A case series of macrolide treatment failures in community acquired pneumonia.

This was a retrospective, multi-center study of patients admitted to hospital with community-acquired pneumonia, caused by Streptococcus pneumoniae, after failing to respond to >2 days of outpatient macrolide therapy. 122 cases, treated between 2000-2004, were enrolled from 31 North American sites between January 2004 - March 2005. Non-susceptible isolates (predominately low-level resistance: erythromycin MICs of 1-16 mcg/ml) were recovered from 87 patients (71%). Bacteremia was present in 63 patients (52%). The in-hospital mortality rate was 5.7 %; all 7 patients who died were bacteremic, 6 had a non-susceptible isolate. We report here the largest series of macrolide failures published to date. The patients were notable for their high rates of macrolide resistance, bacteremia, and mortality. High-level macrolide resistance remains rare among US patients failing outpatient macrolides. The majority of cases and virtually all of the mortality occurred in patients with low-level resistant strains.

Is more than one quinolone needed in clinical practice?

OBJECTIVE: To review clinical information on fluoroquinolone antimicrobials to distinguish between these agents and help define their place in clinical practice. DATA SOURCES: Primary and review articles on fluoroquinolones available commercially in the US as of August 2000 were identified through MEDLINE (from 1993-August 2000) and secondary sources. STUDY SELECTION AND DATA EXTRACTION: All pertinent, published, clinical trials for levofloxacin, moxifloxacin, and gatifloxacin were included. Minimal data were included for quinolones with restricted or limited uses, including trovafloxacin, sparfloxacin, enoxacin, and lomefloxacin. Due to the quantity of data on ciprofloxacin, only more recent or pivotal trials or articles summarizing data on specific infections were included. Relevant information was included if it was believed to assist in differentiating between the fluoroquinolones for infections for which these agents would most commonly be considered. DATA SYNTHESIS: Fluoroquinolones are a potent class of intravenous and oral broad-spectrum antimicrobial agents used for treating a wide range of community-acquired and nosocomial infections. More than 10 quinolones have been approved for use; although some of these have been withdrawn from the market, numerous others are under investigation. It has become increasingly important to be able to differentiate between these agents. CONCLUSIONS: Differences in safety, antimicrobial spectrum of activity, and resistance development support the selective use of various fluoroquinolones in differing clinical situations.

Cost-effectiveness of gatifloxacin vs ceftriaxone with a macrolide for the treatment of community-acquired pneumonia.

STUDY OBJECTIVE: To determine the cost-effectiveness of sequential IV to oral gatifloxacin therapy vs IV ceftriaxone with or without IV erythromycin to oral clarithromycin therapy to treat community-acquired pneumonia (CAP) patients requiring hospitalization. PATIENTS: Two hundred eighty-three patients enrolled in a randomized, double-blind, clinical trial were eligible for inclusion in the cost-effectiveness analysis. METHODS: Data collected included patient demographics, clinical and microbiological outcomes, length of stay (LOS), and antibiotic-related LOS (LOSAR). Costs evaluated include drug acquisition (level 1); plus costs of preparation, dispensing, and administration, treating adverse events, and clinical failures (level 2); plus hospital per diem costs (level 3). Robustness of economic findings was tested using sensitivity analyses. RESULTS: Two hundred three patients were clinically and economically evaluable (98 receiving gatifloxacin and 105 receiving ceftriaxone). IV erythromycin was administered to 35 patients in the ceftriaxone-treated group. Oral conversion was achieved in 98% of patients in each group. Clinical cure and microbiological eradication rates did not differ statistically (98% and 97% with gatifloxacin vs 92% and 92% with ceftriaxone, respectively). Overall, neither geometric mean LOS nor LOSAR differed significantly (4.2 days and 4.1 days with gatifloxacin vs 4.9 days and 4.9 days with ceftriaxone, respectively). Treatment failures in the ceftriaxone group contributed to a mean incremental increase in LOSAR of 1.09 days and increased mean cost per patient. The geometric mean costs per patient (level 3) were $5,109 for gatifloxacin and $6,164 for ceftriaxone (p = 0.011). The cost-effectiveness ratios (mean cost per expected success) were $5,236:1 and $7,047:1 for gatifloxacin and ceftriaxone, respectively. CONCLUSIONS: Gatifloxacin monotherapy for CAP patients requiring hospitalization is clinically effective and provides an economic advantage compared to the regimen of ceftriaxone with or without erythromycin IV with a switch to oral clarithromycin.

What have we learned from pharmacokinetic and pharmacodynamic theories?

Pharmacokinetic characteristics and pharmacodynamic properties dictate antimicrobial response and, along with natural immune responses, clinical outcomes. As new agents are developed with long half-lives, we will lose the ability to differentiate between concentration-dependent and time-dependent properties. The area under the inhibitory concentration curve (AUIC) defines drug regimens as a ratio of drug exposure to minimum inhibitory concentration (MIC) and allows them to be compared with each other. With AUIC and agents with long half-lives, these comparisons are possible regardless of chemical classification or concentration or time-dependent activity. Historical examples of reduced drug exposure from decreased doses (i.e., cefaclor, clarithromycin, and ciprofloxacin), and thus low AUIC values, directly correlate with drug resistance. In the face of rising MICs (as is occurring worldwide with Streptococcus pneumoniae), close attention to appropriate dosing and concentration above the MIC may delay and potentially even prevent antibiotic resistance. Creating selective pressure on reliable antibiotics by inappropriately reducing their doses will undoubtedly challenge these agents and may destroy entire drug classes with similar mechanisms of action or resistance.

Economic justification of antimicrobial management programs: implications of antimicrobial resistance.

The relationship between the problem of antimicrobial resistance and efforts to control antimicrobial costs is explored. Antimicrobial drug management typically centers around controlling costs and controlling antimicrobial resistance. Selection of therapeutic alternatives without adherence to a well-developed program or without a rationale based on data from the medical literature may promote antimicrobial resistance. Attempts to select alternatives can produce cost shifting rather than cost containment. The annual cost associated with antimicrobial resistance in the United States is estimated to be as high as $47 billion. In one study, patients with bacteremia caused by methicillin-resistant Staphylococcus aureus had an average length of stay 2.7 days longer than patients with susceptible strains and a mean cost of care that was $3500 higher. Infection control is one of the most important duties of health care practitioners. Given today's prevailing reimbursement structure, hospitals with high rates of nosocomial and resistant infections are likely to lose money. A basic problem with the current approach to controlling resistance is that the two most common strategies, highly restrictive formularies and drug cycling, work in opposition. Antimicrobial management programs should be directed at ensuring the most appropriate use of antimicrobials rather than focusing on limiting choices.

Clinical efficacy of intravenous followed by oral azithromycin monotherapy in hospitalized patients with community-acquired pneumonia. The Azithromycin Intravenous Clinical Trials Group.

The purpose of this study was to evaluate intravenous (i.v.) azithromycin followed by oral azithromycin as a monotherapeutic regimen for community-acquired pneumonia (CAP). Two trials of i.v. azithromycin used as initial monotherapy in hospitalized CAP patients are summarized. Clinical efficacy is reported from an open-label randomized trial of azithromycin compared to cefuroxime with or without erythromycin. Bacteriologic and clinical efficacy results are also presented from a noncomparative trial of i.v. azithromycin that was designed to give additional clinical experience with a larger number of pathogens. Azithromycin was administered to 414 patients: 202 and 212 in the comparative and noncomparative trials, respectively. The comparator regimen was used as treatment for 201 patients; 105 were treated with cefuroxime alone and 96 were given cefuroxime plus erythromycin. In the comparative trial, clinical outcome data were available for 268 evaluable patients with confirmed CAP at the 10- to 14-day visit, with 106 (77%) of the azithromycin patients cured or improved and 97 (74%) of the comparator patients cured or improved. Mean i.v. treatment duration and mean total treatment duration (i.v. and oral) for the clinically evaluable patients were significantly (P < 0.05) shorter for the azithromycin group (3.6 days for the i.v. group and 8.6 days for the i.v. and oral group) than for the evaluable patients given cefuroxime plus erythromycin (4.0 days for the i.v. group and 10.3 days for the i.v. and oral group). The present comparative study demonstrates that initial therapy with i.v. azithromycin for hospitalized patients with CAP is associated with fewer side effects and is equal in efficacy to a 1993 American Thoracic Society-suggested regimen of cefuroxime plus erythromycin when the erythromycin is deemed necessary by clinicians.

Comparison of the fluoroquinolones based on pharmacokinetic and pharmacodynamic parameters.

Assessment of pharmacodynamic activity from standard in vitro minimum inhibitory concentrations (MICs) alone is insufficient to predict in vivo potency. Achievable serum and tissue concentrations as well as pharmacokinetic characteristics must be considered. When pharmacokinetic and pharmacodynamic values are combined, the area under the inhibitory curve (AUIC) and peak concentration:MIC ratio predict clinical cure for fluoroquinolones. Clinical data and animal models indicate that a peak:MIC of 10:1 and above and an AUIC of 125 and above are predictive of a clinical cure for this class of antimicrobials against gram-negative organisms. The values may be used to compare and contrast fluoroquinolones to determine which would be best for treating a specific microorganism. Pharmacodynamic data also can be used to design regimens that minimize the risk of suboptimal drug levels. Ensuring the optimal fluoroquinolone dosage based on pharmacodynamic principles would diminish the emergence of resistant organisms and prevent treatment failures.

Cost effectiveness of cephalosporin monotherapy and aminoglycoside/ureidopenicillin combination therapy. For the treatment of febrile episodes in neutropenic patients.

OBJECTIVE: To assess the relative cost effectiveness of cephalosporin monotherapy options and aminoglycoside/ureidopenicillin combination therapy for the treatment of febrile episodes in adult patients with neutropenia. DESIGN AND SETTING: This was a retrospective cost-effectiveness analysis conducted from the institutional perspective. METHODS: The analysis was based on 741 febrile episodes in adult patients with neutropenia enrolled in 5 randomised trials: 3 comparing monotherapy with ceftazidime or cefepime, and 2 comparing cefepime monotherapy versus aminoglycoside/ureidopenicillin combination therapy. Resource utilisation included costs for study antibacterials, treatment of adverse effects and failures, and hospitalisation. The primary end-point was the overall cost of treatment per patient. Cost-effectiveness ratios were also analysed. RESULTS: No significant differences in clinical success rates were detected. Median per-patient costs in the monotherapy comparisons were $US7849 for cefepime and $US7788 for ceftazidime [1997 values; not significantly different (NS)]. Corresponding costs for the monotherapy versus combination therapy comparisons were $US9780 for cefepime and $US10 159 for gentamicin/ureidopenicillin (NS). Despite a higher acquisition cost for cefepime, there were no statistically significant differences in cost effectiveness compared with either ceftazidime monotherapy or gentamicin/ureidopenicillin combination therapy. Sensitivity analyses revealed that monotherapy can be cost effective compared with combination therapy in many situations. CONCLUSION: There were no economic differences between the 3 regimens tested. Therefore drug cost should not be a deciding factor when choosing antibacterial therapy for the treatment of febrile episodes in adult patients with neutropenia.

Pharmacoeconomics of antimicrobial therapy.

Switch therapy, sequential therapy, and step-down therapy are discussed in terms of their contribution to reducing antimicrobial expenditures. Pharmacoeconomics is the science used to identify and compare the costs and consequences of drug therapy in terms of efficacy, safety, and overall health care. Pharmacoeconomic studies of antimicrobials for respiratory-tract infections have identified significant cost savings associated with regimens that are optimized for a particular patient on the basis of a drug's pharmacokinetic profile. For fluoroquinolones, optimal therapy has been associated with targeting the specific pharmacodynamic variable known as the ratio of the area under the serum concentration-time curve from 0 to 24 hours (AUC) to the minimum inhibitory concentration, also referred to as the area under the inhibitory curve (AUIC). Several studies have shown that regimens that achieve targeted AUIC values of 125 to 250 against gram-negative aerobic bacteria are cost-effective; cost savings are linked to decreased time to bacterial eradication and higher AUICs. Additional cost-effective measures for hospitals and health care institutions include the implementation of formalized i.v.-to-oral conversions and streamlining programs. Pharmacoeconomic analysis of therapies for respiratory-tract and other infections demonstrates that reducing health care costs may best be achieved by curing the infection in the shortest possible time through dosage optimization individualized to the patient.

Influence of fluoroquinolone purchasing patterns on antimicrobial expenditures and Pseudomonas aeruginosa susceptibility.

The influence of using ofloxacin in place of ciprofloxacin on hospital fluoroquinolone expenditures, total antimicrobial expenditures, and susceptibility of Pseudomonas aeruginosa to fluoroquinolones was studied. Hospitals with fluoroquinolone expenditures of at least $1 per occupied bed per year were administered annual surveys covering the years 1993 through 1996. The two most recent consecutive years of data were compared among hospitals that used ciprofloxacin as their primary fluoroquinolone during both years (group 1), hospitals whose ofloxacin purchases increased from accounting for < or =25% of total fluoroquinolone expenditures during year 1 to accounting for >25% during year 2 (group 2), and hospitals whose ofloxacin purchases accounted for at least 25% of total fluoroquinolone expenditures for both years (group 3). A total of 109 hospitals were included in the study. Most hospitals spent more on fluoroquinolones and total antimicrobials in year 2 than year 1. Group 3 hospitals had a significant increase in expenditures for fluoroquinolones and non-fluoroquinolone antipseudomonal antimicrobials. Group 2 hospitals did not realize antimicrobial cost savings and had higher rates of Pseudomonas aeruginosa resistance than hospitals that used ciprofloxacin. Whether a hospital changed its pattern of ciprofloxacin and ofloxacin purchasing was not significantly associated with expenditures for fluoroquinolones, nonfluoroquinolone antimicrobial agents, or all antimicrobials. Susceptibility of P. aeruginosa to ciprofloxacin was lower in hospitals with greater proportions of ofloxacin use. Individual hospital, ciprofloxacin expenditures, and study year were found to be predictive of P. aeruginosa susceptibility to ciprofloxacin among all pooled hospitals.

How should we evaluate new anti-infectives for respiratory tract infections?

In assessing the outcomes of anti-infective therapy, microbiological and clinical efficacy have been the most important factors considered. However, increasing attention is being paid to pharmacoeconomic considerations, which include much more than simply the cost of the drug. Nursing and pharmacy time involved in drug preparation and administration, laboratory costs and time in therapeutic drug monitoring, and hospital costs for in-patient care are all factors to be considered. Therapeutic failure caused by using an inexpensive but ineffective drug can thus be very expensive if it leads to prolonged hospitalization. The effort to curb anti-infective drug costs has led to the following strategies: sequential therapy using equipotent oral formulations of intravenous agents; switch therapy, ie, changing to a different class; and step-down therapy, ie, converting to an oral antimicrobial with less potency. Maximal cost effectiveness is related to rapid and effective therapy.

Cost effectiveness of ciprofloxacin plus metronidazole versus imipenem-cilastatin in the treatment of intra-abdominal infections.

OBJECTIVE: To compare the cost effectiveness of sequential intravenous (i.v.) to oral ciprofloxacin plus metronidazole (CIP/MTZ i.v./PO) with that of i.v. ciprofloxacin plus i.v. metronidazole (CIP/MTZ i.v.) and i.v. imipenem-cilastatin (IMI i.v.) in patients with intra-abdominal infections. DESIGN AND PARTICIPANTS: Patients enrolled in a double-blind randomised clinical trial were eligible for inclusion into this cost-effectiveness analysis. Decision analysis was used to characterise the economic outcomes between groups and provide a structure upon which to base the sensitivity analyses. 1996 cost values were used throughout. SETTING: The economic perspective of the analysis was that of a hospital provider. MAIN OUTCOME MEASURES AND RESULTS: Among 446 economically evaluable patients, 176 could be switched from i.v. to oral administration. The 51 patients randomised to CIP/MTZ i.v./PO who received active oral therapy had a success rate of 98%, mean duration of therapy of 9.1 days and mean cost of $US7678. There were 125 patients randomized to either CIP/MTZ i.v. or IMI i.v. who received oral placebo while continuing on active i.v. antibacterials; their success rate was 94%, mean duration of therapy was 10.1 days and mean cost was $US8774 (p = 0.029 vs CIP/MTZ i.v./PO). Of the 270 patients who were unable to receive oral administration, 97 received IMI i.v. and had a success rate of 75%, mean duration of therapy of 13.8 days and a mean cost of $US12,418, and 173 received CIP/MTZ i.v. and had a success rate of 77%, mean duration of therapy of 13.4 days and mean cost of $US12,219 (p = 0.26 vs IMI i.v.). CONCLUSIONS: In patients able to receive oral therapy, sequential i.v. to oral treatment with ciprofloxacin plus metronidazole was cost effective compared with full i.v. courses of ciprofloxacin plus metronidazole or imipenem-cilastatin. In patients unable to receive oral therapy, no difference in mean cost was found between i.v. imipenem-cilastatin or i.v. ciprofloxacin plus i.v. metronidazole.

Genesis of methicillin-resistant Staphylococcus aureus (MRSA), how treatment of MRSA infections has selected for vancomycin-resistant Enterococcus faecium, and the importance of antibiotic management and infection control.

We extensively studied the epidemiology and time course of endemic methicillin-resistant Staphylococcus aureus (MRSA) in the Millard Fillmore Hospital, a 600-bed teaching hospital in Buffalo. The changeover from methicillin-susceptible S. aureus to MRSA begins on the first hospital day, when patients are given cefazolin as presurgical prophylaxis. Under selective antibiotic pressure, colonizing flora change within 24 to 48 hours. For patients remaining hospitalized, subsequent courses of third-generation cephalosporins further select and amplify the colonizing MRSA population. Therefore, managing antibiotic selective pressure might be essential. Other strategies include attention to dosing, so that serum concentrations of drug exceed the minimum inhibitory concentration, and antibiotic cycling. Although there are some promising new antibiotics on the horizon, it is necessary to deal with many resistance patterns by using the combined strategies of infection control and antibiotic management.

Assessing antibacterial pharmacoeconomics in the intensive care unit.

Intensive care units (ICUs) represent areas of high use of antibacterials and other pharmacy goods and services. Many institutions view their ICUs as a target for drug-use surveillance and cost-containment programmes. Economic assessment of antibacterial interventions in the ICU should include all direct costs and patient outcomes. Nonetheless, many of these institutions focus their efforts at reducing antibacterial costs without considering the consequences of these actions. It is possible that devoting more resources to antibacterials can have an overall positive economic impact if more appropriate antibacterial use reduces length of stay, decreases bacterial resistance or lowers frequency of adverse complications. Two consequences of antibacterial use which can result in substantial economic burdens to institutions are drug-induced complications (toxicities and adverse events) and the development of antibacterial-resistant organisms. These events are logical targets for performing pharmacoeconomic studies to evaluate appropriate and inappropriate antibacterial use. Either of these problems can increase length of stay, which is the single most important variable influencing the overall cost of patient care. The primary goal of patient care is to hasten patients' clinical improvement. This will result in decreased antibacterial acquisition costs, decreased lengths of ICU and hospital stays, and ultimately decreased consumption of hospital resources. These can be accomplished by using strategies to guide antibacterial use in order to reduce failures, adverse events, toxicity and antimicrobial resistance.

Cost-effectiveness comparison of sequential ofloxacin versus standard switch therapy.

OBJECTIVE: To compare the cost-effectiveness of sequential intravenous-to-oral ofloxacin versus intravenous-to-oral standard switch therapy for the treatment of patients with sepsis who are hospitalized with bacterial infections. DESIGN: Cost-effectiveness analysis from a provider perspective, including resources important to an integrated healthcare network, of a randomized, open-label, controlled, clinical trial. SETTING: Millard Fillmore Health System, Buffalo, NY. PATIENTS: Hospitalized adults requiring parenteral antibiotics for a complicated urinary tract infection, lower respiratory tract infection, or skin and soft tissue infection. INTERVENTIONS: Sequential intravenous-to-oral ofloxacin or standard intravenous-to-oral switch antibiotics. OUTCOME MEASURES: Clinical outcomes and direct costs associated with hospitalization, primary physician services, specialist physician services, and outpatient care. RESULTS: Eighty-two of 89 patients randomized into the two treatment groups were evaluable. Standard switch therapy failed with 12 patients versus 10 patients receiving ofloxacin. Complete economic data were available for 74 patients. Sequential ofloxacin therapy resulted in a 1-day-shorter antibiotic-related hospitalization without evidence of recurrent infection during the posttherapy follow-up evaluations. An average cost savings of $399 per patient was achieved in the sequential ofloxacin group. Although this difference did not attain statistical significance (probably due to the large variance), it is an economically significant finding. The cost-effectiveness ratios were $5735 per successful outcome for the standard switch therapy group versus $5126 per successful outcome in the sequential ofloxacin group. CONCLUSIONS: Sequential ofloxacin was as effective and consistently less expensive than standard switch antibiotics in the initial evaluation and in the sensitivity analysis of room cost and drug acquisition cost. Standard switch therapy would have to be greater than 25% more effective than sequential ofloxacin therapy to change the economic decision.

Changing the infection control paradigm from off-line to real time: the experience at Millard Fillmore Health System.

In 1993, several departments at Millard Fillmore Health System joined efforts to initiate a new approach to infection control. The main emphasis of this program is to move infection control to a real-time mode to manage patient outcomes daily. The principal objective was to decrease the number of nosocomial infections by 10%, with a particular emphasis on surgical-site infections. Besides real-time surveillance, we are critically evaluating several aspects of the management of nosocomial infections. High-level computer support has been the frame-work upon which this program was built. We have microcomputers that are linked directly to microbiology, pharmacy, billing, and admissions, downloading data several times daily. An expert software system merges all of the data, and from this we can target patients for real-time interventions. The computer system allows all inpatients to be screened for either infection control or antibiotic management interventions on a daily basis, with minimal time being spent on data collection and maximal efforts devoted to interventions at the bedside. Additionally, the infection management program will assist in maintaining the extraordinarily low expenditures on antimicrobial agents. During 1993, the Millard Fillmore Health System spent $924,884 on antibiotics, an amount approximately 50% that of comparably sized hospitals.

Cost-effectiveness of ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients.

A cost-effectiveness analysis was performed following a double-blind, randomized study of ampicillin/sulbactam (A/S) versus imipenem/cilastatin (I/C) for the treatment of limb-threatening foot infections in 90 diabetic patients. There were no significant differences between the treatments in terms of clinical success rate, adverse-event frequency, duration of study antibiotic treatment, or length of hospitalization. Costs of the study antibiotics, treatment of failures and adverse events, and hospitalization were calculated. Mean per-patient treatment cost in the A/S group was $14,084, compared with $17,008 in the I/C group (P = .05), primarily because of lower drug and hospitalization costs and less-severe adverse events in the A/S group. Sensitivity analyses varying drug prices or hospital costs demonstrated that A/S was consistently more cost-effective than I/C. Varying the clinical success rate for each drug revealed that I/C would have to be 30% more effective than A/S to change the economic decisions.

Cost-effectiveness of abbreviating the duration of intravenous antibacterial therapy with oral fluoroquinolones.

Comprehensive economic analyses should include outpatient as well as inpatient resources. A healthcare system that includes both inpatient and outpatient care, such as prescriptions, physician care, laboratory tests and multiple other items, has been termed an Integrated Healthcare Network (IHN). Thus, cost-effectiveness analyses from the perspective of an IHN are necessary. We report a cost-effectiveness analysis from an IHN perspective on 187 evaluable hospitalised patients with serious infection who participated in randomised clinical trials that evaluated either: (i) standard regimens of intravenous (i.v.) antibacterial therapy, usually followed by oral antibacterial therapy; or (ii) an abbreviated regimen of intravenous antibacterials for 2 to 4 days, followed by either oral ciprofloxacin or oral enoxacin as early switch therapy. Clinical success rates were similar for the 2 treatment groups. The median number of days of in-hospital antibacterial treatment was 11 for standard i.v. therapy and 10 for switch therapy. Adverse events occurred in 33% of the standard i.v. therapy group and in 50% of the switch therapy group. Sensitivity analysis of drug price and hospital bed cost showed that switch therapy was consistently more cost effective than standard i.v. therapy. Standard i.v. therapy would have to be 10% more effective than switch therapy to change the economic decision. In this analysis, switch therapy was a cost-effective treatment with no demonstrated change in efficacy compared with standard i.v. therapy.

In nosocomial pneumonia, optimizing antibiotics other than aminoglycosides is a more important determinant of successful clinical outcome, and a better means of avoiding resistance.

In in vitro and animal models, antibiotics show good relationships between concentration and response, when response is quantified as the rate of bacterial eradication. The strength of these in vitro relationships promises their utility for dosage regimen design and predictable cure of infections such as nosocomial pneumonia. In spite of their intuitive logic, close relationships between dosage and bacterial eradication have not been easy to show in clinical studies of nosocomial pneumonia. Presumably, a variety of patient, disease, bacterial, and pharmacokinetic variables cloud these relationships in patients, and delay their elucidation in patient trials. Patients with serious infections like nosocomial pneumonia require bactericidal antimicrobial activity. Studies in our laboratory show that the minimum effective antimicrobial action is an area under the inhibitory titer (AUIC) of 125, in which AUIC is calculated as the 24 hour serum area under the curve (AUC) divided by the minimum inhibitory concentration (MIC) of the pathogen. This target AUIC may be achieved with either a single antibiotic or it can be the sum of AUIC values of two or more antibiotics. There is considerable variability in the actual AUIC value for patients when antibiotics are administered in their usual recommended dosages. Examples of this variance will be provided using aminoglycosides, fluoroquinolones, and beta-lactams. The achievement of minimally effective antibiotic action, consisting of an AUIC of at least 125, is associated with bacterial eradication in about 7 days for beta-lactams and quinolones. Adding an aminoglycoside to beta-lactams may produce a slight increase in their rate of bacterial killing in vivo, but because of their narrow therapeutic window, and the associated low doses in relation to MIC, there are situations in which the aminoglycosides may be unable to add sufficient additional AUIC. Antibiotic activity indices allow clinicians to evaluate individualized patient regimens. Furthermore, antibiotic activity is a predictable clinical endpoint with predictable clinical outcome. This value also is highly predictive of the development of bacterial resistance. Antimicrobial regimens that do not achieve an AUIC of at least 125 cannot prevent the selective pressure that leads to overgrowth of resistant bacterial subpopulations. The methods based on the determination of AUIC have clinical applicability in routine practice, through software developed for this purpose. These indices can assist with patient management strategies in a prospective manner because they can identify patients at high risk of therapeutic failure or acquired resistance early in therapy before therapy fails. Our studies show that calculations of AUIC can be used to prospectively target regimens to improve the chances of cure with nosocomial pneumonia and other serious infections. A clinical intervention team has been organized to optimize antimicrobial regimens as early in therapy as possible, to lower the high cost events such as failure and acquired bacterial resistance.