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MEDICAL FRONTIERS - 21st European Congress of Clinical Microbiology and Infectious Diseases/ 27th International Congress of Chemotherapy

Milan, Italy / May 7-10, 2011

Rationale for Early Discharge

One approach to improving methicillin-resistant Staphylococcus aureus (MRSA) outcomes is adoption of early outpatient therapy. Most patients do not require intravenous (i.v.) antibiotics, and those who do will normally only need them for 24 to 48 hours, stated Dr. Matthew Dryden, Department of Microbiology and Communicable Disease, Royal Hampshire Hospital, Winchester, UK, during the ECCMID/ICC scientific sessions.

Indications for commencing or continuing i.v. antimicrobial therapy are significant sepsis, compromised oral route (i.e. vomiting, severe diarrhea), a deteriorating clinical condition, a rising white cell count or C-reactive protein, positive blood cultures with a significant organism in the past 24 hours, a specific indication for i.v. therapy (e.g. meningitis, S. aureus bacteremia) and no available oral formulation.

In a study of MRSA-associated soft tissue infection cited by Dr. Dryden, the mean duration of i.v. therapy was significantly shorter in patients treated with linezolid compared to those treated with vancomycin. A shorter duration of therapy has economic consequences, as leaving the hospital earlier and management outside the hospital can reduce costs, he remarked.

Early discharge could be a better approach for managing infection, affirmed Dr. Dryden. Patients prefer to be at home where they feel less isolated socially and have greater control over their condition and their therapy. Additionally, home therapy carries less risk of contracting or transmitting infection. The number of bed days saved and the number of days of i.v. lines saved with early discharge could represent significant cost savings.

In the Going Home study (Glycopeptides to Oral Treatment at Home) carried out at the Hammersmith Hospitals in London, UK, 155 patients on an i.v. glycopeptide were either discharged on an oral antibiotic (n=64) or stayed in the hospital to receive treatment (n=91). Seventeen patients in the latter group were switched to oral therapy. The 1215 days of outpatient treatment in the group discharged represent the number of bed days saved. Switching to oral therapy in the hospital saved 511 days of i.v. therapy (Figure 1).

Figure 1.

An audit tool to assess patients on antibiotic therapy and whether they could be discharged from the hospital safely on antibiotics (oral or i.v.) could result in significant financial benefits, Dr. Dryden told delegates. Among 1356 patients reviewed in acute medical and surgical wards in 6 hospitals, 99 of 429 patients on antibiotics had them discontinued after an assessment, including 26 on i.v. antibiotics. Of 139 who remained on i.v. antibiotics, 47 (34%) could be switched to oral therapy. Eighty-nine (20%) of the 429 patients were recommended for discharge; of these, 10 required outpatient i.v. therapy, 55 required oral outpatient therapy and 24 had their antibiotics stopped.

If patients recommended for discharge were discharged on the day of their review, 481 bed days could have been saved, yielding a savings of £120,450 (approximately CAD$190,294).

An economic analysis delivered in a poster session here estimated the cost savings from using an evaluation tool to assess suitability for early discharge from hospital wards to be £170,000 (about $268,569). The evaluation tool used bedside review of antibiotic use and infection management in acute medical and surgical patients in 30 acute wards across the UK.

Of 291 patients on antibiotics, 82 were judged to be suitable for discharge: 54 on oral antibiotics and 28 on i.v. antibiotics. Thirty-six of the 54 on oral antibiotics and 6 of 28 on i.v. could stop therapy, and 18 more on i.v. antibiotics could switch to oral, reported Dr. Dryden and Prof. Alastair Gray, Health Economics Research Centre, University of Oxford, UK.

Implementing these recommendations would have reduced the number of in-patient days by 494, saving £186,731 (about $294,993). Offsetting this in-patient saving with costs of assessment, extra community support, and outpatient therapy yielded a net savings of £170,198 (about $268,888).

Re-evaluating MRSA Pneumonia Therapies

In the US, hospital-acquired pneumonia (HAP) is the second most common of all nosocomial infections (~15%) and the most common in the ICU (~30%). An estimated 10% to 15% of all HAP are caused by MRSA.

Once considered the mainstay of anti-staphylococcal treatment in hospitals, “vancomycin should no longer be considered the gold standard for gram-positive resistant infections,” Prof. Robert Masterton, NHS Ayrshire & Arran, Hampshire, UK, told ECCMID/ICC delegates.

He called attention to a possible vancomycin minimum inhibitory concentration (MIC) creep against both MRSA and methicillin-sensitive S. aureus reported at some institutions, based on an increased frequency of isolates for which MICs are elevated. Such an elevation in MICs would infer a loss of activity. Although a vancomycin MIC creep (using geometric mean MIC) has not been confirmed, increased MICs are a consistent predictor of mortality in MRSA-associated HAP, ventilator-associated pneumonia and health care-associated pneumonia (HCAP), “starting at levels below those considered resistant,” stated Prof. Masterton.

“We have spent time in the past decade trying to adjust vancomycin to make it more effective,” he remarked, but achieving lower vancomycin MICs has proven difficult and higher trough levels has resulted in a significant increase in nephrotoxicity.

The latest guidelines from the Infectious Diseases Society of America (IDSA) for the treatment of MRSA (Clin Infect Dis 2011;52:e18-55) recommend empiric therapy for hospitalized patients with severe community-acquired pneumonia (CAP), noted Prof. Hartmut Lode, Research Centre for Medical Studies, Charité University School of Medicine, Berlin, Germany.

In pneumonia, optimal therapy must provide pathogen coverage and must be initiated in a timely fashion, using the correct route and the correct dose, he explained. Optimal pharmacodynamic exposure should be ensured at the infection site (i.e. epithelial lining fluid and alveolar macrophages in the case of pneumonia).

The choices for MRSA HCAP or CAP in the IDSA guidelines are i.v. vancomycin, i.v. or oral linezolid, or i.v. or oral clindamycin for 7 to 21 days. These guidelines support 2008 guidelines from the British Society for Antimicrobial Chemotherapy in which empiric therapy with linezolid and high-dose clindamycin is recommended if risk assessment suggests the possibility of community-acquired MRSA.

In the double-blind ZEPHyR study, 448 patients with culture-positive MRSA-severe HCAP were more likely to be successfully treated or cured within 7 to 30 days after treatment with linezolid compared to vancomycin (57.6% vs. 46.6%, P=0.042), reported Prof. Jean Chastre, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.

In MRSA HCAP, clinical success is at least equal and microbiologic success is greater with linezolid compared to vancomycin, reported Dr. Daniel Kett and colleagues, Miller School of Medicine, University of Miami, Florida, in a poster session here at ECCMID/ICC.

78 patients with HCAP and culture-proven MRSA received at least 1 dose of either agent in a double-blind, randomized study. Cure rates at the end of the study were 57% in the linezolid group and 44% in the vancomycin group, a difference that was not statistically significant. However, microbiologic success at the end of treatment and at the end of study was significantly greater: 81% vs. 64% and 66% vs. 3
re 2).

Figure 2.

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Pharmacodynamic Principles for Therapy Optimization

Emergence of multidrug-resistant pathogens is a worldwide problem for gram-positive and gram-negative pathogens that cause infection in the hospital. Two challenges in managing patients with complicated infections are selecting the most appropriate antimicrobial agent and managing antibiotic usage to reduce the prevalence of drug-resistant infections.

Early treatment and therapy optimization using pharmacodynamic principles is crucial to improving the probability of positive outcomes, noted Prof. Francesco Scaglione, Department of Pharmacology, University of Milan, Italy. For example, with some drug classes (i.e. aminoglycosides), higher maximum concentration (C_max):peak MIC ratio is associated with higher response rates. For beta-lactam antibiotics, continuous infusion may be the optimal method of administration to maintain drug concentrations above the MIC.

In the case of vancomycin, increasing MIC values in MRSA clinical isolates makes optimizing its dose critical to its continued use. An area under the curve (AUC):MIC ratio >400 has been shown to improve the likelihood of successful outcomes, but even high-dose infusion cannot always achieve adequate AUC:MIC ratios depending on renal function, explained Prof. Scaglione.

In critically ill patients with varying degrees of organ dysfunction, optimal pharmacodynamics parameters target AUC:MIC ratio for fluoroquinolones, linezolid, daptomycin and tigecycline; for aminoglycosides, it is the Cmax:MIC ratio, and for beta-lactam antibiotics, it is the time above the MIC.

Intra-abdominal Infections

The development of resistance in the past 15 years in intra-abdominal infections has paralleled an increase in mortality from these infections. High-risk complicated intra-abdominal infections implies patients with a high risk of treatment failure and a high risk of the isolation of resistant pathogens. Inappropriate empiric therapy carries an increased risk of mortality that cannot be reversed by subsequent modification of the regimen, affirmed Dr. Christoph Wenisch, Department of Infectious Disease and Tropical Medicine, Kaiser-Franz-Josef Hospital, Vienna, Austria.

The criteria for selection of an antimicrobial agent for complicated intra-abdominal infections include tissue penetration, the susceptibility profile of the local population, guideline recommendations (used only as a framework; must be tailored to the patient’s needs) and antibiotic stewardship protocols.

In the setting of multidrug-resistant MRSA, IDSA guidelines suggest linezolid, daptomycin, tigecycline and vancomycin as options. Empiric therapy is recommended for health care-acquired intra-abdominal infections colonized with MRSA or a suspicion of MRSA based on treatment failure and significant antibiotic exposure.

Complicated Infections

For patients with Staphylococcus-associated deep tissue infections or organisms that are not very susceptible, more aggressive dosing regimens of vancomycin to keep trough levels higher and to achieve a higher AUC:MIC ratio are being recommended as tolerance and resistant organisms emerge. However, even these aggressive measures do not ensure good clinical outcomes and increase the risk of toxicity, necessitating consideration of other anti-staphylococcal drugs for use in complicated infections.

In the treatment of MRSA complicated skin and skin structure infections (cSSSIs), linezolid appears to offer an advantage in the subset of patients with vascular disease, according to Dr. Therèse M. Duane, Medical College of Virginia, Richmond. Her pooled analysis of 2 prospective clinical trials of 477 patients with lower-extremity MRSA-cSSSI showed significantly higher rates of clinical success at study end with linezolid (600 mg i.v. or orally q 12 h) vs. vancomycin (15 mg/kg or 1 g i.v. q 12 h) in patients with vascular disease: 80.4% with linezolid vs. 66.7% with vancomycin (P=0.02). In the overall cohort, vascular disease and treatment with vancomycin were predictors of clinical failure at study end. Among the subset with vascular disease, treatment with vancomycin and prior hospitalization were predictors of clinical failure at study end.

In a post hoc analysis of a prospective, open-label randomized study, time to resolution of signs of inflammation was not different between linezolid- and vancomycin-treated patients with confirmed MRSA cSSSI, as presented by Dr. Alan D. Tice, Infections Limited Hawaii, Honolulu, in an ECCMID/ICC poster session.

In the study, 640 patients were randomized to oral or i.v. linezolid (600 mg q 12 h) or i.v. vancomycin (15 mg/kg q 12 h with dose adjustment based on trough levels and creatinine clearance). Resolution of fever, erythema, induration, purulent discharge, pain, swelling, tenderness and warmth was not significantly different between treatment groups at either day 3 or day 7, in patients with or without diabetes.

There is no escalation of resistance to linezolid as determined by susceptibility testing of gram-positive isolates collected from European medical centres, reported Dr. Ronald Jones, JMI Laboratories, North Liberty, Iowa. Among the 5532 gram-positive organisms collected, linezolid
and the overall resistance rate was 0.05% (Table 1).

Table 1.

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Summary

MRSA infection in hospitals presents a major clinical challenge. Appropriate antibiotic therapy, reducing the duration of hospital stay and controlling the costs of treatment are now important factors that influence clinical choices. As such, an appropriate management strategy can include early discharge from the hospital, including options for a switch from i.v. to oral therapy for infections due to MRSA. The management of complicated infections in the hospital has grown more challenging since the emergence of multidrug-resistant pathogens, necessitating early treatment and therapy optimization using pharmacodynamic principles to improve the probability of successful outcomes.