Optimal Dose

As the literature regarding the treatment of infections in the ICU has evolved over the years, studies have identified several elements that influence the dose of an antibiotic that is most likely to result in the best clinical efficacy. The manner in which antibiotics kill bacteria varies among different classes of drugs, but the two pharmacodynamic categories of killing that have been best categorized are time-dependent killing and concentration-dependent killing.¹¹ In time-dependent killing, also referred to as concentration-independent killing, maximum bacterial killing occurs when the drug concentration remains above the minimal inhibitory concentration (MIC). Examples of antibiotics that demonstrate time-dependent killing include β-lactam antibiotics (i.e., penicillins, cephalosporins, carbapenems, and monobactams) and vancomycin. Conversely, in concentration-dependent killing, maximum bacterial killing occurs when the peak drug concentration is approximately 10 times the MIC. Examples of agents with concentration-dependent killing are fluoroquinolones and aminoglycosides. The relevance of such antibiotic properties in the management of patients with serious infections has been well demonstrated.

The pharmacologic properties of vancomycin have been nicely summarized, emphasizing the fact that vancomycin exhibits time-dependent killing.¹² Accordingly, the length of time that concentrations of vancomycin are maintained above the pathogen’s MIC is critical to bacterial eradication, with a key variable in the treatment of pneumonia being the percentage of time that drug levels in the alveolar space exceed the MIC. As drug levels decline, organisms have the potential to regrow, increasing the chance of clinical failure. The clinical relevance of this pharmacologic principle may support the development of the practice habit of more frequent (every 6 hours) or continuous-infusion vancomycin dosing for infections like pneumonia in which vancomycin penetration to the target site may not be optimal.

Because a goal with time-dependent antibiotics is to maintain levels above the MIC of the organism for as long as possible during the dosing cycle, research has explored extended-infusion dosing of several time-dependent agents, including β-lactam antibiotics and vancomycin. In a study of 194 patients with infection caused by Pseudomonas aeruginosa, piperacillin-tazobactam was administered intravenously either every 4 to 6 hours over 30 minutes or every 8 hours over 4 hours.¹³ The 14-day mortality rate was significantly lower among patients who received extended-infusion therapy than among patients who received intermittent-infusion therapy (12.2% versus 31.6%, respectively; P = 0.04). In another study designed to assess blood levels of antibiotic based on both dose and pattern of administration, meropenem was administered to two study groups, each with eight healthy volunteers.¹⁴ One group received 500 mg as an intravenous infusion over 30 minutes three times a day or a 250-mg loading dose followed by a 1500-mg continuous infusion over 24 hours; the second group received 1000 mg as an intravenous infusion over 30 minutes three times a day or a 500-mg loading dose followed by a 3000-mg continuous infusion over 24 hours. Investigators performed pharmacokinetic calculations and used Monte Carlo simulations for 10,000 simulated subjects. The results of the analyses of the probability of MIC attainment with the high dose were 4 mg/L with continuous infusion and 0.5 mg/L with intermittent infusion. With the low dose, results were 2 mg/L with continuous infusion and 0.25 mg/L with intermittent infusion. Such data emphasize that intermittent infusion of a low dose of a time-dependent drug may result in MICs adequate to treat relatively sensitive organisms such as Klebsiella pneumoniae but may result in less-than-optimal killing of organisms that have intrinsically higher MICs (for example, P. aeruginosa). Other reports have explored the efficacy of continuous-infusion vancomycin.^15,16 A systematic review and meta-analysis suggests that extended or continuous infusion of carbapenems or piperacillin/tazobactam may be associated with lower mortality.¹⁷

The postantibiotic effect (PAE), in which microbial killing persists despite loss of detectable serum levels, complements the concentration-dependent killing of gram-negative bacilli exhibited by aminoglycosides, and these two properties may serve as the basis for once-daily aminoglycoside therapy.¹⁸ It has been suggested that giving the same total dose in larger concentration less often will result in better killing, longer PAE period, and reduced aminoglycoside toxicity that has been associated with elevated trough levels. Such pharmacologic and clinical data were the foundation for the move toward once-daily aminoglycoside dosing.

In such a dosing schedule, the single doses of gentamicin or tobramycin that have been used once daily have included 5 mg/kg and 7 mg/kg of body weight. The experience with once-daily therapy using 7 mg/kg in 2184 adult patients has been reported.¹⁹ Excluded from such therapy were patients with ascites, burns involving greater than 20% total body surface area, pregnancy, end-stage renal disease requiring dialysis, and enterococcal endocarditis. The review stated that it was unnecessary to draw standard peak and trough samples and that monitoring could be completed by obtaining a single random blood sample between 6 and 14 hours after the start of an aminoglycoside infusion. The treating clinician could subsequently adjust the dosing interval in accordance with a provided nomogram. Several important observations were made in this large group of patients: (1) Despite the prolonged drug-free period, bacterial regrowth was not clinically evident; (2) no increase in either ototoxicity or nephrotoxicity was found; and (3) efficacy was promoted in a cost-effective manner.¹⁹ A meta-analysis evaluating the safety and efficacy of once-daily aminoglycosides in 1200 patients from 16 trials found no difference concerning efficacy and safety between single-dose and multiple-dose regimens.²⁰

To achieve optimal clinical benefits while minimizing the unintended consequences of selecting resistant bacteria, clinicians must simultaneously consider multiple variables when using concentration-dependent drugs in the treatment of serious infections. In a study of lower respiratory tract infections caused by P. aeruginosa, ciprofloxacin was administered intravenously as a dose of 200 to 300 mg every 12 hours.²¹ Resistance emerged at a rate greater than 70% during therapy. This was similar to the 75% rate predicted by a pharmacodynamic study.²² By contrast, a randomized comparison of imipenem and ciprofloxacin for treatment of nosocomial pneumonia used a ciprofloxacin regimen of 400 mg given intravenously every 8 hours and noted emergence of resistance during therapy in 33% of cases in which Pseudomonas was the causative pathogen.²³ This rate was similar to the 38% predicted by the pharmacodynamic study previously cited.²² These data emphasize the importance of considering not only the dosing interval but also the dose of antibiotic administered when using concentration-dependent antibiotics to treat infections in the critically ill.

In addition to dosing interval and initial dose, antibiotic clearance plays an integral role in adequacy of antibiotic therapy. Although it is routinely accepted that reductions in antibiotic dosing are appropriate in advancing acute kidney injury,²⁴ clinicians may fail to escalate drug administration in the increasingly reported clinical phenomenon of augmented renal clearance (ARC).²⁵ ARC is defined as the enhanced renal elimination of circulating solutes due to an increased creatinine clearance (CrCl > 130 mL/minute/1.73 m²). Prevalence of ARC is higher in burn,²⁶ major trauma,²⁷ traumatic brain injury,²⁸ and febrile neutropenic²⁹ ICU patients; however, it is difficult to traditionally recognize as derived estimates of glomerular filtration, such as the modification of diet in renal disease (MDRD) equation and Cockcroft-Gault (CG) formula are less accurate than direct measurement.³⁰ In 48 ICU patients with measured CrCl, Udy and colleagues demonstrated that CrCl values 130 mL/minute/1.73 m² or greater were associated with initial trough concentrations of β-lactams less than MIC in 82% (P < 0.001). Moreover, CrCl remained a significant predictor of subtherapeutic concentrations after multivariate analysis.³¹ ARC has importance in vancomycin dosing as well. Baptista and associates performed a prospective, single-center, observational cohort study of 93 consecutive septic patients in the ICU treated with vancomycin by continuous infusion after a weight-based loading dose. Investigators compared patients with and without ARC. A statistically significant correlation between subtherapeutic vancomycin serum concentration and ARC was observed in the first 3 days of treatment.³²

An interaction between renal clearance and hypoalbuminemia also plays a prominent role in pharmacokinetics. In fact, Ulldemolins and colleagues demonstrated that in critically ill patients with hypoalbuminemia, unbound flucloxacillin concentrations fell below concentrations necessary for treatment of methicillin-susceptible Staphylococcus aureus (MSSA) 4 hours after standard bolus infusions.³³ The combination of increased volume of distribution due to hypoalbuminemia combined with ARC presents a daily situation in which lower achieved antibacterial exposures could result in subtherapeutic dosing, particularly for time-dependent antibiotics.³⁴ Because accurate and timely drug exposure is necessary for optimal clinical benefit,³ ARC and associated factors like hypoalbuminemia must be identified to prevent subtherapeutic pharmacologic treatment.

Penetration at the Site of Infection: Tissue-Targeted Therapy

The importance of antibiotic pharmacokinetic properties has recently received heightened attention for the treatment of pneumonia caused by multidrug-resistant gram-positive cocci. Indeed, pulmonary pharmacokinetics underlie the findings that the use of linezolid for pneumonia caused by methicillin-resistant S. aureus (MRSA), when compared with vancomycin in traditional regimens, results in improved clinical outcomes.35–38 Understanding the relevance of pharmacokinetic properties will help the critical care physician navigate through the recent published literature for these infections.

Pulmonary pharmacokinetics specifically address the tissue penetration and distribution of antibiotics within the lung.³⁹ Early studies investigating antibiotic penetration in pulmonary infections occurring in the ICU were related to aminoglycosides and fluoroquinolones. Although aminoglycoside levels in the interstitium of the lung are acceptable, levels in pulmonary secretions reach a mean of only about 20% of the concomitant serum level.⁴⁰ By contrast, the concentrations of quinolones in lung tissue significantly exceed the concomitant serum concentrations, and levels in bronchial secretions also have been reported to exceed those in serum.⁴¹ Despite the fact that quinolones have better penetration into the lung and less potential for nephrotoxicity than aminoglycosides, available data show a trend toward improved survival in patients with VAP treated with an aminoglycoside-containing, but not with a quinolone-containing, combination.⁴² A concern with fluoroquinolones in combination therapy directed against gram-negative organisms is the selection of resistance, particularly in organisms such as P. aeruginosa, in which the resultant resistance may be to multiple classes of antibiotics.⁴³ Because of the coexistent potential for clinical efficacy and nephrotoxicity with aminoglycosides, some investigators have suggested, on the basis of clinical trials, discontinuation of the aminoglycoside after 5 days if the patient is improving.⁴⁴

Existing pharmacokinetic evidence reveals the extremely poor lung tissue penetration of vancomycin. Cruciani and associates investigated vancomycin pharmacokinetics in 30 human lung tissue sections after administration of a 1-g dose over 1 hour.⁴⁵ A comparison of serum-to-tissue concentration over the dosing interval was used to generate a graph allowing determination of a concentration ratio. Overall, the serum-to-lung tissue concentration ratio was determined to be 21%. Not surprisingly, investigation has confirmed even poorer penetration into epithelial lining fluid.⁴⁶ These data raise concern that the traditional dosing regimens of vancomycin (1 g given intravenously every 12 hours) and low target serum trough concentrations (5 to 10 µg/mL) will generate lung tissue concentrations below the MIC for S. aureus. The issues surrounding suboptimal vancomycin dosing are reflected in the 2005 published ATS/IDSA guidelines for treatment for adults with HAP, VAP, and HCAP, in which it was noted that retrospective pharmacokinetic modeling suggested that the vancomycin failures may be related to inadequate dosing. Because of these concerns the authors recommend that trough levels for vancomycin should be 15 to 20 µg/mL.¹⁰ This recommendation of intensified vancomycin dosing is supported in a joint vancomycin clinical guideline for treating all complicated infectious caused by MRSA.⁴⁷

In contrast with the poor pulmonary pharmacokinetic properties of vancomycin, several studies of linezolid confirm excellent lung penetration in healthy volunteer subjects and with in vitro modeling.48–50 Boselli and coworkers investigated the steady-state plasma pharmacokinetic variables and epithelial lining fluid concentrations of linezolid administered to critically ill patients with VAP.⁵¹ Epithelial lining fluid concentrations of linezolid approximated 100% of corresponding plasma values, with drug concentrations that exceeded the susceptibility breakpoint (4 mg/mL) for S. aureus throughout the greater part of the dosing interval. The principle of antibiotic pharmacokinetics has supported the conclusion that linezolid is superior to vancomycin in traditional dosing regimens for MRSA pneumonia based on retrospective analysis of the two multinational, double-blind, randomized studies published to date.³⁸ A subsequent randomized, controlled clinical trial of linezolid versus vancomycin in the treatment of nosocomial pneumonia favored linezolid; furthermore, a subgroup analysis of this investigation did not suggest a benefit in those patients with vancomycin troughs of 15 mg/L or more on day 3.⁵²

In light of the difficulty in achieving adequate drug levels in pulmonary tissue, many clinicians consider the use of topical, aerosolized antibiotics to deliver drug directly to the site of infection. The agents most commonly employed in this manner are tobramycin and colistin.⁵³ Most of our experience with, and evidence supporting, nebulized tobramycin originates from small studies and meta-analyses assessing the utility of these agents in the management of chronic respiratory disease such as cystic fibrosis, not in the treatment of acute infection.⁵⁴ Although the risk of toxicity appears lower with the administration of nebulized tobramycin, certain populations, such as those with renal insufficiency, may be at risk.⁵⁵ Because of the increasing prevalence of multidrug-resistant gram-negative organisms such as Acinetobacter baumannii and P. aeruginosa, clinicians have employed colistimethate via intravenous infusion⁵⁶ or aerosolization^57,58 as therapy for VAP and HAP. Intravenous colistimethate appears to be safe (with a risk of nephrotoxicity similar to that for intravenous aminoglycosides) and effective, though there are few randomized, controlled trials from which to draw firm conclusions; furthermore, the optimal dosing strategy is unclear.⁵⁹ Although the aerosolized route of colistimethate administration appears to be safe,⁶⁰ its efficacy has not been established.

Role of Combination Therapy

Immunomodulating Effect of Antibiotics

Although most classification schemes group antibiotics according to their chemical structure and spectrum of coverage, certain antibiotics may possess additional properties that have important clinical implications. The interaction of antibiotics with host immune response, bacterial population kinetics, and bacterial gene expression for exotoxin production are examples of the pleiotropic, or “off target,” properties of antibiotics. For the critical care physician, this is especially relevant in the treatment of life-threatening infection caused by gram-positive cocci and may be the basis for combination therapy in the treatment of infections caused by such pathogens.

Streptococcal toxic shock syndrome is a clinical infection in which bacteria produce exotoxins that act as host superantigens, precipitating shock, multiple organ failure, and death. Although Streptococcus pyogenes demonstrates exquisite in vitro sensitivity to penicillin, experimental studies of infection by this pathogen have demonstrated reduced efficacy against organisms in the stationary phase of bacterial growth. This phenomenon has been termed the Eagle effect, whereby high organism population density and slow organism division make treatment with an antibiotic dependent on cell wall synthesis ineffective.⁸⁰ Some cite the Eagle effect as a justification for use of the bacteriostatic antibiotic clindamycin in the treatment of toxic shock syndrome. In addition, clindamycin is an antibiotic that inhibits bacterial protein synthesis, and this pharmacodynamic property is independent of the stage of bacterial growth.⁸¹ Clindamycin inhibits bacterial exotoxin production, facilitates phagocytosis of S. pyogenes by inhibiting M protein synthesis, and suppresses the production of penicillin-binding proteins (PBPs). Furthermore, evidence exists that demonstrates clindamycin has immunomodulatory effects, suppressing monocyte synthesis of tumor necrosis factor-α (TNF-α).^82,83 All of these pleiotropic qualities have resulted in the recommendation for clindamycin use in necrotizing skin or soft tissue infections and toxic shock syndrome caused by S. pyogenes.⁸¹

The dramatic increase in the worldwide incidence of highly virulent, community-acquired infection with CA-MRSA has resulted in increasing reports of necrotizing skin and soft tissue infections as well as necrotizing pneumonia confronting the critical care physician.84–86 CA-MRSA virulence has been attributed to expression of several virulence factors: α-hemolysins (AH), toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxin B, and Panton-Valentine leukocidin (PVL). The association of staphylococcal virulence with the current CA-MRSA epidemic prompted Stevens and colleagues to investigate the impact of antibiotics on the expression of virulence-associated exotoxin genes.⁸⁷ These investigators were able to demonstrate markedly suppressed in vitro production of staphylococcal toxin genes by clindamycin and linezolid such that no PVL production was noted up to 12 hours after antibiotic administration. Of interest, subinhibitory concentrations of the cell wall–active agent nafcillin were found to increase toxin production. These findings led the investigators to conclude that the inhibition of protein synthesis is an important consideration in the selection of antimicrobial agents for treatment of serious infections caused by toxin-producing gram-positive cocci.⁸⁷

A growing body of evidence exists to support the benefit of macrolide therapy for bacteremic pneumonia caused by Streptococcus pneumoniae.88–96 Although multiple explanations have been proposed, efficacy appears to extend beyond the drug’s spectrum of antimicrobial activity. The macrolide class of antibiotics exerts a broad range of immunomodulatory effects, including suppression of harmful interleukin host responses and inhibition of neutrophil oxidant burst and degranulation.^88–90 These pleiotropic effects have received an increasing focus of attention and further illustrate how immune modulation influences recommendations for therapy in the intensive care setting.

Timing

The impact of the timing of antibiotic therapy has been addressed in several ways with regard to patients in the ICU. In an analysis based on 107 consecutive patients receiving mechanical ventilation and antibiotic treatment for VAP, Iregui and colleagues noted that 30.8% (33 of 107) received antibiotic treatment that was delayed for 24 hours or more after initially meeting diagnostic criteria for VAP; these patients were classified as having initially delayed appropriate antibiotic therapy (IDAAT).⁹⁷ Two major variables were identified in these patients with IDAAT: (1) a delay in writing an antibiotic order (in 75.8% of the cases); and (2) the presence of a bacterial species resistant to the initially prescribed antibiotic regimen (in 18.2%). The investigators found that hospital mortality rate was 69.7% for the patients with IDAAT, in contrast with only 28.4% for the patients without IDAAT (P < 0.01). An earlier study noted that, in patients with VAP, modification of the antibiotic regimen to cover pathogens based on the susceptibility report did not eliminate the increased mortality rate associated with inadequate empiric therapy.⁵ Acknowledgment of this finding was the basis for the statement that secondary modifications of an initially failing antibiotic regimen do not substantially improve the outcome for critically ill patients.⁹⁸ These results challenge the clinician to promptly order antibiotics that cover the involved pathogens even before culture results are available.

The importance of antibiotic timing in patients with community-acquired pneumonia was assessed in a retrospective cohort study of pneumonia in 18,209 Medicare patients.⁹⁹ In this trial, conducted in a random sample of inpatients 65 years of age or older with community-acquired pneumonia who had not received antibiotics as outpatients, the influence on clinical outcome was assessed for use of antibiotics prescribed according to standard guidelines published at the time of the analysis and not identification of pathogens isolated from the patients. Of the patients who received antibiotics within 4 hours of hospital arrival, 83.2% were prescribed a guideline-recommended regimen, in contrast with 71.8% of the patients who received antibiotics after 4 hours of arrival. The results of this analysis found an association between the administration of antibiotics within 4 hours of hospital arrival and a decrease in mortality rate and length of stay. The investigators postulated that antibiotics may interrupt or minimize the effects of the acute lung injury process that occurs as part of the systemic inflammatory response in patients with bacterial pneumonia.

The IDSA practice guidelines for management of adult patients with meningitis note the lack of prospective clinical data on the relationship of the timing of antimicrobial administration of antimicrobial agents to clinical outcome in patients with bacterial meningitis.¹⁰⁰ Data from a retrospective cohort study of 269 adult patients with community-acquired bacterial meningitis provide some insights into the timing of antibiotic therapy in the absence of definitive recommendations.¹⁰¹ Using these and other data, the IDSA acknowledged that evidence for definitive recommendations is inadequate and concluded that a reasonable assumption is to administer treatment for bacterial meningitis before the infection advances to a high level of clinical severity.¹⁰⁰ Referring to meningitis as a “neurologic emergency,” the guideline recommended that appropriate therapy for meningitis be initiated as soon as possible after the diagnosis is considered to be likely.¹⁰⁰ In support of the importance of prompt timing, this document also noted the potential in certain patients for administration of antibiotics before hospital admission if the patient initially presents outside the hospital.

For the critical care clinician, sepsis is a clinical entity in which adequate antibiotic therapy has been associated with improved clinical outcomes.2,3,7,8,79 In recognition of the importance of prompt therapy in influencing clinical outcomes in patients with sepsis, the 2008 Surviving Sepsis Campaign guidelines offered a specific recommendation regarding the timing of antimicrobial therapy for the septic patient: “Intravenous antibiotic therapy should be started as early as possible and within the first hour of recognition of septic shock and severe sepsis without septic shock. Appropriate cultures should be obtained before initiating antibiotic therapy but should not prevent prompt administration of antimicrobial therapy.”¹⁰²

Special Pharmacologic Properties

As the focus of antibiotic research has expanded beyond the characterization of in vitro properties for a particular agent, the importance of antibiotic performance at the in vivo target tissue level is becoming increasingly recognized. It was with the 2003 introduction of a novel antibiotic, daptomycin, for treatment of infections caused by resistant gram-positive cocci that the relevance of “organ-specific deactivation” initially was described.¹⁰³ Daptomycin is an intravenous cyclic lipopeptide with rapid, concentration-dependent killing and bactericidal activity against a broad spectrum of gram-positive cocci.^104–106 It demonstrates a unique mechanism of action, with calcium-dependent insertion into the phospholipid bacterial cell membrane. This results in cell depolarization via potassium efflux, causing disruption of DNA, RNA, and protein synthesis.¹⁰⁷

As a result of two multicenter, randomized controlled trials comparing it with penicillinase-resistant penicillin or vancomycin,¹⁰⁸ daptomycin, at a daily dose of 4 mg/kg (for patients with CrCl greater than 30 mL/minute), received U.S. Food and Drug Administration (FDA) approval for the treatment of complicated skin and soft tissue infections. A subsequent randomized, open-label trial investigated use of daptomycin in S. aureus bacteremia and endocarditis.¹⁰⁹ This trial prompted FDA approval of daptomycin for treatment of S. aureus bacteremia, including right-sided endocarditis, at a daily intravenous dose of 6 mg/kg.

Phase 3 clinical trials also were conducted for the treatment of community-acquired pneumonia in hospitalized patients. Despite daptomycin’s potent in vitro bactericidal activity against S. pneumoniae, clinical outcomes were disappointing and inferior to those with the comparator, ceftriaxone. Although daptomycin is known to exhibit poor penetration into epithelial lining fluid, the reason for treatment failure was not fully elucidated until Silverman and colleagues described a unique organ-specific inactivation process.¹⁰³ Daptomycin’s inactivation was linked to its mechanism of bactericidal action: calcium-dependent membrane lipid binding.^{103,107,110,111} Using a mouse model, investigators demonstrated drug sequestration and inactivation by binding to phospholipid vesicles that are found in pulmonary surfactant.¹⁰³ For this reason daptomycin is not considered an appropriate therapeutic agent for treatment of pneumonia, largely because of the presence of surfactant at the target tissue. This phenomenon appears to be unique to daptomycin¹⁰³ but raises the question of unrecognized organ-specific inactivation for other classes of antibiotics and other target organs.

Recent antibiotic developments have introduced the possibility of managing life-threatening infections with antimicrobial agents administered at a prolonged dosing interval. A long drug half-life (T_1/2) is conducive to completion of treatment courses in the outpatient setting and maximizes patient compliance. In the context of critical care, exploiting an antibiotic’s T_1/2 historically has been used in settings such as hemodialysis with end-stage renal disease. Less frequent antibiotic dosing diminishes the burden of intravenous access and increases the possibility of treatment outside an intensive care environment.

Mechanisms of Action and of Resistance

On the most fundamental level, an antibiotic must bind to a target site before the pharmacologic property that kills the organism can be invoked. As examples, β-lactams bind to PBPs to prevent synthesis of the bacterial cell wall, and fluroquinolones bind to DNA gyrase to prevent replication of the genetic elements required for bacterial replication. For an antibiotic to reach its target site, there must be penetration through the outermost part of the bacterial cell wall. Impermeability of those sites precludes the drug from getting to its target site. Once an antibiotic enters the outermost portion of the bacterial cell wall but before it binds to its target site, there are two potential mechanisms by which the drug can be precluded from having its effect: one is enzymatic destruction of the antibiotic; the other is extrusion of the drug from the bacteria via pumps referred to as efflux pumps. Because of the importance of enzymatic destruction and of efflux that leads to the drug resistance encountered in the critical care setting, these two mechanisms of action will be discussed in some detail. However, it is important to consider the importance of target-site binding and of impaired penetration because both of these mechanisms of resistance have practical implications for the clinician.

The Clinical Relevance for Understanding Antibiotic Resistance

An understanding of this concept takes on significance with the increasingly common problem in ICUs of the development of resistance to multiple antibiotics. Referred to as multidrug-resistant organisms, these pathogens may be the cause of clinical failure of antibiotic treatment if an inappropriate therapeutic regimen is used. A common mistake in clinical practice is to assume that the major predisposition to a pattern of resistance is the overuse of the broadest category of antibiotic to which a pathogen is resistant. Several examples are important in the understanding of this concept.

A classic example of multidrug resistance in gram-negative organisms is the resistance in P. aeruginosa. As previously noted, multiple resistance mechanisms regulated by genetic operons on the chromosomes of P. aeruginosa have been described, including efflux pumps, AmpC β-lactamases, and outer membrane porin closure.122,158 For infections such as HAP and VAP, in which P. aeruginosa is a pathogen targeted with empiric therapy and for which fluoroquinolones are offered as an option in the initial regimen,^10,15,159 data on the risk of fluoroquinolones leading to multidrug resistance via efflux mechanisms become especially noteworthy. Additionally, because of the ability of certain organisms such as P. aeruginosa to express multiple mechanisms of resistance, many experts recommend avoiding the use of traditional antipseudomonal agents (i.e., a pseudomonal-sparing regimen) when treating infections in which Pseudomonas is not a suspected pathogen, as the use of overuse these agents may result in the development of multidrug resistance in Pseudomonas isolates.¹⁴¹

The experience with carbapenem-resistant A. baumannii in Brooklyn, New York, provides an important insight into the problem of selection of resistance by one class of antibiotic to an entirely different class. In a study to evaluate the endemicity of A. baumannii, all unique patient isolates of this pathogen were collected from 15 Brooklyn hospitals over a 3-month period.¹⁵² Antibiotic susceptibilities, ribotyping, and the relationship between antibiotic use and resistance rates were determined. Among the 224 carbapenem-resistant strains of A. baumannii, ribotyping demonstrated that one strain accounted for two thirds of the isolates and was present in all of the 15 participating hospitals. The strongest predisposition to selection for this pathogen was cephalosporin use. Known A. baumannii resistance mechanisms include chromosomally associated β-lactamases and porin protein mutations,¹⁶⁰ so it can be assumed that this represents selection of carbapenem-resistant mutant strains by the cephalosporins.

A retrospective analysis of critically ill trauma patients with late-onset gram-negative pneumonia showed that the antibiotic most associated with pneumonia due to Stenotrophomonas maltophilia was cefepime.¹⁶¹ These data on cephalosporins as a risk factor for S. maltophilia infection are similar to those in an earlier report that identified use of ceftazidime and imipenem as associated with similar rates of S. maltophilia acquisition in hospitalized patients.¹⁶² The suggestion by these reports is that broad-spectrum agents, more so than one specific agent, may kill sensitive bacteria and allow pathogens such as Stenotrophomonas to become clinically expressed.

Decreasing Broadness or Number of Agents

Classically, there have been three ways that de-escalation can occur. The most intuitively understood is changing from a broad-spectrum agent to a narrower spectrum agent based on culture and sensitivity data. As is well known to those who practice in the intensive care setting, culture data are often negative in the sickest patients, and the option of de-escalating based on culture data is often not available. The de-escalating process becomes less clear when diagnostic studies do not yield an obvious pathogen. Perhaps an appropriate manner of employing the information gained by a negative culture is to allow the nonrecovery of certain organisms to influence the alteration of an existing regimen. HAP, including VAP, provides a clinically applicable example of this concept. In an attempt to minimize mortality rates, patients with HAP typically receive as empiric therapy a three-drug regimen that includes coverage against MRSA and P. aeruginosa. Guidelines of the ATS/IDSA for HAP have suggested that clinically improving patients not on antibiotics when cultures are obtained may have therapy against MRSA and P. aeruginosa stopped if sputum cultures are negative for these pathogens.¹⁰

A third technique for de-escalating is to shorten the duration of therapy.

Duration of Therapy

Because antibiotics may be a risk factor for resistance,¹²¹ it is important in the process of antibiotic stewardship to identify opportunities to minimize exposure to these therapeutic agents. One possibility is by decreasing the duration of therapy to the shortest duration necessary to achieve an optimal clinical outcome.¹⁶³ Often the decisions regarding traditional durations of therapy find their basis not in controlled trials or prospective studies, but rather in expert opinion. Although certain infections, such as S. aureus bacteremia, require well-defined and often prolonged durations of intravenous therapy,^164,165 trials in VAP have challenged some of the classic tenets and have resulted in recommendations for shorter durations of therapy when compared to the traditional regimens.

Dennesen and coworkers¹⁶⁶ evaluated the response to antimicrobial therapy administered according to ATS guidelines in 27 patients diagnosed with VAP in a study that initially used a bronchoalveolar lavage (BAL) along with clinical parameters to confirm the diagnosis of VAP but subsequently used semiquantitative tracheal aspirates for microbiologic surveillance. All patients in this study received appropriate antibiotic therapy. After initiation of antibiotic therapy, T_max (maximal temperature over a 24-hour period), PaO₂/FIO₂ (ratio used to quantify impairment of oxygen gas exchange in the lung), white blood cell count, and semiquantitative cultures of endotracheal aspirate were monitored. Resolution of clinical parameters occurred primarily within the first 6 days of therapy. Using cultures of endotracheal aspirates, the investigators found that colonization with P. aeruginosa persisted throughout the duration of treatment, whereas colonization with S. aureus, H. influenzae, and S. pneumoniae resolved shortly after initiation of therapy. Acquired colonization, predominantly with resistant pathogens such as P. aeruginosa or members of Enterobacteriaceae, usually occurred in week 2 and frequently preceded a recurrent episode of lung infection. On the basis of these data, it was suggested that 7 days may be an appropriate duration of therapy for patients with VAP.

Ibrahim and colleagues¹⁶⁷ evaluated a clinical guideline for the treatment of VAP using 7 days of therapy. A total of 102 patients were prospectively evaluated, 50 before institution of the guidelines and 52 after institution. In addition to more frequent choice of adequate initial antibiotic treatment after implementation of the clinical guideline, patients also had shorter antibiotic courses when treated under the guideline. No mortality rate difference was noted between the two groups. As was the case with the study by Dennesen and coworkers,¹⁶⁶ a second episode of VAP was more likely to occur in the patients receiving the longer, traditional duration of therapy.

Chastre and associates¹⁶⁸ conducted a prospective, multicenter, randomized, double-blind study of 401 patients with VAP confirmed by quantitative cultures obtained by bronchoscopic protected specimen brush (PSB) or BAL, or both. Only patients who had received initial appropriate antibiotic therapy were included. Therapy was divided into two categories: short course, which was given for 8 days in 197 patients, versus long course, which was given for 15 days in 204 patients. Clinical efficacy was similar between the short-course and long-course groups. Because slightly more patients with nonfermenting gram-negative bacilli (e.g., P. aeruginosa and A. baumannii) assigned to the 8-day regimen had pulmonary infection recurrences, the investigators were unable to demonstrate the noninferiority of the 8-day regimen for infection by such pathogens compared with the 15-day course of therapy. Multiresistant pathogens more frequently caused recurrences in patients who received the 15-day regimen. Even though the findings from this study do not definitively prove that therapy for HAP or VAP can be limited to 7 days, they lend support to the findings by Dennesen¹⁶⁶ and Ibrahim¹⁶⁷ and their colleagues.

1. Dellit, TH, Owens, RC, McGowan, JE, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007; 44(2):159–177.

2. Harbarth, S, Garbino, J, Pugin, J, et al. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. Am J Med. 2003; 115(7):529–535.

3. Ibrahim, EH, Sherman, G, Ward, S, et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000; 118(1):146–155.

4. Kollef, MH, Ward, S. The influence of mini-BAL cultures on patient outcomes: Implications for the antibiotic management of ventilator-associated pneumonia. Chest. 1998; 113(2):412–420.

5. Luna, CM, Vujacich, P, Niederman, MS, et al. Impact of BAL data on the therapy and outcome of ventilator-associated pneumonia. Chest. 1997; 111(3):676–685.

6. Rello, J, Gallego, M, Mariscal, D, et al. The value of routine microbial investigation in ventilator-associated pneumonia. Am J Respir Crit Care Med. 1997; 156(1):196–200.

7. Vallés, J, Rello, J, Ochagavía, A, et al. Community-acquired bloodstream infection in critically ill adult patients: Impact of shock and inappropriate antibiotic therapy on survival. Chest. 2003; 123(5):1615–1624.

8. Kumar, A, Ellis, P, Arabi, Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest. 2009; 136(5):1237–1248.

9. Kollef, MH. Inadequate antimicrobial treatment: An important determinant of outcome for hospitalized patients. Clin Infect Dis. 2000; 31(Suppl 4):S131–S138.

10. American Thoracic Society/Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and health care-associated pneumonia. Am J Respir Crit Care Med. 2005; 171(4):388–416.

11. Ebert, SC, Craig, WA. Pharmacodynamic properties of antibiotics: Application to drug monitoring and dosage regimen design. Infect Control Hosp Epidemiol. 1990; 11(6):319–326.

12. Bodi, M, Ardanuy, C, Rello, J. Impact of gram-positive resistance on outcome of nosocomial pneumonia. Crit Care Med. 2001; 29(4 Suppl):N82–86.

13. Lodise, TP, Jr., Lomaestro, B, Drusano, GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: Clinical implications of an extended-infusion dosing strategy. Clin Infect Dis. 2007; 44(3):357–363.

14. Krueger, WA, Bulitta, J, Kinzig-Schippers, M, et al. Evaluation by Monte Carlo simulation of the pharmacokinetics of two doses of meropenem administered intermittently or as a continuous infusion in healthy volunteers. Antimicrob Agents Chemother. 2005; 49(5):1881–1889.

15. Rello, J, Paiva, JA, Baraibar, J, et al. International conference for the development of consensus on the diagnosis and treatment of ventilator-associated pneumonia. Chest. 2001; 120(3):955–970.

16. Wysocki, M, Delatour, F, Faurisson, F, et al. Continuous versus intermittent infusion of vancomycin in severe staphylococcal infections: Prospective multicenter randomized study. Antimicrob Agents Chemother. 2001; 45(9):2460–2467.

17. Falagas, ME, Tansarli, GS, Ikawa, K, Vardakas, KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: A systematic review and meta-analysis. Clin Infect Dis. 2013; 56(2):272–282.

18. Vogelman, B, Craig, WA. Kinetics of antimicrobial activity. J Pediatr. 1986; 108(5 Pt 2):835–840.

19. Nicolau, DP, Freman, CD, Belliveau, PP, et al. Experience with a once-daily aminoglycoside program administered to 2,184 adult patients. Antimicrob Agents Chemother. 1995; 39(3):650–655.

20. Galloe, AM, Graudal, N, Christensen, HR, Kampmann, JP. Aminoglycosides: Single or multiple daily dosing? A meta-analysis on efficacy and safety. Eur J Clin Pharmacol. 1995; 48(1):39–43.

21. Peloquin, CA, Cumbo, TJ, Nix, DE, et al. Evaluation of intravenous ciprofloxacin in patients with nosocomial lower respiratory tract infections. Impact of plasma concentrations, organism, minimum inhibitory concentration, and clinical condition on bacterial eradication. Arch Intern Med. 1989; 149(10):2269–2273.

22. Drusano, GL, Louis, A, Deziel, M, et al. The crisis of resistance: Identifying drug exposures to suppress amplification of resistant mutant subpopulations. Clin Infect Dis. 2006; 42(4):525–532.

23. Fink, MP, Snydman, DR, Niederman, MS, et al. Treatment of severe pneumonia in hospitalized patients: Results of a multicenter, randomized, double-blind trial comparing intravenous ciprofloxacin with imipenem-cilastatin. The Severe Pneumonia Study Group. Antimicrob Agents Chemother. 1994; 38(3):547–557.

24. Gilbert, B, Robbins, P, Livornese, LL, Jr. Use of antibacterial agents in renal failure. Infect Dis Clin North Am. 2009; 23(4):899–924.

25. Udy, AA, Roberts, JA, Boots, RJ, et al. Augmented renal clearance: Implications for antibacterial dosing in the critically ill. Clin Pharmacokinet. 2010; 49(1):1–16.

26. Conil, JM, Georges, B, Fourcade, O, et al. Assessment of renal function in clinical practice at the bedside of burn patients. Br J Clin Pharmacol. 2007; 63(5):583–594.

27. Cherry, RA, Eachempati, SR, Hydo, L, Barie, PS. Accuracy of short-duration creatinine clearance determinations in predicting 24-hour creatinine clearance in critically ill and injured patients. J Trauma. 2002; 53(2):267–271.

28. Udy, A, Boots, R, Senthuran, S, et al. Augmented creatinine clearance in traumatic brain injury. Anesth Analg. 2010; 111(6):1505–1510.

29. Lortholary, O, Lefort, A, Tod, M, et al. Pharmacodynamics and pharmacokinetics of antibacterial drugs in the management of febrile neutropenia. Lancet Infect Dis. 2008; 8(10):612–620.

30. Baptista, JP, Udy, AA, Sousa, E, et al. A comparison of estimates of glomerular filtration in critically ill patients with augmented renal clearance. Crit Care. 2011; 15(3):R139.

31. Udy, AA, Varghese, JM, Altukroni, M, et al. Subtherapeutic initial β-lactam concentrations in select critically ill patients: Association between augmented renal clearance and low trough drug concentrations. Chest. 2012; 142(1):30–39.

32. Baptista, JP, Sousa, E, Martins, PJ, Pimentel, JM. Augmented renal clearance in septic patients and implications for vancomycin optimisation. Int J Antimicrob Agents. 2011; 39(5):420–423.

33. Ulldemolins, M, Roberts, JA, Wallis, SC, et al. Flucloxacillin dosing in critically ill patients with hypoalbuminaemia: special emphasis on unbound pharmacokinetics. J Antimicrob Chemother. 2010; 65(8):1771–1778.

34. Ulldemolins, M, Roberts, JA, Rello, J, et al. The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients. Clin Pharmacokinet. 2011; 50(2):99–110.

35. Kollef, MH, Rello, J, Cammarata, SK, et al. Clinical cure and survival in gram-positive ventilator-associated pneumonia: Retrospective analysis of two double-blind studies comparing linezolid with vancomycin. Intensive Care Med. 2004; 30(3):388–394.

36. Rubinstein, E, Cammarata, S, Oliphant, T, et al. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: A randomized, double-blind, multicenter study. Clin Infect Dis. 2001; 32(3):402–412.

37. Wunderink, RG, Cammarata, SK, Oliphant, TH, et al. Continuation of a randomized, double-blind, multicenter study of linezolid versus vancomycin in the treatment of patients with nosocomial pneumonia. Clin Ther. 2003; 25(3):980–992.

38. Wunderink, RG, Rello, J, Cammarata, SK, et al. Linezolid vs. vancomycin: Analysis of two double-blind studies of patients with methicillin-resistant Staphylococcus aureus nosocomial pneumonia. Chest. 2003; 124(5):1789–1797.

39. Honeybourne, D. Antibiotic penetration into lung tissues. Thorax. 1994; 49(2):104–106.

40. Thys, JP, Klastersky, J, Mombelli, G. Peak or sustained antibiotic serum levels for optimal tissue penetration. J Antimicrob Chemother. 1981; 8(Suppl C):29–36.

41. Berre, J, Thys, JP, Husson, M, et al. Penetration of ciprofloxacin in bronchial secretions after intravenous administration. J Antimicrob Chemother. 1988; 22(4):499–504.

42. Fowler, RA, Flavin, KE, Barr, J, et al. Variability in antibiotic prescribing patterns and outcomes in patients with clinically suspected ventilator-associated pneumonia. Chest. 2003; 123(3):835–844.

43. Niederman, MS. Reexamining quinolone use in the intensive care unit: Use them right or lose the fight against resistant bacteria. Crit Care Med. 2005; 33(2):443–444.

44. Gruson, D, Hilbert, G, Vargas, F, et al. Rotation and restricted use of antibiotics in a medical intensive care unit. Impact on the incidence of ventilator-associated pneumonia caused by antibiotic-resistant gram-negative bacteria. Am J Respir Crit Care Med. 2000; 162(3 Pt 1):837–843.

45. Cruciani, M, Gatti, G, Lazzarini, L, et al. Penetration of vancomycin into human lung tissue. J Antimicrob Chemother. 1996; 38(5):865–869.

46. Lamer, C, de Beco, V, Soler, P, et al. Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients. Antimicrob Agents Chemother. 1993; 37(2):281–286.

47. Rybak, M, Lomaestro, B, Rotschafer, JC, et al. Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm. 2009; 66(1):82–98.

48. Conte, JE, Jr., Golden, JA, Kipps, J, Zurlinden, E. Intrapulmonary pharmacokinetics of linezolid. Antimicrob Agents Chemother. 2002; 46(5):1475–1480.

49. Honeybourne, D, Tobin, C, Jevons, G, et al. Intrapulmonary penetration of linezolid. J Antimicrob Chemother. 2003; 51(6):1431–1434.

50. MacGowan, AP, Alasdair, P. Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with gram-positive infections. J Antimicrob Chemother. 2003; 51(Suppl 2):17–25.

51. Boselli, E, Breilh, D, Rimmele, T, et al. Pharmacokinetics and intrapulmonary concentrations of linezolid administered to critically ill patients with ventilator-associated pneumonia. Crit Care Med. 2005; 33(7):1529–1533.

52. Wunderink, RG, Niederman, MS, Kollef, MH, et al. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: A randomized, controlled study. Clin Infect Dis. 2012; 54(5):621–629.

53. Wood, GC. Aerosolized antibiotics for treating hospital-acquired and ventilator-associated pneumonia. Expert Rev Anti Infect Ther. 2011; 9(11):993–1000.

54. Conway, SP. Nebulized antibiotic therapy: The evidence. Chron Respir Dis. 2005; 2(1):35–41.

55. Kahler, DA, Schowengerdt, KO, Fricker, FJ, et al. Toxic serum trough concentrations after administration of nebulized tobramycin. Pharmacotherapy. 2003; 23(4):543–545.

56. Montero, M, Horcajada, JP, Sorlí, L, et al. Effectiveness and safety of colistin for the treatment of multidrug-resistant Pseudomonas aeruginosa infections. Infection. 2009; 37(5):461–465.

57. Sabuda, DM, Laupland, K, Pitout, J, et al. Utilization of colistin for treatment of multidrug-resistant Pseudomonas aeruginosa. Can J Infect Dis Med Microbiol. 2008; 19(6):413–418.

58. Kofteridis, DP, Alexopoulou, C, Valachis, A, et al. Aerosolized plus intravenous colistin versus intravenous colistin alone for the treatment of ventilator-associated pneumonia: A matched case-control study. Clin Infect Dis. 2010; 51(11):1238–1244.

59. Imberti, R, Cusato, M, Villani, P, et al. Steady-state pharmacokinetics and BAL concentration of colistin in critically ill patients after IV colistin methanesulfonate administration. Chest. 2010; 138(6):1333–1339.

60. Rattanaumpawan, P, Lorsutthitham, J, Ungprasert, P, et al. Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by gram-negative bacteria. J Antimicrob Chemother. 2010; 65(12):2645–2649.

61. Moellering, RC, Jr., Wennersten, C, Weinberg, AN. Studies on antibiotic synergism against enterococci. I. Bacteriologic studies. J Lab Clin Med. 1971; 77(5):821–828.

62. Rahal, JJ, Jr. Antibiotic combinations: The clinical relevance of synergy and antagonism. Medicine. 1978; 57(2):179–195.

63. Korzeniowski, O, Sande, MA. Combination antimicrobial therapy for Staphylococcus aureus endocarditis in patients addicted to parenteral drugs and in nonaddicts: A prospective study. Ann Intern Med. 1982; 97(4):496–503.

64. Moellering, RC, Jr., Eliopoulos, GM. Principles of anti-infective therapy. In: Mandel GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. 6th ed. Philadelphia: Churchill Livingstone; 2005:242–253.

65. Hilf, M, Yu, VL, Sharp, JA, et al. Antibiotic therapy for Pseudomonas aeruginosa bacteremia: Outcome correlations in a prospective study of 200 patients. Am J Med. 1989; 87(5):540–546.

66. Lepper, MH, Dowling, HF. Treatment of pneumococcic meningitis with penicillin compared with penicillin plus aureomycin: Studies including observations on an apparent antagonism between penicillin and aureomycin. Arch Intern Med. 1951; 88(4):489–494.

67. Blot, SI, Vandewoude, KH, Hoste, EA, Colardyn, FA. Outcome and attributable mortality in critically ill patients with bacteremia involving methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Arch Intern Med. 2002; 162(19):2229–2235.

68. Cosgrove, SE, Sakoulas, G, Perencevich, EN, et al. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: A meta-analysis. Clin Infect Dis. 2003; 36(1):53–59.

69. Shorr, AF, Combes, A, Kollef, MH, Chastre, J. Methicillin-resistant Staphylococcus aureus prolongs intensive care unit stay in ventilator-associated pneumonia, despite initially appropriate antibiotic therapy. Crit Care Med. 2006; 34(3):700–706.

70. Shorr, AF, Tabak, YP, Gupta, V, et al. Morbidity and cost burden of methicillin-resistant Staphylococcus aureus in early onset ventilator-associated pneumonia. Crit Care. 2006; 10(3):R97.

71. Grohs, P, Kitzis, MD, Gutmann, L. In vitro bactericidal activities of linezolid in combination with vancomycin, gentamicin, ciprofloxacin, fusidic acid, and rifampin against Staphylococcus aureus. Antimicrob Agents Chemother. 2003; 47(1):418–420.

72. Sweeney, MT, Zurenko, GE. In vitro activities of linezolid combined with other antimicrobial agents against staphylococci, enterococci, pneumococci, and selected gram-negative organisms. Antimicrob Agents Chemother. 2003; 47(6):1902–1906.

73. Sahuquillo, AJM, Colombo, GM, Gil, BA, et al. In vitro activity of linezolid in combination with doxycycline, fosfomycin, levofloxacin, rifampicin, and vancomycin against methicillin-susceptible Staphylococcus aureus. Rev Esp Quimioter. 2006; 19(3):252–257.

74. Chiang, FY, Climo, M. Efficacy of linezolid alone or in combination with vancomycin for treatment of experimental endocarditis due to methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2003; 47(9):3002–3004.

75. Liu, C, Bayer, A, Cosgrove, SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011; 52(3):e18–55.

76. Paul, M, Benuri-Silbiger, I, Soares-Weiser, K, Leibovici, L. Beta lactam monotherapy versus beta lactam-aminoglycoside combination therapy for sepsis in immunocompetent patients: Systematic review and meta-analysis of randomised trials. BMJ. 2004; 328(7441):668–681.

77. Allan, JD, Jr. Antibiotic combinations. Med Clin North Am. 1987; 71(6):1079–1091.

78. Bliziotis, IA, Samonis, G, Vardakas, KZ, et al. Effect of aminoglycoside and beta-lactam combination therapy versus beta-lactam monotherapy on the emergence of antimicrobial resistance: A meta-analysis of randomized, controlled trials. Clin Infect Dis. 2005; 41(2):149–158.

79. Harbarth, S, Nobre, V, Pittet, D. Does antibiotic selection impact patient outcome? Clin Infect Dis. 2007; 44(1):87–93.

80. Eagle, H. Experimental approach to the problem of treatment failure with penicillin. I. Group A streptococcal infection in mice. Am J Med. 1952; 13(4):389–399.

81. Bisno, AL, Stevens, DL. Streptococcal infections of skin and soft tissues. N Engl J Med. 1996; 334(4):240–245.

82. Gemmell, CG, Peterson, PK, Schmeling, D, et al. Potentiation of opsonization and phagocytosis of Streptococcus pyogenes following growth in the presence of clindamycin. J Clin Invest. 1981; 67(5):1249–1256.

83. Stevens, DL, Bryant, AE, Hackett, SP. Antibiotic effects on bacterial viability, toxin production, and host response. Clin Infect Dis. 1995; 20(Suppl 2):S154–S157.

84. Francis, JS, Doherty, MC, Lopatin, U, et al. Severe community-onset pneumonia in healthy adults caused by methicillin-resistant Staphylococcus aureus carrying the Panton-Valentine leukocidin genes. Clin Infect Dis. 2005; 40(1):100–107.

85. Fridkin, SK, Hagerman, JC, Morrison, M, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005; 352(14):1436–1444.

86. Miller, LG, Perdreau-Remington, F, Rieg, G, et al. Necrotizing fasciitis caused by community-associated methicillin-resistant Staphylococcus aureus in Los Angeles. N Engl J Med. 2005; 352(14):1445–1453.

87. Stevens, DL, Ma, Y, Salmi, DB, et al. Impact of antibiotics on expression of virulence-associated exotoxin genes in methicillin-sensitive and methicillin-resistant Staphylococcus aureus. J Infect Dis. 2007; 195(2):202–211.

88. Baddour, LM, Yu, VL, Klugman, KP, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. Am J Respir Crit Care Med. 2004; 170(4):440–444.

89. Garcia Vazquez, E, Mensa, J, Martinez, JA, et al. Lower mortality among patients with community-acquired pneumonia treated with a macrolide plus a beta-lactam agent versus a beta-lactam agent alone. Eur J Clin Microbiol Infect Dis. 2005; 24(3):190–195.

90. Martinez, FJ. Monotherapy versus dual therapy for community-acquired pneumonia in hospitalized patients. Clin Infect Dis. 2004; 38(Suppl 4):S328–S340.

91. Martinez, JA, Horcajada, JP, Almela, M, et al. Addition of a macrolide to a beta-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia. Clin Infect Dis. 2003; 36(4):389–395.

92. Mufson, MA, Stanek, RJ. Bacteremic pneumococcal pneumonia in one American city: A 20-year longitudinal study, 1978-1997. Am J Med. 1999; 107(1A):34S–43S.

93. Mufson, MA, Stanek, RJ. Revisiting combination antibiotic therapy for community-acquired invasive Streptococcus pneumoniae pneumonia. Clin Infect Dis. 2006; 42(2):304–306.

94. Waterer, GW. Monotherapy versus combination antimicrobial therapy for pneumococcal pneumonia. Curr Opin Infect Dis. 2005; 18(2):157–163.

95. Waterer, GW, Somes, GW, Wunderink, RG. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Arch Intern Med. 2001; 161(15):1837–1842.

96. Weiss, K, Low, DE, Cortes, L, et al. Clinical characteristics at initial presentation and impact of dual therapy on the outcome of bacteremic Streptococcus pneumoniae pneumonia in adults. Can Respir J. 2004; 11(8):589–593.

97. Iregui, M, Ward, S, Sherman, G, et al. Clinical importance of delays in the initiation of appropriate antibiotic treatment for ventilator-associated pneumonia. Chest. 2002; 122(1):262–268.

98. Höffken, G, Niederman, MS. Nosocomial pneumonia: The importance of a de-escalating strategy for antibiotic treatment of pneumonia in the ICU. Chest. 2002; 122(6):2183–2196.

99. Houck, PM, Bratzler, DW, Nsa, W, et al. Timing of antibiotic administration and outcomes for Medicare patients hospitalized with community-acquired pneumonia. Arch Intern Med. 2004; 164(6):637–644.

100. Tunkel, AR, Hartman, BJ, Kaplan, SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004; 39(9):1267–1284.

101. Aronin, SI, Peduzzi, P, Quagliarello, VJ. Community-acquired bacterial meningitis: Risk stratification for adverse clinical outcome and effect of antibiotic timing. Ann Intern Med. 1998; 129(11):862–869.

102. Dellinger, RP, Levy, MM, Carlett, JM, et al. Surviving sepsis campaign: International guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008; 36(1):296–327.

103. Silverman, JA, Mortin, LI, VanPraagh, AD, et al. Inhibition of daptomycin by pulmonary surfactant: In vitro modeling and clinical impact. J Infect Dis. 2005; 191(12):2149–2152.

104. Fuchs, PC, Barry, AL, Brown, SD. In vitro bactericidal activity of daptomycin against staphylococci. J Antimicrob Chemother. 2002; 49(3):467–470.

105. King, A, Phillips, I. The in vitro activity of daptomycin against 514 gram-positive aerobic clinical isolates. J Antimicrob Chemother. 2001; 48(2):219–223.

106. Wise, R, Andrews, JM, Ashby, JP. Activity of daptomycin against gram-positive pathogens: A comparison with other agents and the determination of a tentative breakpoint. J Antimicrob Chemother. 2001; 48(4):563–567.

107. Silverman, JA, Perlmutter, NG, Shapiro, HM. Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus. Antimicrob Agents Chemother. 2003; 47(8):2538–2544.

108. Arbeit, RD, Maki, D, Tally, FP, et al. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis. 2004; 38(12):1673–1681.

109. Fowler, VG, Jr., Boucher, HW, Corey, GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006; 355(7):653–665.

110. Jung, D, Rozek, A, Okon, M, Hancock, REW, et al. Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin. Chem Biol. 2004; 11(7):949–957.

111. Lakey, JH, Ptak, M. Fluorescence indicates a calcium-dependent interaction between the lipopeptide antibiotic LY146032 and phospholipid membranes. Biochemistry. 1988; 27(13):4639–4645.

112. Paterson, DL. “Collateral damage” from cephalosporin or quinolone antibiotic therapy. Clin Infect Dis. 2004; 38(Suppl 4):S341–S345.

113. Hota, B. Infection control or formulary control: What is the best tool to reduce nosocomial infections due to methicillin-resistant Staphylococcus aureus? Clin Infect Dis. 2006; 42(6):785–787.

114. National Nosocomial Infections Surveillance System. National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control. 2004; 32(8):470–485.

115. Bisognano, C, Vaudaux, P, Rohner, P, et al. Induction of fibronectin-binding proteins and increased adhesion of quinolone-resistant Staphylococcus aureus by subinhibitory levels of ciprofloxacin. Antimicrob Agents Chemother. 2000; 44(6):1428–1437.

116. Cohen, SH, Gerding, DN, Johnson, S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31(5):431–455.

117. Blazquez, J. Hypermutation as a factor contributing to the acquisition of antimicrobial resistance. Clin Infect Dis. 2003; 37(9):1201–1209.

118. Loo, VG, Poirier, L, Miller, LA, et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med. 2005; 353(23):2442–2449.

119. McDonald, LC, Killgore, GE, Thompson, A, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005; 353(23):2433–2441.

120. Pépin, J, Saheb, N, Coulombe, MA, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: A cohort study during an epidemic in Quebec. Clin Infect Dis. 2005; 41(9):1254–1260.

121. Trouillet, JL, Chastre, J, Vuagnat, A, et al. Ventilator-associated pneumonia caused by potentially drug-resistant bacteria. Am J Respir Crit Care Med. 1998; 157(2):531–539.

122. Lister, PD, Wolter, DJ. Levofloxacin-imipenem combination prevents the emergence of resistance among clinical isolates of Pseudomonas aeruginosa. Clin Infect Dis. 2005; 40(Suppl 2):S105–S114.

123. Quale, J, Bratu, S, Gupta, J, Landman, D, et al. Interplay of efflux system, ampC, and oprD expression in carbapenem resistance of Pseudomonas aeruginosa clinical isolates. Antimicrob Agents Chemother. 2006; 50(5):1633–1641.

124. Gaynes, R, Edwards, JR. The National Nosocomial Infections Surveillance System, overview of nosocomial infections caused by gram-negative bacilli. Clin Infect Dis. 2005; 41:848–854.

125. Sanders, WE, Jr., Sanders, CC. Enterobacter spp. : Pathogens poised to flourish at the turn of the century. Clin Microbiol Rev. 1997; 10(2):220–241.

126. Sanders, CC, Sanders, WE, Jr. Type I beta-lactamases of gram-negative bacteria: Interactions with beta-lactam antibiotics. J Infect Dis. 1986; 154(5):792–800.

127. Chow, JW, Fine, MJ, Shlaes, DM, et al. Enterobacter bacteremia: Clinical features and emergence of antibiotic resistance during therapy. Ann Intern Med. 1991; 115(8):585–590.

128. Jacobson, KL, Cohen, SH, Inciardi, JF, et al. The relationship between antecedent antibiotic use and resistance to extended-spectrum cephalosporins in group I beta-lactamase-producing organisms. Clin Infect Dis. 1995; 21(5):1107–1113.

129. Paterson, DL, Bonomo, RA. Extended-spectrum beta-lactamases: A clinical update. Clin Microbiol Rev. 2005; 18(4):657–686.

130. Paterson, DL, Ko, W-C, Von Gottberg, A, et al. International prospective study of Klebsiella pneumoniae bacteremia: Implications of extended-spectrum beta-lactamase production in nosocomial infections. Ann Intern Med. 2004; 140(1):26–32.

131. Rodríguez-Baño, J, Navarro, MD, Romero, L, et al. Clinical and molecular epidemiology of extended-spectrum beta-lactamase-producing Escherichia coli as a cause of nosocomial infection or colonization: Implications for control. Clin Infect Dis. 2006; 42(1):37–45.

132. Paterson, DL, Ko, W-C, Von Gottberg, A, et al. Antibiotic therapy for Klebsiella pneumoniae bacteremia: Implications of production of extended-spectrum beta-lactamases. Clin Infect Dis. 2004; 39(1):31–37.

133. Jacoby, GA, Munoz-Price, LS. The new beta-lactamases. N Engl J Med. 2005; 352(4):380–391.

134. Craig, WA, Bhavnani, SM, Ambrose, PG. The inoculum effect: Fact or artifact? Diagn Microbiol Infect Dis. 2004; 50(4):229–230.

135. Wang, M, Sahm, DF, Jacoby, GA, et al. Emerging plasmid-mediated quinolone resistance associated with the qnr gene in Klebsiella pneumoniae clinical isolates in the United States. Antimicrob Agents Chemother. 2004; 48(4):1295–1299.

136. Wang, CX, Cai, PQ, Guo, Y, et al. Emerging plasmid-mediated quinolone resistance associated with the qnrA gene in Enterobacter cloacae clinical isolates in China. J Hosp Infect. 2006; 63(3):349–350.

137. Gruteke, P, Goessens, W, Van Gils, J, et al. Patterns of resistance associated with integrons, the extended-spectrum beta-lactamase SHV-5 gene, and a multidrug efflux pump of Klebsiella pneumoniae causing a nosocomial outbreak. J Clin Microbiol. 2003; 41(3):1161–1166.

138. Pitout, JD, Nordmann, P, Laupland, KB, Poirel, L. Emergence of Enterobacteriaceae producing extended-spectrum beta-lactamases (ESBLs) in the community. J Antimicrob Chemother. 2005; 56(1):52–59.

139. Ben-Ami, R, Rodríguez-Baño, J, Arslan, H, et al. A multinational survey of risk factors for infection with extended-spectrum beta-lactamase-producing Enterobacteriaceae in nonhospitalized patients. Clin Infect Dis. 2009; 49(5):682–690.

140. Qi, C, Pilla, V, Yu, JH, Reed, K. Changing prevalence of Escherichia coli with CTX-M-type extended-spectrum beta-lactamases in outpatient urinary E. coli between 2003 and 2008. Diagn Microbiol Infect Dis. 2010; 67(1):87–91.

141. Paramythiotou, E, Lucet, JC, Timsit, JF, et al. Acquisition of multidrug-resistant Pseudomonas aeruginosa in patients in intensive care units: Role of antibiotics with antipseudomonal activity. Clin Infect Dis. 2004; 38(5):670–677.

142. Carmeli, Y, Lidji, SK, Shabtai, E, et al. The effects of group 1 versus group 2 carbapenems on imipenem-resistant Pseudomonas aeruginosa: An ecological study. Diagn Microbiol Infect Dis. 2011; 70(3):367–372.

143. Nicolau, DP, Carmeli, Y, Crank, CW, et al. Carbapenem stewardship: Does ertapenem affect Pseudomonas susceptibility to other carbapenems? A review of the evidence. Int J Antimicrob Agents. 2012; 39(1):11–15.

144. Rodriguez-Bano, J, Navarro, MD, Retamar, P, et al. Beta-Lactam/beta-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum beta-lactamase-producing Escherichia coli: A post hoc analysis of prospective cohorts. Clin Infect Dis. 2012; 54(2):167–174.

145. Queenan, AM, Bush, K. Carbapenemases: The versatile beta-lactamases. Clin Microbiol Rev. 2007; 20(3):440–458.

146. Patel, N, Harrington, S, Dihmess, A, et al. Clinical epidemiology of carbapenem-intermediate or -resistant Enterobacteriaceae. J Antimicrob Chemother. 2011; 66(7):1600–1608.

147. Kritsotakis, EI, Tsioutis, C, Roumbelaki, M, et al. Antibiotic use and the risk of carbapenem-resistant extended-spectrum-β-lactamase-producing Klebsiella pneumoniae infection in hospitalized patients: Results of a double case-control study. J Antimicrob Chemother. 2011; 66(6):1383–1391.

148. Hirsch, EB, Tam, VH. Detection and treatment options for Klebsiella pneumoniae carbapenemases (KPCs): An emerging cause of multidrug-resistant infection. J Antimicrob Chemother. 2010; 65(6):1119–1125.

149. Quale, J, Spelman, D. Carbapenemases. In: Basow D, ed. UpToDate. Waltham, MA: UpToDate, 2012.

150. Daikos, GL, Markogiannakis, A. Carbapenemase-producing Klebsiella pneumoniae: When might we still consider treating with carbapenems? Clin Microbiol Infect. 2010; 17(8):1135–1141.

151. Bratu, S, Landman, D, Haag, R, et al. Rapid spread of carbapenem-resistant Klebsiella pneumoniae in New York City: A new threat to our antibiotic armamentarium. Arch Intern Med. 2005; 165(12):1430–1435.

152. Landman, D, Quale, JM, Mayorga, D, et al. Citywide clonal outbreak of multiresistant Acinetobacter baumannii and Pseudomonas aeruginosa in Brooklyn, NY: The preantibiotic era has returned. Arch Intern Med. 2002; 162(13):1515–1520.

153. Levy, SB. Active efflux mechanisms for antimicrobial resistance. Antimicrob Agents Chemother. 1992; 36(4):695–703.

154. Livermore, DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: Our worst nightmare? Clin Infect Dis. 2002; 34(5):634–640.

155. Nikaido, H. Antibiotic resistance caused by gram-negative multidrug efflux pumps. Clin Infect Dis. 1998; 27(Suppl 1):S32–S41.

156. Masuda, N, Sakagawa, E, Ohya, S, et al. Substrate specificities of MexAB-OprM, MexCD-OprJ, and MexXY-oprM efflux pumps in Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2000; 44(12):3322–3327.

157. Poole, K. Multidrug efflux pumps and antimicrobial resistance in Pseudomonas aeruginosa and related organisms. J Mol Microbiol Biotechnol. 2001; 3(2):255–264.

158. Livermore, DM. Of Pseudomonas, porins, pumps and carbapenems. J Antimicrob Chemother. 2001; 47(3):247–250.

159. Chastre, J, Fagon, JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med. 2002; 165(7):867–903.

160. Urban, C, Segal-Maurer, S, Rahal, JJ. Considerations in control and treatment of nosocomial infections due to multidrug-resistant Acinetobacter baumannii. Clin Infect Dis. 2003; 36(10):1268–1274.

161. Hanes, SD, Demirkan, K, Tolley, E, et al. Risk factors for late-onset nosocomial pneumonia caused by Stenotrophomonas maltophilia in critically ill trauma patients. Clin Infect Dis. 2002; 35(3):228–235.

162. Carmeli, Y, Samore, MH. Comparison of treatment with imipenem vs. ceftazidime as a predisposing factor for nosocomial acquisition of Stenotrophomonas maltophilia: A historical cohort study. Clin Infect Dis. 1997; 24(6):1131–1134.

163. Hayashi, Y, Paterson, DL. Strategies for reduction in duration of antibiotic use in hospitalized patients. Clin Infect Dis. 2011; 52(10):1232–1240.

164. Fowler, VG, Jr., Olsen, MK, Corey, GR, et al. Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch Intern Med. 2003; 163(17):2066–2072.

165. Mermel, LA, Allon, M, Bouza, E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009; 49(1):1–45.

166. Dennesen, PJW, van der Ven, AJ, Kessels, AGH, et al. Resolution of infectious parameters after antimicrobial therapy in patients with ventilator-associated pneumonia. Am J Respir Crit Care Med. 2001; 163(6):1371–1375.

167. Ibrahim, EH, Ward, S, Sherman, G, et al. Experience with a clinical guideline for the treatment of ventilator-associated pneumonia. Crit Care Med. 2001; 29(6):1109–1115.

168. Chastre, J, Wolff, M, Fagon, JY, et al. Comparison of 8 vs. 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: A randomized trial. JAMA. 2003; 290(19):2588–2598.

169. Burke, JP, Pestotnik, SL. Antibiotic use and microbial resistance in intensive care units: Impact of computer-assisted decision support. J Chemother. 1999; 11(6):530–535.

170. Bergstrom, CT, Lo, M, Lipsitch, M. Ecological theory suggests that antimicrobial cycling will not reduce antimicrobial resistance in hospitals. Proc Natl Acad Sci U S A. 2004; 101(36):13285–13290.