CAP)

Easy IVPO Switch Therapy for Levofloxacin Associated with Significant Economic Benefits

Levofloxacin Effective in Treating Legionnaires' Disease

Potentiation of Levofloxacin Activity Against Gram-Negative Bacteria

Cardiovascular Safety Results Updated

2001 Resistance Trends Confirm Levofloxacin Maintaining Excellent Activity

Evaluating the Role of Fluoroquinolones in Pediatric Infections

Introduction

The 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (41st ICAAC) was held in Chicago from December 1619, 2001, where it maintained its place as the foremost infectious disease meeting in the world. Despite the logistical problems that likely resulted from its postponement following the September terrorist attacks, the 41st ICAAC was able to provide a leading forum in which all involved in the field of infectious disease could meet and debate the latest research results. Resistance trends and the safety of antimicrobial therapy were issues highlighted at the meeting, and the importance of the fluoroquinolones was increasingly recognized. Of these agents, levofloxacin stands out as one of the most clinically useful agents, as it combines excellent efficacy with an unparalleled safety record.

Oral Levofloxacin As Successful as IVPO Ceftriaxone/Clarithromycin in Community-Acquired Pneumonia (CAP)

In a very useful prospective, randomized study presented by Dr. Veronique Erard, et al., Division des Maladies Infectieuses, Centre Hospitalier-Universitaire Vaudois, Lausanne, Switzerland, the efficacy and safety of therapy with levofloxacin 500 mg b.i.d. PO was compared to ceftriaxone 2 g q24h IV with or without clarithromycin 500 mg b.i.d. IV or PO followed by oral antibiotics in patients hospitalized with CAP. The clinical outcome was assessed at day 30, and immunocompromized patients or those admitted to ICU were not enrolled. The study was performed over one year with 117 patients enrolled (79 levofloxacin group, 38 comparator group). Patient demographic variables were similar for both groups with 64% of the levofloxacin group described as belonging to the Fine IV or V category, compared to 63% in the comparator group.

Results clearly demonstrated levofloxacin PO therapy to be as effective as IVPO standard therapy (Table 1). In fact, the group treated with levofloxacin PO had a lower mortality and a reduced length of stay (LOS) in hospital. The incidence of antibiotic related adverse events (AEs) were similar for both groups (6% for the levofloxacin group and 5% for the comparator group), with gastrointestinal adverse drug reactions (ADRs) being the most common. Thus, levofloxacin PO can be recommended for the treatment of patients with CAP, with such therapy likely to be associated with important cost savings, as well as being more acceptable to patients and medical staff.

Easy IVPO Switch Therapy for Levofloxacin Associated with Significant Economic Benefits

The economic benefits of levofloxacin PO versus IV comparator therapy were supported by a study that assessed the pharmacoeconomic impact of a pharmacist-managed automatic IVPO conversion program. Dr. J.L. Kuti and colleagues, Hartford Hospital, Hartford, CT, USA performed the study due to increasing cost constraints being placed upon health care systems, with pressure to reduce LOS and use of IV treatment. In this study, the pharmacist was able to use criteria to decide when a patient could be converted from IV to PO therapy. A prospective observational study was conducted for two months (POS) and compared with results during the pharmacist conversion program (PCP). Levofloxacin was the agent of choice for the study, with an easy IVPO conversion therapy, and excellent oral bioavailability. Data were collected from the time of admission until the time to meet criteria, during the period of PO therapy, LOS, number of patients requiring further IV therapy (PCP program only), clinical outcome (PCP only) and resource consumption. The criteria used to convert to PO therapy were: temperature < 38.3 C, heart rate (HR) < 100/min, respiratory rate (RR) < 24/min, systolic blood pressure (SBP) > 90 mm Hg, and a patient able to take oral therapy. Costs were analyzed as follows: Level I related solely to acquisition cost of the drug: Level II costs include level I plus labor and supplies; Level III costs include level II plus cost of hospital stay. Results confirmed that age, gender and type of infection were similar for the POS and PCP groups. Although the average day to meet oral conversion criteria was the same for both groups, significantly more patients were switched to PO therapy in the PCP group, and these were switched, on average, four days earlier. The median LOS for the PCP group was also significantly shorter than the POS group. Of the 53 patients who were candidates for oral conversion in the PCP group, the clinical success rate was 95%. These results demonstrated a significant reduction in costs associated with the earlier switch to levofloxacin PO using the pharmacist program (Table 2). While clinical outcome was not compromised, the use of the conversion program was associated with a total provider savings of approximately US$3,000 per patient.

With reports of some treatment failures associated with erythromycin, physicians have been interested in new effective treatments for Legionnaires' disease. A retrospective, observational study by Dr. Maria L. Pedro-Botet, et al., Infectious Diseases Unit and Department of Microbiology, Hospital Universitari Germans Trias i Pujol Barcelona, Spain, compared the clinical outcome of hospitalized patients with Legionella pneumonia treated with erythromycin or levofloxacin/ofloxacin. Fifty-three patients were evaluated (33 received erythromycin, 16 received levofloxacin and 4 ofloxacin). The time to apyrexia was 77.8 hr in the erythromycin group versus a much shorter 54.3 hr for the levofloxacin group. A total of 39% of the erythromycin group developed complications whereas only three of the patients receiving fluoroquinolones did so (15%). Results demonstrated a significant benefit associated with levofloxacin compared to erythromycin in terms of reduced LOS (11 days for levofloxacin, 14 days for comparator, p = 0.1). The directly related mortality was 12% in the erythromycin group and 10% in the fluoroquinolone group (p = 0.5) (Figure 1). The researchers concluded that levofloxacin/ofloxacin was as effective as erythromycin in the treatment of Legionnaires' disease. In addition, the levofloxacin treatment was associated with a shorter febrile time, a reduced LOS and showed a trend toward fewer complications and a lower mortality rate.

Potentiation of Levofloxacin Activity Against Gram-Negative Bacteria

A number of excellent basic scientific reports were presented outlining the potentiation of levofloxacin activity against Pseudomonas aeruginosa and Escherichia coli when used in conjunction with a broad-spectrum efflux pump inhibitor. In one report presented by Dr. D. Griffith and co-workers, Essential Therapeutics, Inc., Mountain View, CA, USA, a neutropenic mouse thigh model and mouse sepsis models of infection were used to evaluate levofloxacin activity against a P. aeruginosa isolate that over expresses the MexAB-OprM efflux pump. Researchers demonstrated that in the mouse sepsis model, levofloxacin activity was potentiated by adding the pump inhibitor MC-04, 124, and that levofloxacin ED₅₀ (50% effective dose, or the dose associated with 50% survival at 72 hr) dropped from 100 mg/kg to 46 mg/kg. This was approximately a two-fold reduction in ED₅₀.

In the neutropenic mouse thigh infection model, the addition to 30 mg/kg levofloxacin of MC-04, 124 was associated with increased bacterial killing of P. aeruginosa (Figure 2). This combination treatment was more effective than 60 mg/kg levofloxacin alone, indicating at least a 2-fold increase in activity. The use of levofloxacin plus efflux pump inhibitors, while still in the preclinical stage, may ultimately prove to be useful in the clinical setting.

Cardiovascular Safety Results Updated

A report by Dr. Gary J. Noel, et al., The Robert Wood Johnson Pharmaceutical Research Institute, Raritan, NJ, USA, added further clarification of the effect of individual fluoroquinolones on QTc interval. It was noted that levofloxacin, ciprofloxacin and moxifloxacin have been used widely with only rare reports of dysrhythmias developing. However, it was seen as necessary to confirm this in a healthy volunteer study, which looked carefully at any changes in QTc interval. A double blind, randomized, crossover study was performed with subjects given 1,000 mg levofloxacin, 1,500 mg ciprofloxacin and 800 mg moxifloxacin. Another study was carried out investigating different doses of levofloxacin (500 mg, 1,000 mg, and 1,500 mg). The mean change in QTc after infusion of the agent was -1.25 for placebo, 3.88 for levofloxacin, 2.27 for ciprofloxacin and 16.34 for moxifloxacin. The difference in mean QTc change, maximum QTc change, and QTc change at T_max from baseline for levofloxacin and ciprofloxacin compared to moxifloxacin were significant (p < 0.001). The difference between levofloxacin and ciprofloxacin was not significant. In the dose escalation levofloxacin study, the mean change in QTc from baseline was -0.69, 1.36, 2.81 and 6.89 msec for placebo, 500 mg, 1,000 mg and 1,500 mg doses, respectively. Thus, the researchers concluded that QTc prolongation was noted and was significantly greater after an 800 mg dose of moxifloxacin than after 1,000 mg levofloxacin or 1,500 mg ciprofloxacin. At present the clinical relevance of these differences is not known, but would tend to indicate greater cardiac safety for levofloxacin and ciprofloxacin compared to moxifloxacin.

2001 Resistance Trends Confirm Levofloxacin Maintaining Excellent Activity

There is always a great deal of interest in the latest TRUST (Tracking Resistance in the United States Today) surveillance results, with these now building up a longitudinal database allowing interpretation of ongoing trends. One of the most important results were those concerning multidrug-resistant pneumococci covering the 19972001 period, reported by Dr. Laurie J. Kelly, et al., Focus Technologies Inc., Herndon, WA, USA and Hilversum, The Netherlands, and Ortho-McNeil Pharmaceutical, Raritan, NJ, USA. Agents tested included penicillin, ceftriaxone, azithromycin, trimethoprimsulfamethoxazole (TMPSMX), and levofloxacin. Isolates were analyzed to identify if they were single-drug resistant (SDR), double-drug resistant (DDR) or multidrug resistant (MDR). Results showed that while SDR decreased from 15.2% to 13.3% over this time, DDR (8.5% to 10.2%) and MDR (6.2% to 13.5%) rates both increased. The DDR and MDR isolates were identified across almost all geographic regions, and all specimen types and age groups. Researchers noted that in the latest 2001 results, 16.9% of Streptococcus pneumoniae demonstrated high-level resistance to penicillin, 27.5% were resistant to azithromycin and 28.1% resistant to TMPSMX. These levels indicated that therapeutic efficacy was not assured using these agents. In contrast, levofloxacin resistance was only 0.8% and had not increased significantly over the 19972001 period (Table 3). In addition, among the S. pneumoniae examined, levofloxacin was the least likely agent to be associated with phenotypes of SDR (< 2%), DDR (< 3%) or MDR (< 2%). Thus, of all the agents tested, levofloxacin consistently demonstrated the lowest prevalence of resistance, regardless of region, specimen type or patient age.

Evaluating the Role of Fluoroquinolones in Pediatric Infections

The use of fluoroquinolones in the pediatric population has been gaining momentum, with concerns over ADRs now reduced. Two randomized, open-label parallel-group single-dose multicenter Phase I trials using levofloxacin in children were performed by Dr. S. Chien and colleagues, The Robert Wood Johnson Pharmaceutical Research Institute, Raritan, NJ, USA. Subjects were enrolled if they were aged 6 months to 16 years with normal hepatic and renal function with a documented or presumed bacterial infection that had not already been treated with a fluoroquinolone. Subjects received a single intravenous dose of levofloxacin 7 mg/kg infused over 1 hour. Plasma samples were collected before administration and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24 hours in Study 1, and at 0, 1, 1.5, 2, 3, 4, 6, 10, 16 and 24 hours in Study 2. Forty pediatric patients of both sexes in five age groups were enrolled (0.52, 25, 510, 1012, 1216 years). Results supported the safety of levofloxacin with no serious ADRs reported. All of the reported adverse events were mild or moderate with the majority of ADRs not deemed to be related to levofloxacin. No children withdrew from the study due to unacceptable toxicity and there were no reports of joint-related problems. The pharmacokinetic parameters are listed in Table 4. These demonstrate that drug concentration versus time profiles were superimposable between the 0.52-year and 25-year age groups: between the 58- and 810-year age groups, and between the 1012- and 1216-year age groups. The peak levels attained and volume of distribution were similar for all age groups. As the age of the subjects increased, their clearance of levofloxacin decreased. This resulted in total systemic exposure (AUC) increasing with increasing age. Using steady state values, 5 mg/kg was recommended as the dose for all ages in urinary tract infection (UTI) and 10 mg/kg for CAP in all ages. These results provide a base for further investigations into the use of levofloxacin in selected pediatric patients with serious infections.