Treatment Of Serious Infections Research Articles

Infection control practitioner as advocate for the antibiogram: Launching local interventions to prevent antimicrobial resistance

ISSUE: Antimicrobial susceptibility data are often aggregated into “antibiograms,” which provide a summary picture of common organisms and their susceptibility to many antimicrobial agents. Local antibiograms (e.g., by unit, hospital, or facility) provide a starting point for making decisions about empiric antimicrobial treatment. Clinicians are not making use of the antibiogram information, nor taking into account the local patterns of resistance and the further increase of resistant strains resulting from inappropriate antibiotic therapy. PROJECT: The antibiotic imipenem is used within the acute care areas as a last resort medication for the treatment of serious infections. Current surveillance systems monitoring emerging drug resistance detect susceptibility patterns for each acute care entity. In this study, four hospitals that comprise part of a network were used to compare their resistance patterns to imipenem for the organism Pseudomonas aeruginosa, using their respective antibiograms. The dependent variable is the resistance of the organism; independent variables are the hospitals themselves and the time elapsed. A full model two-way ANOVA analysis was performed, with a subsequent one-way ANOVA performed as the reduced model. RESULTS: Retrospective review of the antibiogram resistance patterns for three time periods were analyzed from each of the four hospitals. Full model: Two-way ANOVA analysis indicates that Hu Hospital has the largest average resistance. Hi Hospital has a small average, indicating a higher percentage of susceptible isolates of Pseudomonas aeruginosa. Over time, the mean value of resistance did not change very much. Resistance patterns for one of the four hospitals were quite distinctly different (p = 0.012), illustrating the need to monitor local data even when working within a multisite system. Reduced model: One-way ANOVA results confirmed that the one hospital had substantially higher rates of resistance than the other three hospitals. LESSONS LEARNED: One of the hospitals had a different antibiogram and resistance pattern than the other three hospitals. Knowledge of local patterns of resistance contained within the antibiogram will allow the infection control nurse to be alert to significant shifts in the populations of organisms within the locale and report those findings to all stakeholders. This information can be shared via Internet and PDA for real-time clinical decisions at the bedside.

Continuous infusion of ticarcillin–clavulanate for home treatment of serious infections: clinical efficacy, safety, pharmacokinetics and pharmacodynamics

Continuous infusion (CI) ticarcillin–clavulanate is a potential therapeutic improvement over conventional intermittent dosing because the major pharmacodynamic (PD) predictor of efficacy of β-lactams is the time that free drug levels exceed the MIC. This study incorporated a 6-year retrospective arm evaluating efficacy and safety of CI ticarcillin–clavulanate in the home treatment of serious infections and a prospective arm additionally evaluating pharmacokinetics (PK) and PD. In the prospective arm, steady-state serum ticarcillin and clavulanate levels and MIC testing of significant pathogens were performed. One hundred and twelve patients (median age, 56 years) were treated with a CI dose of 9.3–12.4 g/day and mean CI duration of 18.0 days. Infections treated included osteomyelitis (50 patients), septic arthritis (6), cellulitis (17), pulmonary infections (12), febrile neutropenia (7), vascular infections (7), intra-abdominal infections (2), and Gram-negative endocarditis (2); 91/112 (81%) of patients were cured, 14 (13%) had partial response and 7 (6%) failed therapy. Nine patients had PICC line complications and five patients had drug adverse events. Eighteen patients had prospective PK/PD assessment although only four patients had sufficient data for a full PK/PD evaluation (both serum steady-state drug levels and ticarcillin and clavulanate MICs from a bacteriological isolate), as this was difficult to obtain in home-based patients, particularly as serum clavulanate levels were found to deteriorate rapidly on storage. Three of four patients with matched PK/PD assessment had free drug levels exceeding the MIC of the pathogen. Home CI of ticarcillin–clavulanate is a safe, effective, convenient and practical therapy and is a therapeutic advance over traditional intermittent dosing when used in the home setting.

Fourth-Generation Cephalosporins: In vitro Activity against Nosocomial Gram-Negative Bacilli Compared with β-Lactam Antibiotics and Ciprofloxacin

The in vitro activity of two new expanded spectrum fourth-generation cephalosporins, cefepime and cefpirome, was compared with that of five antibacterial agents, ceftazidime, cefoperazone, cefotaxime, imipenem, and ciprofloxacin, that are commonly used in the treatment of serious infections caused by aerobic gram-negative bacteria. The agar dilution method described by the US National Committee for Clinical Laboratory Standards was used to determine the minimum inhibitory concentrations of antibiotics tested. Three hundred and two clinical isolates, representing a cross-section of Klebsiella and Enterobacter species and Pseudomonas aeruginosa were tested. The most potent β-lactams were imipenem, cefepime, and cefpirome, which demonstrated significant activity against the majority of strains in all three genera of bacteria, as did ciprofloxacin. Ceftazidime was active against P. aeruginosa, but was less potent against Klebsiella and Enterobacter species. Cefoperazone and cefotaxime were less active than ceftazidime against P. aeruginosa. Cefepime had slightly greater activity than cefpirome against the gram-negative bacteria tested. These data indicate that cefepime and cefpirome are highly active against many frequently resistant nosocomial bacterial strains that are traditionally responsible for difficult-to-treat infections.

Successful management of discovered pH dependence in vancomycin recovery studies: novel HPLC method for microdialysis and plasma samples

Vancomycin is a glycopeptide antibiotic approved for the treatment of serious infections or patients allergic to beta-lactams. A rapid HPLC assay using UV detection for the determination in microdialysate and human plasma was developed. After sample preparation, using methanol and trichloroacetic acid for plasma and water for microdialysate, 20 microL were injected and separated on a RP(18) column. Overall, the assay exhibited good precision and accuracy. The diffusion properties of vancomycin investigated in in vitro microdialysis experiments revealed an unfavourable concentration dependence avertable by keeping a constant pH using phosphate buffer as perfusate. The mean relative recoveries were 27.8% [coefficient of variation (CV) 11.1%] and 33.2% (CV 8.3%) for retrodialysis and recovery experiments, respectively. Following characterization of vancomycin in in vitro microdialysis, the developed setting is suitable for application in (pre-)clinical studies.

Treating Serious Infections: Focus on Cefepime

Antibiotic resistance among medically important pathogens is curtailing the therapeutic value of many of the standard broad-spectrum antibiotics used for empiric treatment of serious infections. This article presents a brief overview of the etiology of serious infections and the threat of emerging resistance, and reviews the adverse impact of inadequate empiric treatment on patient outcomes and hospital ecology. The treatment of two clinically important infections with cefepime--pneumonia in hospitalized patients and febrile neutropenia--also is discussed.

Antimicrobial resistance rates and clonality results from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Programme: Report of year five (2003)

The U.S. Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Programme in the fifth year continues to monitor the spectrum of activity and potency of meropenem within medical centers where carbapenems are used for the treatment of serious infections. The antimicrobial activity of 11 broad-spectrum agents (including initial comparisons for levofloxacin) was assessed against 2,848 isolates in 2003. The minimum inhibitory concentration (MIC) results demonstrate the continued high potency of meropenem against all monitored pathogens. Against all Gram-negative bacilli tested, the overall rank order of susceptibility was meropenem (96.3%) > imipenem (95.6%) > cefepime (93.7%) > tobramycin (91.9%) > piperacillin/tazobactam (90.2%) > ceftazidime (90.1%) > gentamicin (89.6%) > levofloxacin (82.8%) > ciprofloxacin (82.5%) > aztreonam (81.8%) > ceftriaxone (72.3%). Clonal-based resistances were observed that adversely influenced carbapenem resistance rates, particularly among Klebsiella spp. and Acinetobacter baumannii isolates. Continued surveillance of the carbapenem class and other broad-spectrum agents is warranted to monitor activity against pathogens causing serious infections in hospitalized patients.

New antibiotics for treatment of serious infections due to antibiotic-resistant Gram-positive cocci

New antibiotics for treatment of serious infections due to antibiotic-resistant Gram-positive cocci

Results of a multicenter, randomized, open-label efficacy and safety study of two doses of tigecycline for complicated skin and skin-structure infections in hospitalized patients

Background: Tigecycline is a broad-spectrum glycylcycline antibiotic being investigated for the treatment of serious infections in hospitalized patients. Tigecycline has been shown to be efficacious against serious infections in animals, and preliminary studies in healthy adults have shown that tigecycline has an acceptable tolerability profile. Objective: This study compared the clinical and microbiological efficacy, pharmacokinetic properties, and tolerability of 2 doses of tigecycline in hospitalized patients with a complicated skin and skin-structure infection (cSSSI). Methods: This Phase II, randomized, open-label study was conducted between September 1999 and March 2001 at 14 investigative centers across the United States. Patients were randomized to receive tigecycline 25 or 50 mg IV q12h for 7 to 14 days. The primary efficacy end point was the clinically observed cure rate among clinically evaluable (CE) patients at the test-of-cure visit. Secondary end points were the clinical cure rate at the end of treatment and bacteriologic response in microbiologically evaluable (ME) patients. Also, in vitro tests of susceptibility to tigecycline were performed for selected pathogens known to cause skin infections, including methicillin-resistant and methicillin-susceptible Srreptococcus pyogenes, Staphylococcus aureus, Escherichia coli, Enterococcus faecalis, and Enterococcus faecium. Tolerability assessments also were conducted. Results: A total of 160 patients received ≥1 dose of tigecycline; 109 patients were CE, and 91 were ME. The majority of patients (74%) were men, and the mean (SD) age was 49.0 (14.8) years. At the test-of-cure visit, the clinical cure rate in the 25-mg group was 67% (95% CI, 53.3%–79.3%) and in the 50-mg group was 74% (95% CI, 60.3%–85.0%). In the 25-mg group, 56% of the patients had eradication (95% CI, 40.0%–70.4%) of the pathogens compared with 69% (95% CI, 54.2%–82.3%) in the 50-mg group. Values for the minimum concentration of tigecycline that is inhibitory for 90% of all isolates ranged from 0.06 to 0.50 μg/mL for the selected pathogens. Both tigecycline doses were generally well tolerated. Nausea and vomiting were the most common adverse events. Conclusions: In this study, tigecycline appeared efficacious and showed a favorable pharmacokinetic profile and an acceptable safety profile in the treatment of hospitalized patients with cSSSI. In patients who received 50-mg doses of tigecycline q12h, the clinical cure rates and microbial eradication rates were 74% and 70%, respectively, and were 67% and 56% in patients who received 25-mg doses.

Assessment of molecularly imprinted sol–gel materials for selective room temperature phosphorescence recognition of nafcillin

Sol–gel imprinted materials were prepared against nafcillin, a semisynthetic β-lactamic antibiotic employed in the treatment of serious infections caused by penicillinase-producing staphylococci. Two approaches were addressed for preparation of the imprinted materials and the controls: as conventional monoliths, which were ground and sieved to a desired particle size for rebinding analysis, and as films on supporting glass slides. The specific binding sites that are created during the imprinting process are analyzed via selective room temperature phosphorescence (RTP) (sol–gel films) measurements as well as via competitive room temperature phosphorescence ligand assay. Results demonstrated the importance of the physical configuration of the imprinted material for minimizing non-specific binding. The close similarities between the structures of different β-lactamic antibiotics made it possible to interpret the roles of the template structure on specific molecular recognition. In this article, we introduce the use of room temperature phosphorescence as selective transduction method for the template. The imprinted sol–gel films displayed enhanced specific binding characteristics respect to the monolithic sol–gel and can be envisaged for the use as recognition matrices for the screening and rapid selection of antibiotics from a combinatorial library or for the rapid control of nafcillin in biological samples (e.g. milk, serum, urine).

Organization of the teicoplanin gene cluster in Actinoplanes teichomyceticus.

The glycopeptide teicoplanin is used for the treatment of serious infections caused by Gram-positive pathogens. The tcp gene cluster, devoted to teicoplanin biosynthesis in the actinomycete Actinoplanes teichomyceticus, was isolated and characterized. From sequence analysis, the tcp cluster spans approximately 73 kb and includes 39 ORFs participating in teicoplanin biosynthesis, regulation, resistance and export. Of these, 34 ORFs find a match in at least one of the five glycopeptide gene clusters previously characterized. Putative roles could be assigned for most of the tcp genes. The two glycosyltransferases responsible for attaching amino sugars to amino acids 4 and 6 of the teicoplanin aglycon were overexpressed in Escherichia coli and characterized. They both recognize N-acetylglucosamine as the substrate. tGtfA can add a sugar residue in the presence or absence of N-acetylglucosamine at amino acid 4, while tGtfB can only glycosylate the teicoplanin aglycon.

Genetic analysis of a high-level vancomycin-resistant isolate of Staphylococcus aureus.

Vancomycin is usually reserved for treatment of serious infections, including those caused by multidrug-resistant Staphylococcus aureus. A clinical isolate of S. aureus with high-level resistance to vancomycin (minimal inhibitory concentration = 1024 microg/ml) was isolated in June 2002. This isolate harbored a 57.9-kilobase multiresistance conjugative plasmid within which Tn1546 (vanA) was integrated. Additional elements on the plasmid encoded resistance to trimethoprim (dfrA), beta-lactams (blaZ), aminoglycosides (aacA-aphD), and disinfectants (qacC). Genetic analyses suggest that the long-anticipated transfer of vancomycin resistance to a methicillin-resistant S. aureus occurred in vivo by interspecies transfer of Tn1546 from a co-isolate of Enterococcus faecalis.

Antagonism between penicillin and erythromycin against Streptococcus pneumoniae: does it exist?

Penicillin and erythromycin are commonly used for the treatment of serious infections caused by Streptococcus pneumoniae and combined as empiric therapy of community-acquired pneumonia. A concern about potential antagonism between these drugs prompted a protocol designed to test the hypothesis in timed kill curve experiments with several interpretive criteria applied. Four clinical isolates of S.pneumoniae from the United States referred to the SENTRY Antimicrobial Surveillance Program and one QC strain (ATCC 49619) were tested. Minimum Inhibitory Concentration (MIC) and Minimum Bactericidal Concentration (MBC) were determined for each isolate using reference dilution methods (NCCLS). Penicillin MBC results matched very closely to the MIC values. Penicillin and erythromycin were tested at clinically relevant concentrations of 10 and 1 μg/ml, respectively, alone and in combination. Interpretations were calculated comparing the penicillin + erythromycin killing effect versus penicillin or erythromycin rates tested alone. There was consistent bactericidal activity against S. pneumoniae by each drug alone and combined over the monitored five-hour period, except for an erythromycin induced-resistant isolate. Drug interactions ranged from synergy to antagonism, depending on the criteria applied. Antagonism risk of macrolide-penicillin combinations appeared to be minimal and method-dependent by in vitro tests.

Voriconazole: a new triazole antifungal agent.

Voriconazole is a second-generation azole antifungal agent that shows excellent in vitro activity against a wide variety of yeasts and molds. It can be given by either the intravenous or the oral route; the oral formulation has excellent bioavailability. The side effect profile of voriconazole is unique in that non-sight-threatening, transient visual disturbances occur in approximately 30% of patients given the drug. Rash (which can manifest as photosensitivity) and hepatitis also occur. The potential for drug-drug interactions is high and requires that careful attention be given to dosage regimens and monitoring of serum levels and effects of interacting drugs. Voriconazole has been approved for the treatment of invasive aspergillosis and refractory infections with Pseudallescheria/Scedosporium and Fusarium species, and it will likely become the drug of choice for treatment of serious infections with those filamentous fungi.

Solution Chemistry of Copper(II)−Gentamicin Complexes: Relevance to Metal-Related Aminoglycoside Toxicity

The adverse effect to the inner ear of aminoglycosides, drugs widely administered for the treatment of serious infections, appears to result from the interaction of these drugs with Cu(II) or Fe(II)/Fe(III) ions. To understand more completely the metal-induced side effects of one such antibiotic, gentamicin, we studied copper(II) coordination to gentamicin C1a by potentiometry, UV-vis, CD, and EPR spectroscopies, and ESI mass spectrometry. Only monomeric complexes of the CuH(n)L stoichiometry, with n ranging from 3 to -2, were detected over the pH range of 4-12. CuH(3)L and CuH(2)L complexes exhibit the same coordination mode, binding copper(II) through the amino nitrogen atom and a deprotonated alcoholic oxygen atom of the garosamine ring. In the CuHL and CuL complexes a second amino nitrogen atom of the purpurosamine ring participates in central ion coordination. Finally, the additional axial binding of the deprotonated oxygen of the hydroxyl group of the 2-deoxystreptamine moiety occurs in the CuH(-)(1)L and CuH(-)(2)L complexes. Interactions of the Cu(II)-gentamicin-H(2)O(2) system at pH 7.4 with N,N-dimethyl-p-nitrosoaniline, arachidonic acid, and plasmid DNA confirmed that gentamicin complexes facilitate oxidative reactions leading to peroxidation of arachidonic acid and scission of double-stranded DNA mediated by copper-bound reactive oxygen species. However, the stability constants of Cu(II)-gentamicin complexes are inferior to the binding constants of copper(II) complexes with other components of human serum or cells. Computer simulations of copper(II) distribution in the human blood plasma showed that the concentration of gentamicin would have to be at impossible levels (100 M) before a significant fraction of Cu(II) ions would be bound to gentamicin. Further, once introduced into aqueous solution, histidine replaces gentamicin in Cu(II)-gentamicin complexes. Therefore, Cu(II)-gentamicin complexes might not exist under physiological conditions.

Novel agents for the treatment of resistant Gram-positive infections

Bacteria have proved themselves able to develop resistance to every antibiotic used clinically. Traditional agents used for treatment of serious infections caused by Gram-positive species have recently been supplemented with the introduction of linezolid, quinupristin-dalfopristin, several new quinolones and telithromycin. However, resistance to many of these agents has already been reported and, although each currently retains activity against the vast majority of clinical isolates of its target species, their long-term efficacy is uncertain. We must look to develop other compounds to replace and hopefully improve upon existing anti-Gram-positive agents. Daptomycin (a lipopeptide), oritavancin and dalbavancin (both second-generation glycopeptides) and ramoplanin (a glycolipodepsipeptide) are among the agents in advanced stages of development and, at present, many seem likely to proceed to licensing. In addition, it is encouraging that many agents active against novel bacterial targets have been discovered and are in earlier stages of development. In the next two decades, we should be optimistic that a regular flow of new anti-Gram-positive agents will enable us to offset the constant spectre of bacterial resistance.

Evaluation of the in vitro activity of six broad-spectrum β-lactam antimicrobial agents tested against recent clinical isolates from India: a survey of ten medical center laboratories

The widespread use of β-lactam antimicrobial agents as first-line therapy for the treatment of serious infections has led to the development of various resistances that have compromised the use of some agents. In certain countries, the lack of local or national surveillance programs limits the ability to detect these resistant strains and prevent their dissemination. A 10 medical center study in India was initiated to benchmark prevailing resistance rates for a range of bacterial pathogens to β-lactams, and it found high rates of β-lactamase-mediated resistance in Escherichia coli and Klebsiella spp. These rates included: cephalosporins (55.6–61.3% resistance), with extended-spectrum β-lactamase (ESBL) phenotypes noted in over 60% of E. coli isolates and in Salmonella spp. (3.2–8.1%). Imipenem, a carbapenem, was the only antimicrobial agent tested with 100% activity against Enterobacteriaceae. Cefpirome was the most active of the tested cephalosporins, and all were fully active against methicillin-susceptible staphylococci with the exception of ceftazidime. Molecular and susceptibility characterization of 52 selected ESBL-producing strains showed a high level of co-resistance with aminoglycosides and fluoroquinolones, and clonal dissemination of resistant strains within medical centers. Collaborative studies, such as those presented here, can accurately detect changes in resistance patterns, and their continued use may help limit the further development and spread of bacterial resistances in India.

Quinupristin–dalfopristin: a streptogramin antibiotic

Over the past 10 years, hospitals have witnessed the growing resistance of gram-positive organisms to many antibiotics. In September 1999, quinupristin–dalfopristin (Synercid) was approved by the U.S. Food and Drug Administration. It is the first injectable streptogramin antibiotic and is indicated for the treatment of serious infections (bacteremia and complicated skin infections) caused by vancomycin-resistant Enterococcus faecium (VREF) and methicillin-susceptible Staphylococcus aureus and Streptococcus pyogens. The dosage is 7.5 mg/kg intravenously every 8 hours for VREF infections and every 12 hours for skin and skin structure infections. The most common side effect is pain and inflammation at the infusion site. Other side effects include nausea, arthralgias, myalgias, diarrhea, vomiting, and rash. The average wholesale price of quinupristin–dalfopristin is $107 for a 500-mg vial.

Linezolid (Zyvox)

Linezolid (Zyvox) is a member of the first new category of antibiotics in 35 years. It is an oxazolidinone that blocks bacterial protein synthesis by a method unlike any other antibiotic, making cross-resistance unlikely. It is available in oral and intravenous formulations and can be used to treat infections caused by gram-positive organisms resistant to most other antibiotics, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. As with any medication, adverse effects have been noted with linezolid, but they usually are mild to moderate in intensity. Most commonly seen are headache, nausea, vomiting, and diarrhea. Linezolid is a very expensive antibiotic and should be used only for treatment of serious infections caused by microorganisms that are resistant to other antibiotics. Linezolid is a Pregnancy Category C drug. Physicians should use the antibiotic with caution in pregnant and lactating women and only when the benefit clearly outweighs the potential risk to the fetus or infant.

Practical aspects of choosing an antibiotic for patients with a reported allergy to an antibiotic.

Physicians often must select antibiotics for patients who are reported to have an antibiotic allergy. For penicillins, the sensitivity of penicillin skin testing for predicting serious allergic reactions is excellent. For other beta-lactam antibiotics, penicillin skin testing is useful for excluding the possibility of sensitivity to the beta-lactam ring. For other antibiotics, the patient history remains the most useful tool for determining whether a serious reaction is likely to occur with further drug exposure. The cross-reactivity between penicillins and second- or third-generation cephalosporins (excluding cefamandole) is probably no higher than is the cross-reactivity between penicillins and other classes of antibiotics. When a patient has a suspected immunoglobulin E-mediated antibiotic allergy, desensitization therapy should be considered, if the efficacy of alternate antibiotics is in doubt. For the treatment of serious infections, it is usually possible to safely administer the antibiotic of choice despite a history of possible antibiotic allergy.

Potency and antimicrobial spectrum update for piperacillin/tazobactam (2000): emphasis on its activity against resistant organism populations and generally untested species causing community-acquired respiratory tract infections

The in vitro activity of piperacillin/tazobactam and several comparison broad-spectrum compounds was assessed against recent clinical isolates of Gram-positive and -negative bacteria from geographically diverse medical centers in Europe, North and Latin America participating in various surveillance programs in 2000. Several organisms were characterized for phenotypic expression of various resistant determinants such as extended-spectrum β-lactamase (ESBL) or amp C cephalosporinase hyperproduction, and vancomycin resistance in enterococci (VRE). Piperacillin/tazobactam retained activity (MIC 50) against oxacillin-susceptible Staphylococcus spp. (0.12–0.5 μg/ml), Bacillus spp. (0.5 μg/ml), vancomycin-susceptible enterococci (>4 μg/ml), and Corynebacterium spp. (2 μg/ml; not including C. jeikeium) with susceptibility rates of 100.0, 91.7, 85.7 and 81.8%, respectively. Piperacillin/tazobactam inhibited all Streptococcus spp. strains at ≤ 16 μg/ml, including penicillin-resistant strains many of which were co-resistant to erythromycin (90%) and other β-lactams. A specific breakpoint for these streptococci when testing piperacillin/tazobactam appears needed to prevent false-resistant reports using penicillin as a class representative. The carbapenems among β-lactams were the most active agents against the ESBL-producing species of Escherichia coli and Klebsiella pneumoniae and those strains which hyper-express amp C enzymes including Citrobacter spp. and Enterobacter spp. Piperacillin/tazobactam only exhibited modest activity against the “amp C resistance group” strains (68.8% susceptible or intermediate, MIC ≤ 64 μg/ml). Piperacillin/tazobactam (MIC 50, 8 μg/ml; 79.5% susceptible) was the most active agent tested against multi-drug resistant isolates of Pseudomonas aeruginosa. Against sampled Haemophilus influenzae (39.2% ampicillin-resistant), piperacillin/tazobactam (MIC 90, ≤ 0.06 μg/ml), ceftriaxone and ceftazidime inhibited 100.0% of the isolates at ≤ 0.25 μg/ml. These in vitro surveillance results from the year 2000 on three continents, demonstrated a sustained potent activity of piperacillin/tazobactam against selected problematic nosocomial and community-acquired pathogens. The potential importance of these findings is that this β-lactamase inhibitor combination can be used an empiric treatment of serious infections in hospital environments where resistance has emerged, as well as covering nearly all isolates of fastidious respiratory tract pathogens acquired in the community setting.