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Tarragona, Spain
Reus, Spain
Dr. Rello is chief of the Critical Care Department, Joan XXIII University Hospital. Dr. Mallol is Chairman of the Pharmacology Department, School of Medicine and Health Sciences, Universitat Rovira & Virgili.
Correspondence to: Jordi Rello, MD, PhD, Critical Care Department, Joan XXIII University Hospital, Carrer Mallafre Guasch 4, 43007 Tarragona, Spain; e-mail: jrello.hj23.ics{at}gencat.net
The goal of antimicrobial prescription in pneumonia is to achieve effective active drug concentrations that result in clinical cure while avoiding antibiotic-associated toxicity or emergence of resistances. Until recently, the in vitro susceptibility of microorganism was considered the reference aspect for antibiotic efficacy for pneumonia1 and defined the concept of appropriate therapy. Pinder et al2 emphasized that standard antimicrobial dosing regimens are based on research often performed decades ago and for the most part with patients who were not critically ill. At the present time, other factors and circumstances should be considered to achieve what we call appropriate, adequate, or optimal therapy for pneumonia and to determine what is the best dosing regimen for a specific patient.
Appropriate (or concordant) antimicrobial therapy is only based on the in vitro susceptibility of the organisms. Timely administration of appropriate antimicrobial therapy, particularly in the subset of patients with highest severity, is a crucial factor to improve survival and ensure prompt clinical resolution.34 However, a multicenter study5 demonstrated that despite appropriate therapy with glycopeptides, an increased attributable mortality occurred in patients with ventilator-associated pneumonia (VAP) due to methicillin-resistant Staphylococcus aureus (MRSA), compared with matched intubated control subjects without VAP-MRSA.
Therefore, adequate antimicrobial therapy should take in account the interaction between the bacterial pathogen and the antimicrobial agent at the minimal inhibitory concentration (MIC). Effective drug concentration levels at the infectious site (alveolar macrophages for intracellular organisms and epithelial lining fluid [ELF] for extracellular pathogens) are also required. Moreover, antimicrobials may exhibit significantly different behavior in the lung consistent with their hydrophilic or lipophilic characteristics.1 Lipophilic compounds (macrolides, fluoroquinolones, rifampin, or linezolid) may achieve higher levels in ELF, compared with hydrophilic agents (ß-lactams, aminoglycosides, or vancomycin) and are the only compounds able to accumulate in alveolar macrophages.
Optimal therapy for pneumonia should take in to consideration additional factors ahead of the in vitro susceptibility and penetration to the infectious site. For example, several studies67 suggest that combination therapy with a macrolide might be preferred above monotherapy with a ß-lactam or combination therapy with a fluoroquinolone in specific subsets of patients with severe community-acquired pneumonia, such as those with severe pneumococcal bacteremic episodes.
The determination of the best dosing regimen for specific patients is probably the most complex issue. To ensure optimal pharmacodynamic exposure at the infection site, we should prescribe higher doses than those traditionally recommended, and a loading dose should be considered. The maximal bacterial burden and individual patients’ conditions, such as an enhanced renal blood flow or an increased volume of distribution in hyperdynamic patients, who are receiving mechanical ventilation or have severe sepsis, may lead to underdosing.
The most recent advances in research on pneumonia are focusing on improving our understanding of the patterns of clinical resolution, and many opportunities exist to improve resolution and reduce clinical failure. Ensuring clinical cure and prevention of resistance to the antimicrobial agents should take in account the pharmacokinetic/pharmacodynamic (PK/PD) characteristics of the agents. Therefore, different dosing regimens may be preferred for time-dependent agents (eg, vancomycin) compared with concentration-dependent agents (eg, fluoroquinolones). Finally, the presence of postantibiotic effect in some agents is another factor influencing the prescription regimen.
Clinical failures and mortality rates of patients with S aureus pneumonia treated with vancomycin have been consistently reported > 50%.8 A key PK/PD determinant of outcome is the percentage of time that the drug levels in the alveolar space exceed the MIC (time greater than MIC), and this can be optimized using continuous infusion.5 The area under the 24-h curve (AUC) to MIC dosing is a second key element.9 One possible option to ensure an adequate AUC-MIC value is to increase the dose of vancomycin, although this decision might be associated with higher rates of ear and kidney toxicity.
Among patients with community-acquired staphylococcal pneumonia,10 clinical and bacteriological responses were best when the area under the inhibitory curve (AUIC, a surrogate for AUC-MIC) was > 400. A second study11 that involved 70 patients, including 35 patients with MRSA, reported a success rate of 76% for episodes with AUIC > 345 and only 22% for AUIC < 345. Therefore, some researchers12 have suggested that the dose of vancomycin should be adjusted to reach these values. Moreover, in some cases, concentrations needed for effective therapy should be considerably higher because of the effect of protein binding, increase in volume of distribution in hyperdynamic patients with severe sepsis, presence of some virulence factors, or a high bacterial inoculum.
In this scenario, metaanalyses1314 concluded that linezolid was superior to vancomycin for therapy of MRSA pneumonia. Differences in MIC, tissue penetration, or the degree of protein binding may explain these discrepancies. In addition, the label dose of vancomycin administered in the trials might be suboptimal,2 and many experts have advocated that when increasing the dose, the differences in outcome might not be significant.
In this context, the study by Kollef et al15 in this issue of CHEST (see page 947) adds an additional piece to the puzzle of the best antimicrobial therapy.1 Their findings suggest that time to apyrexia was shorter in the AUIC > 400 group. However, a disappointing finding was that greater vancomycin trough concentrations failed to increase the hospital survival of patients with health-care associated pneumonia.
Efforts to improve survival in patients with MRSA pneumonia should concentrate on alternative agents to glycopeptides rather than in adjusting what is the best antimicrobial dose. In our opinion, the challenge to define what is optimal therapy for MRSA pneumonia should focus as a target in the 5% attributable mortality associated with methicillin-sensitive S aureus VAP treated with ß-lactams. This should be the objective of the ongoing clinical trials for MRSA pneumonia with newer agents with strong anti-MRSA activity such as tigecycline, ceftobiprole, telavancin, iclaprim, or garenoxacin.
Footnotes
Supported in part by FISS05/2410 and CIRIT SGR-05/920.
Dr. Rello has served in the Speakers Bureau and is a consultant for Pfizer, Wyeth Pharmaceuticals, Arpida, Basilea, Johnson & Johnson, and Schering Plough, and he has received research grants from Lilly and Pfizer.
References
This article has been cited by other articles:
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  L. Vidaur, K. Planas, R. Sierra, G. Dimopoulos, A. Ramirez, T. Lisboa, and J. Rello Ventilator-Associated Pneumonia: Impact of Organisms on Clinical Resolution and Medical Resources Utilization Chest, March 1, 2008; 133(3): 625 - 632. [Abstract] [Full Text] [PDF]
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R. G. Hall II and B. Adams-Huet Vancomycin Dosing for Methicillin-Resistant Staphylococcus aureus Nosocomial Pneumonia Chest, September 1, 2007; 132(3): 1100 - 1101. [Full Text] [PDF]
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