sign in sign up
<<
Home , Ramoplanin

VIEWPOINTS

Bad Bugs Need Drugs: An Update on the Development Pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America

George H. Talbot,1 John Bradley,2,3 John E. Edwards, Jr.,4,5 David Gilbert,6 Michael Scheld,7 and John G. Bartlett8 1Talbot Advisors, Wayne, Pennsylvania; 2Division of Infectious Diseases, Children’s Hospital and Health Center and 3University of California at San Diego, San Diego, 4Division of Infectious Diseases, Harbor–University of California at Los Angeles Medical Center, and the Los Angeles Biomedical Research Institute, Torrance, and 5The David Geffen School of Medicine at UCLA, Los Angeles, California; 6Division of Infectious Diseases, Providence Portland Medical Center and Oregon Health Sciences University, Portland; 7Department of Medicine, University of Virginia School of Medicine, Charlottesville; and 8Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

The Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA) has viewed with concern the decreasing investment by major pharmaceutical companies in antimicrobial research and development. Although smaller companies are stepping forward to address this gap, their success is uncertain. The IDSA proposed legislative and other federal solutions to this emerging public health problem in its July 2004 policy report “Bad Bugs, No Drugs: As R&D Stagnates, a Public Health Crisis Brews.” At this time, the legislative response cannot be predicted. To emphasize further the urgency of the problem for the benefit of legislators and policy makers and to capture the ongoing frustration our clinician colleagues experience in their frequent return to an inadequate medicine cabinet, the AATF has prepared this review to highlight pathogens that are frequently resistant to licensed antimicrobials and for which few, if any, potentially effective drugs are identifiable in the late-stage development pipeline.

Infections caused by multidrug-resistant 10]. Smaller companies are attempting to a Public Health Crisis Brews,” which pro- microbes present daily challenges to in- step forward to address the medical need, posed potential solutions to the problem fectious diseases physicians and their pa- but it is not yet clear that they will have of decreasing antibiotic development by tients in the United States and throughout the financial wherewithal, clinical devel- major pharmaceutical companies [13]. the world [1, 2]. Despite an increasing fre- opment infrastructure, or partnering op- Important members of the US Senate and quency and severity of antimicrobial re- portunities with large pharmaceutical US House of Representatives appear to sistance, the future development of new companies that would allow their prod- have taken notice of the issues raised by anti-infective agents is threatened by the ucts to reach the market [11, 12]. IDSA, because favorable legislation devel- cessation of research in this field by many In March 2003, the Antimicrobial Avail- oped with IDSA’s significant input has major pharmaceutical companies [3–6]. ability Task Force (AATF) of the Infectious been introduced in both Houses of Con- For these larger companies, discovery and Diseases Society of America (IDSA) was gress [14–17]. In the opinion of the AATF, clinical development of novel anti-infec- constituted by the IDSA Board of Direc- passage of legislation that includes the ma- tive agents incurs substantial financial dis- tors. The AATF was charged with evalu- jor concepts in these initial bills would go incentives largely related to the relatively ating current trends related to the re- far toward establishing the dynamic, well- low return on investment that is intrinsic search, development, and manufacture of funded antimicrobial drug discovery in- to anti-infective drug development [7– anti-infective therapies at a time of in- frastructure necessary for the subsequent creasing antimicrobial resistance and, fur- development and production of drugs. Received 27 October 2005; accepted 28 October 2005; thermore, with making recommendations Although patient lives are at the heart electronically published 25 January 2005. to promote the value of these products of IDSA’s advocacy campaign, the favor- Reprints or correspondence: Dr. George H. Talbot, 564 Maplewood Ave., Wayne, PA 19087 ([email protected]) and ensure their future availability. As a able impact of robust programs for dis- Clinical Infectious Diseases 2006;42:657–68 result of such evaluations, the AATF pre- covery and development of antimicrobial 2006 by the Infectious Diseases Society of America. All rights reserved. pared a policy report entitled “Bad Bugs, agents on health care economics must be 1058-4838/2006/4205-0011$15.00 No Drugs: As Antibiotic R&D Stagnates, mentioned. Passage of transformative leg-

Anti-Infective Development Pipeline • CID 2006:42 (1 March) • 657 islation would be a bargain when mea- opment pipeline: (1) the Pharmaceutical commonly found in the environment. sured against the toll of antimicrobial re- Research and Manufacturers Association Although previously considered to be rel- sistance: the loss of thousands of lives and survey of medicines in development for atively avirulent, the Acinetobacter cal- the avoidable cost of billions of health care treatment of infectious diseases was coaceticus-baumannii complex is emerg- dollars. The AATF believes that its message searched according to relevant infection ing as a problematic, multidrug-resistant, to legislators and policy makers will be categories (available at: http://i.phrma nosocomial and community-acquired better communicated, and the chances for .org/newmedicines/); (2) abstracts from pathogen. The incidence of severe infec- enactment of helpful legislation strength- the 2002–2004 Interscience Conferences tion caused by Acinetobacter species has ened, if a more detailed illustration of the on Antimicrobial Agents and Chemother- been increasing. For example, National “bad bugs, no drugs” problem were pro- apy were searched for late-stage investi- Nosocomial Infection Survey data for US vided. The current article offers such a gational antimicrobials by using the search intensive care units indicate that Acine- review. term “phase” [18]; (3) the Web sites of tobacter species caused 6.9% of cases of the 15 major pharmaceutical and the 7 hospital-acquired pneumonia in 2003, largest biotechnology companies identi- METHODS compared with 1.4% in 1975; the rates fied by Spellberg et al. [3] were accessed, The AATF created a list of high-priority of bloodstream infection, surgical site in- and data on drugs in development were bacterial and fungal pathogens on the ba- fection, and urinary tract infection also reviewed; (4) the PubMed database was sis of у1 of the following characteristics: increased during this period (from 1.8% searched for relevant literature published current clinical and/or public health con- to 2.4%, 0.5% to 2.1%, and 0.6% to from January 2003 through August 2005 cern in the United States because of a high 1.6%, respectively) [23]. by using the search terms “antimicrobial incidence of infection and substantial Risk factors for development of A. drug development,” “investigational an- morbidity; infection with high attributable baumannii infection include alcoholism, timicrobials,” and “novel antimicrobials”; mortality rates, even if the population- and (5) ClinicalTrials.gov (available at: smoking, chronic lung disease, and/or in- based incidence is low (e.g., the majority http://www.clinicaltrials.gov) was accessed vasive procedures. Although the organ- of infections occur in immunocomprom- and searched by Condition, with a Disease ism can cause suppurative infection in ised patients in tertiary care medical cen- Heading of “Bacterial and Fungal Infec- virtually any organ system, patients re- ters); and unique virulence or resistance tions.” These searches were comple- ceiving mechanical ventilation are at spe- factors that could circumvent the usual mented by reference to recent reviews of cial risk for hospital-acquired pneumonia therapeutic effect of antimicrobial therapy. the topic [19–22]. Nonabsorbable anti- caused by Acinetobacter species. The in- An additional criterion was the presence microbials administered via the gastroin- fection presents as a multilobar infiltrate, of few or no novel candidates in the late- testinal tract (e.g., ramoplanin) or respi- often with accompanying cavitation, stage US drug-development pipeline for ratory tract (e.g., ) were pleural effusion, and fistula formation. treatment of infection due to these path- excluded from consideration for this US mortality rates for this infection have ogens. We chose to focus only on com- review. been reported to be 19%–54% [23]. pounds in phases 2 or 3 of development The role of Acinetobacter species in (i.e., studies of therapy for specific infec- RESULTS war-related injuries is now well docu- tions, with well-defined inclusion and ex- mented [24]. Soldiers serving in Iraq and clusion criteria), given the high failure rate Members of the AATF identified the fol- Afghanistan have had osteomyelitis and/ of compounds that have not successfully lowing particularly problematic pathogens: or wound infection due to these patho- navigated phase 1 studies (i.e., initial sin- Acinetobacter baumannii, Aspergillus spe- gle- or multiple-dose studies involving cies, extended spectrum b-lactamase gens. Bacteremia may occur 3–5 days af- healthy adult volunteers conducted pri- (ESBL)–producing Enterobacteriaceae, ter the onset of wound infection. Many marily to collect pharmacokinetic and -resistant Enterococcus faecium, of the isolates are multidrug resistant. safety data). For each organism proposed , and - Similar findings were observed in Viet- for the list, a rationale for inclusion was resistant Staphylococcus aureus (MRSA). nam, where Acinetobacter species were drafted and the needs for drug develop- Compounds, if any, in late-stage develop- the most common gram-negative organ- ment identified. The list of pathogens was ment for treatment of infection due to these isms to contaminate extremity injuries not conceived of as exhaustive but rather organisms are shown in tables 1, 2, and 3. and the second most common blood- as illustrative of pathogens considered to stream isolates. An additional, unique be most important. A. baumannii setting for Acinetobacter infection in- The following sources were used to Rationale for interest. Acinetobacter volved survivors of the Asian tsunami in identify the drug candidates in the devel- species are gram-negative organisms December 2004 [25]. These isolates have

658 • CID 2006:42 (1 March) • Talbot et al. Table 1. Antifungal compounds undergoing development in phase 2 or later clinical studies.

Novel Compound (brand name; mechanism Development or manufacturer) Class (mechanism of action) of action? Formulation(s) approval status Comments Anidulafungin (Pfizer) Echinocandin (cell-wall No Intravenous Filed for FDA approval Initial application for esophageal candidiasis rejected by FDA; application synthesis inhibitor) resubmitted August 2005 for use against invasive candidiasis and candidemia; acquired by purchase of Vicuron Pharmaceuticals, 2005 BAL-8557 (Basilea) Azole (cell membrane inhibitor) No Intravenous and oral Phase 3 Phase 2 study conducted in persons with esophageal candidiasis Mycograb (Neutec) Human genetically recombi- Yes Intravenous Phase 3 Therapy for candidiasis; may have potential for therapy of aspergillosis nant antibody targeting im- munodominant yeast heat shock protein 90 Posaconazole (Noxafil; Azole (cell membrane inhibitor) No Oral Phase 3 FDA application filed in 2004 for treatment of invasive fungal infections Schering-Plough) (e.g., aspergillosis, fusariosis, and zygomycosis) in patients with re- fractory disease or intolerance to other therapy. Approved by FDA in June 2005; intravenous formulation undergoing phase 1 study; likely role for therapy of endemic mycoses Ravuconazole (Esai) Azole (cell membrane inhibitor) No Intravenous and oral Unknown Compound returned by Bristol-Myers Squibb to Esai in 2004

NOTE. FDA, US Food and Drug Administration. Table 2. Antimicrobial compounds undergoing development in phase 2 or later clinical studies.

Novel mechanism Development or Compound name(s) (brand name; manufacturer) Class (mechanism of action) of action? Formulation approval status Comments Primarily gram-positive aerobic spectrum (Pfizer) (cell-wall synthe- No Intravenous Filed for FDA approval New drug application filed in December 2004 for complicated skin and skin struc- sis inhibitor) ture infection; active in vitro against staphylococci (including MRSA) and strep- tococci; long half-life allowing once weekly administration; acquired by pur- chase of Vicuron Pharmaceuticals Iclaprim (Arpida) Diaminopyrimidine (dihydrofolate No Intravenous Phase 3 Primarily active in vitro against MRSA; an oral formulation is in early development reductase inhibitor) (Targanta) Glycopeptide (cell-wall synthesis No Intravenous Phase 3 Active in vitro against staphylococci (including MRSA), streptococci, and entero- inhibitor) cocci; has long half-life; acquired from InterMune, 2006 (Theravance) Lipoglycopeptide (cell-wall synthe- Yes Intravenous Phase 3 Active in vitro against staphylococci (including MRSA), streptococci, and sis inhibitor; membrane enterococci perturbation) Topical pleuromutilin, SB-275833 Pleuromutilin (protein synthesis Yes Topical Phase 3 Active in vitro against staphylococci, including -resistant strains, and (GlaxoSmithKline) inhibitor) streptococci Gram-positive and gram-negative aerobic spectra (Basilea; Johnson & Johnson) (cell-wall synthesis No Intravenous Phase 3 Active in vitro against staphylococci (including MRSA), streptococci, and wild-type inhibitor) enteric gram-negative bacilli; licensed by Johnson & Johnson in 2005 Cethromycin (Advanced Life Sciences) Ketolide (protein synthesis inhibitor) No Oral Phase 3 Licensed from Abbott; community respiratory tract pathogen spectrum (Johnson & Johnson) (cell-wall synthesis No Intravenous Phase 3 Acquired with Peninsula Pharmaceuticals, 2005; spectrum similar to that of mar- inhibitor) keted but somewhat more active in vitro against Pseudomonas aeruginosa daloxate (Replidyne) (cell-wall synthesis inhibitor) No Oral Phase 3 Licensed from Daiichi Suntory; community respiratory tract pathogen spectrum, excluding atypical pathogens Garenoxacin (Schering-Plough) Quinolone (topoisomerase inhibitor) No Oral Phase 3 Licensed from Toyama in 2004; Schering-Plough has indicated it may sublicense the compound; community respiratory tract pathogen spectrum PPI-0903, TAK-599 (Cerexa) Cephalosporin (cell-wall synthesis No Intravenous Phase 2 Active in vitro against staphylococci (including MRSA), streptococci, and wild-type inhibitor) enteric gram-negative bacilli; licensed from Takeda by Peninsula Pharmaceuti- cals and transferred to Cerexa in 2005 Prulifloxacin (Optimer) Quinolone (topoisomerase inhibitor) No Oral Phase 3 Licensed from Nippon Shinyaku by Optimer; community respiratory tract patho- gen spectrum RO-4908463, CS-023 (Roche) Carbapenem (cell-wall synthesis No Intravenous Phase 2 Licensed from Sankyo by Roche; undergoing phase 2 study for pneumonia; spec- inhibitor) trum similar to that of marketed carbapenems but somewhat more active in vitro against MRSA and P. aeruginosa

NOTE. FDA, US Food and Drug Administration; MRSA, methicillin-resistant Staphylococcus aureus. been highly resistant to antimicrobial Aspergillus Species agent are common. Additionally, there is drugs. Rationale for interest. Aspergillus spe- substantial interpatient pharmacokinetic Therapy of Acinetobacter infection has cies are filamentous fungi that play a pre- variability, requiring monitoring of blood been complicated by increasing resistance dominant role in infections of immu- concentrations in certain circumstances. due to aminoglycoside-modifying en- nocompromised hosts, especially persons The needs for drug development zymes, ESBLs, carbapenemases, or developing neutropenia as a consequence Currently, once invasive aspergillosis has changes in outer-membrane proteins and of cytotoxic chemotherapy for cancer or developed, cure rates are astonishingly -binding proteins [26]. In some receiving immunosuppressive treatment low, and mortality rates are very high. parts of the United States, many isolates for organ and stem cell transplants [32– Current therapeutic options are charac- are now resistant to all aminoglycosides, 37]. The incidence of invasive Aspergillus terized by drug-drug interactions, tox- , and fluoroquinolones infections has been increasing and is an- icities, and increasing rates of resistance. [27]. The carbapenems and combina- ticipated to continue to do so as the More-efficacious and better-tolerated tions of a b-lactam with a b-lactamase number of immunocompromised pa- therapies are needed. Orally available inhibitor, such as -, tients increases substantially [38]. Al- compounds would be highly useful. In retain useful activity, but resistance rates though the incidence of candidiasis in addition, prophylactic and effective em- are increasing [28]. , previously these populations is higher than that of pirical treatment strategies are desirable abandoned in clinical use because of an invasive aspergillosis, several reasonable for populations of patients susceptible to unacceptably high rate of renal toxicity, alternatives exist for the treatment of aspergillosis. is currently the most reliably active agent candidal infections. The status of various antifungal drugs [29, 30]. Therefore, clinicians must resort Aspergillus infections have a high mor- in late-stage development is shown in ta- to empirical combination therapy, which tality rate (approaching 50%–60%), de- ble 1. Of note, the registration strategy has an unproven utility, and therapeutic spite the best treatment with recently ap- often involves study of candidiasis, as op- failures and relapses can be anticipated. proved antifungals [39]. Improvement of posed to aspergillosis, because of the The needs for drug development. these dismal treatment success rates greater ease of investigating efficacy and The recent US Food and Drug Admin- would increase the chance for patients safety in Candida infections; data on po- istration (FDA) approval of tigecycline with cancer to have a normal life span tential antiaspergillus activity are often for treatment of complicated skin and and allow organ transplant recipients not limited. Of the 5 drugs listed in table 1, skin structure infections and complicated only to survive longer but also to avoid posaconazole and ravuconazole show intra-abdominal infections in adults may repeated transplantations. promise as compounds with activity offer clinicians a therapeutic option, be- Each of the existing agents commonly against Aspergillus species. Vaccine de- cause the compound is active in vitro used for the treatment of aspergillosis has velopment is only in the formative stages. against some current A. baumannii iso- significant limitations. Amphotericin B In summary, a substantive breakthrough lates [31]; studies are ongoing to assess deoxycholate is highly toxic; the newer in the research and development of drugs its efficacy and safety in treatment of Aci- lipid formulations of amphotericin B, al- with antiaspergillus activity is not on the netobacter infections (Evan Loh, personal though somewhat better tolerated than horizon. communication). Because of the poten- amphotericin B deoxycholate, are not tial toxicities inherent in use of antimi- substantially more efficacious. Although ESBL-Producing E. coli and Klebsiella crobials similar to tetracycline to treat the echinocandin caspofungin has re- Species children, studies of tigecycline in this age ceived FDA approval as second-line ther- Rationale for interest. Of all aerobic group are not likely to be undertaken. apy for aspergillosis, it is not approved gram-negative bacilli, E. coli and Kleb- Unfortunately, we could not find an- for primary therapy, and its marketing siella species most frequently cause dis- other compound in the pipeline for treat- authorization was based on study of the ease in humans, with the most common ment of multidrug-resistant Acinetobac- drug in !80 patients [40]. Studies ex- sites of infection being the urinary tract, ter infection (table 2). With the amining the efficacy of caspofungin, li- biliary tract, gastrointestinal tract, and increasing incidence of Acinetobacter in- posomal amphotericin B, and voricona- wounds due to trauma. Bacteremia, hos- fection and increasing rates of multidrug zole (an azole) have shown very low pital-acquired pneumonia, postoperative resistance, A. baumannii is a prime ex- success rates of ∼40% [41–43]. Voricon- meningitis, and other nosocomial infec- ample of a mismatch between unmet azole is now generally considered to be tions produce life-threatening disease medical needs and the current antimi- the drug of choice for the primary treat- [44–50]. Increasing in vitro resistance of crobial research and development ment of invasive aspergillosis [39]. How- these pathogens to b-lactam pipeline. ever, drug-drug interactions with this and to other classes of antimicrobials sig-

Anti-Infective Development Pipeline • CID 2006:42 (1 March) • 661 Table 3. Antistaphylococcal vaccines and immunoglobulins undergoing development in phase 2 or later clinical studies.

Route of Compound name (brand name; manufacturer) Mechanism of action administration Development status Comments Staphylococcus aureus polysaccharide conjugate Polysaccharide conjugate vaccine comprised Intramuscular Terminated Prevention of S. aureus infection in pa- vaccine (StaphVAX; Nabi Biopharmaceuticals) of S. aureus capsular polysaccharides 5 tients with end-stage renal disease un- and 8 conjugated to nontoxic recombinant dergoing hemodialysis; failed in phase 3 Pseudomonas aeruginosa exotoxin S. aureus immune globulin, intravenous [human Hyperimmune, polyclonal immune globulin Intravenous Phase 2 Prevention of infection in patients undergo- formulation] (Altastaph; Nabi raised by vaccination of healthy volunteers ing hemodialysis and infants with very Biopharmaceuticals) with StaphVAX low birth weight Phase 2 Adjunctive therapy of persistent S. aureus bacteremia Tefibazumab (Aurexis; Inhibitex) Humanized monoclonal antibody Intravenous Phase 2 Therapy of S. aureus bacteremia INH-A21 (Veronate; Inhibitex) Donor-selected polyclonal human immune Intravenous Phase 3 Prevention of infection in infants with very globulin enriched in antibody to cell-sur- low birth weight face adhesion proteins BSYX-A110 (MedImmune) Antilipoteichoic acid monoclonal antibody Intravenous Phase 2 Prevention of infection in infants with low birth weight; recently acquired from GlaxoSmithKline S. aureus genetically recombinant antibody (Auro- Human genetically recombinant antibody Intravenous Phase 3 Adjunctive therapy of staphylococcal grab; Neutec) fragment that binds to the immunodomi- infection nant cell surface antigen, GrfA, a staphylo- coccal ATP-binding cassette transporter protein nals the urgent need for new effective the 47% increase in the prevalence the medical need created by the emer- drugs. of resistance among K. pneumoniae iso- gence of carbapenemases. Tigecycline ex- The spectrum and number of b-lac- lates was by far the largest change hibits in vitro activity against ESBL-pro- tamases have increased dramatically in encountered. ducing E. coli and Klebsiella species and recent years [51, 52]. The number of dis- Resistance to other classes of antibac- may prove to be a useful agent for in- crete enzymes identified increased from terials is common among ESBL-produc- fections caused by these pathogens [31]. 13 in 1970 to 282 in 1999; by 2004, the ing organisms. Of 57 ESBL-producing The need for additional discovery and total had jumped to 532 (Karen Bush, clinical isolates of Klebsiella oxytoca col- development efforts for drugs active personal communication). Furthermore, lected from April 2001 through June against ESBL-producing E. coli and Kleb- the substrate range of the enzymes has 2003, a total of 56 were also resistant to siella species is evident. broadened from the aminoglycosides, trimethoprim-sulfa- (e.g., ampicillin) to the extended-spec- methoxazole, and fluoroquinolones [48]. Vancomycin-Resistant E. faecium trum cephalosporins (e.g., The latter results were confirmed in a Rationale for interest. Antibiotic-resis- and ), a (i.e., az- second report: of 91 ESBL–producing tant enterococci have bedeviled infec- treonam), the b-lacta- Klebsiella species, 84% were resistant to tious diseases clinicians for decades [59]. mase inhibitor combinations (e.g., gentamicin, 70% were resistant to tri- On the one hand, it is often difficult to ampicillin and sulbactam), the ureido- methoprim-sulfamethoxazole, 60% were ascertain whether a given isolate is caus- (e.g., ), and, finally, resistant to piperacillin-, and ing disease; on the other hand, when the carbapenems (e.g., and ci- 51% were resistant to ciprofloxacin; none treatment is indicated, the therapeutic lastatin; ; and ) was resistant to imipenem [56]. However, options are limited, especially when bac- [52]. In vitro resistance to 2 other reports document outbreaks of tericidal activity is desirable. More re- and/or aztreonam is used as a phenotypic infection with Klebsiella species that pro- cently, E. faecium has been a particularly marker of one of these new groups of duce carbapenem class A b-lactamases problematic pathogen; in contrast to enzymes, referred to as ESBLs. Unfor- [57, 58]. most isolates of Enterococcus faecalis, E. tunately, the acquisition of new enzymes The acquisition of resistance genes has faecium has exhibited high rates of gly- is not associated with loss of ability to not decreased the pathogenicity or vir- copeptide resistance in the United States. hydrolyze the earlier b-lactams, such as ulence of Klebsiella species and E. coli.In Enterococci are now a significant cause ampicillin. the United States, outbreaks of infection of bloodstream infection in hospitalized The prevalence of ESBL production have increased in frequency since the ini- patients, including patients in and those among E. coli and Klebsiella species varies tial event in 1988 [44–50]. In patients not in intensive care unit wards (9.0% depending on geography, nature of the with bacteremia due to ESBL-producing and 9.8%, respectively) [60]. Other prob- institution, age of population, and pa- K. pneumoniae, the failure to treat with lematic enterococcal infections include tient comorbidities. During a 6-year pe- an antibacterial with in vitro activity re- endocarditis, catheter-associated bacter- riod (1997–2002), Klebsiella species with sulted in a mortality rate of 64%, com- emia, meningitis, and intra-abdominal an ESBL phenotype were identified in pared with a mortality rate of 14% infection [59]. Groups particularly sus- blood cultures at a rate of 42.7% in Latin among patients who received an active ceptible to infection with this pathogen America, 21.7% in Europe, and 5.8% in antibacterial [47]. include patients with neutropenia [59] North America [53]. A 2001 North The needs for drug development. and/or cancer [61], patients receiving American surveillance study of isolates The research and development pipeline long-term hemodialysis [62], and liver from intensive care units found that for agents active against ESBL-producing transplant recipients [63]. Rates of van- prevalences of the ESBL phenotype were gram-negative bacilli is spare (table 2). comycin resistance among E. faecium iso- 11.2% for E. coli and 16.2% for Klebsiella Our search for new, relevant drugs in lates as high as 70% have been reported species [54]. clinical trials at the phase 2 level or be- in high-risk populations [54, 55, 60]; in A more recent survey of selected an- yond identified only 2 carbapenems un- one recent survey of 494 US hospitals, a timicrobial-resistant pathogens associ- der investigation. Doripenem, currently mean rate of 10% across all patient care ated with nosocomial infections in inten- in phase 3 clinical trials, is a carbapenem areas was observed [2]. These pathogens sive care unit patients highlights the with a spectrum of activity against gram- are a particular problem in the intensive problem [55]. The resistance rates re- negative bacteria that is similar to that of care unit [55]. ported for 2003 were compared with data meropenem; RO-4908463 (also known as Although there has been considerable collected from 1998 through 2002. CS-023) is undergoing phase 2 study. controversy as to whether vancomycin Among 9 resistant pathogens reported, Neither of these compounds will address resistance in cases of enterococcal blood-

Anti-Infective Development Pipeline • CID 2006:42 (1 March) • 663 stream infection is independently asso- 68]. The organism is also found in the pathogen [71]. This loss of permeability ciated with mortality, a recent meta-anal- lower respiratory tract airway of children has been an important cause of resistance ysis found a clearly elevated risk (OR, with cystic fibrosis, inciting inflammation to imipenem during the past several 2.52; 95% CI, 1.9–3.4) [64]. Further- that inexorably destroys lung tissue and years. Multiple mechanisms of resistance more, infections due to these organisms ultimately leads to respiratory failure and may be present simultaneously, with each incur substantial economic costs [65]. death [69]. contributing to overall resistance to a The needs for drug development. As with Acinetobacter species and given antibiotic. Because increasing re- In contrast to the situation for some of ESBL-producing Enterobacteriaceae, the sistance is not usually associated with de- the other organisms discussed in this ar- incidence of P. aeruginosa infection creased virulence in P. aeruginosa, infec- ticle, a variety of treatment options for among intensive care unit patients is in- tions are increasingly difficult to treat. vancomycin-resistant E. faecium infec- creasing. Whereas P. aeruginosa was the Increasing rates of antimicrobial resis- tions currently exists (table 2). For ex- etiological agent in 9.6% of cases of hos- tance among P. aeruginosa are a problem ample, quinupristin-dalfopristin and li- pital-acquired pneumonia in US inten- worldwide [71]. In the United States, nezolid have received FDA-approved sive care units in 1975, in 2003 the per- 33% of P. aeruginosa isolates were resis- labeling for treatment of selected types of centage had almost doubled to 18.1% tant to fluoroquinolones in 2002, for an vancomycin-resistant enterococcal infec- [55]. The rate of bloodstream infection increase of 37% from the period 1997 to tions. Although the marketed com- with P. aeruginosa was relatively stable 2001; 22% were resistant to imipenem, pounds and tigecycline are (4.8% in 1975 vs. 3.4% in 2003), but the for an increase of 32%; and 30% were active in vitro against these organisms, rates of surgical site infection and urinary resistant to ceftazidime, for an increase clinical data are not available to confirm tract infection approximately doubled of 22% [74]. These rates remained ele- their clinical efficacy and safety. between 1975 and 2003 (from 4.7% to vated in the 2004 surveillance report However, the available antimicrobials 9.5% and from 9.3% to 16.3%, [55]. In US intensive care units, rates of have various deficiencies. Both quinu- respectively). multidrug resistance (defined as resis- pristin-dalfopristin and linezolid lack Moreover, P. aeruginosa has a greater tance to у3 of the following agents: cef- bactericidal activity; in addition, only li- ability than most gram-positive and tazidime, ciprofloxacin, tobramycin, and nezolid is marketed in an oral formula- many gram-negative pathogens to de- imipenem) among P. aeruginosa in- tion. A clear need for the antienterococ- velop resistance to virtually any antibiotic creased from 4% in 1993 to 14% in 2002 cal armamentarium is an oral, to which it is exposed, because of mul- [75]. Most importantly, current US data bactericidal compound. No such drug is tiple resistance mechanisms that can be document statistically greater mortality in phase 2 or phase 3 development (table present within the pathogen concurrently for hospitalized patients who receive in- 2). Other potential approaches to therapy [70, 71]. In some clinical isolates, resis- adequate empirical antibiotic therapy for and prevention of enterococcal infections tance occurs to all available FDA-ap- P. aeruginosa bloodstream infections are vaccine-based or antibody-based in- proved antibiotics. (30.7%) than for those who receive ap- terventions. Both Nabi Biopharmaceut- The most common resistance mecha- propriate initial therapy (17.8%), high- icals and Inhibitex have preclinical pro- nism is production of b-lactamases, in- grams in these areas but no products in cluding penicillinases, cephalosporinases, lighting the need for development of ef- late-stage development. and carbapenemases [72]. The develop- fective agents [76]. ment of carbapenemases is especially om- Patients with cystic fibrosis represent P. aeruginosa inous, because carbapenems constitute one population that is especially plagued Rationale for interest. P. aeruginosa is the last remaining b-lactam class to by P. aeruginosa infection. Aggressive an invasive, gram-negative bacterial which most clinical isolates historically management of these children with par- pathogen that causes a wide range of se- have been susceptible. In addition, vari- enteral and/or inhaled antibiotics is now vere infections. Life-threatening infection ous efflux pump systems are capable of permitting them to live into their second may occur in patients who become im- actively removing virtually every antibi- and even third decades [77]. Most chil- munocompromised after chemotherapy otic from the intracellular milieu [73]. An dren with cystic fibrosis who survive to for cancer or immunosuppressive ther- additional mechanism of resistance in- adolescence are infected with organisms apy for organ transplantation [66]. Fur- volves mutations that cause changes resistant to all known antibiotics, with thermore, P. aeruginosa causes serious in- within the , leading to a dramatic the possible exception of colistin [29]. fections of the lower respiratory tract, the reduction in the number of porin chan- Eventually, lung transplantation becomes urinary tract, and wounds in younger nels through which antibiotics must the only hope for survival in these ado- and older hospitalized ill patients [67, travel to reach their target inside the lescents and young adults, because anti-

664 • CID 2006:42 (1 March) • Talbot et al. biotic therapy eventually becomes from person-to-person when crowding need is for effective antibiotics that can ineffective. occurs (e.g., in prisons and on athletic be taken orally, allowing for effective The needs for drug development. teams) or when infants and children play step-down therapy for nosocomial infec- There is a clear, unmet need for new an- together, cause skin and skin structure tion or initial therapy for infections ac- tibiotic therapies for P. aeruginosa infec- infection, osteomyelitis, and pneumonia. quired in the community. Some orally tions. Antibiotic agents in phases 2 or 3 Most of these organisms produce Pan- available compounds (e.g., DX-619 and development are limited to the carba- ton-Valentine leukocidin, a virulence fac- iclaprim) are undergoing phase 1 study. , to which resistance is already tor associated with severe, rapidly pro- Additional parenteral options are needed, present (table 2). Novel agents with the gressive infection, even in previously because some patients cannot tolerate ability to inhibit efflux pumps are in pre- healthy persons. Fortunately, Panton- treatment with 1 or more classes of drugs, clinical drug development, but they have Valentine leukocidin–producing com- because of allergy or other adverse drug not entered into human clinical trials. munity-associated MRSA strains contain reactions. Multiple novel approaches to antipseu- the relatively short staphylococcal cas- Topical alternatives to parenteral or domonal drug therapy are desperately sette chromosome IV, which thereby lim- oral therapies are useful in the outpatient needed; these could include new mech- its the number of resistance genes. There- setting. Among newer topical agents, anisms of action that have potent antip- fore, at present, these organisms remain GlaxoSmithKline’s topical pleuromutilin seudomonal activity, as well as innovative susceptible to a variety of non–b-lactam is closest to reaching the clinic (table 2), delivery systems [78]. antibiotics, including orally bioavailable but others (such as an agent from Re- compounds, such as clindamycin, plidyne) are in preclinical development. MRSA doxycycline, and trimethoprim-sulfa- Because many of the consequences of infection with S. aureus are related to Rationale for interest. S. aureus causes methoxazole. toxin production, toxin-targeted or other many types of serious infection, espe- In the United States, vancomycin has virulence factor–based interventions to cially in susceptible populations, such as been the mainstay of therapy for MRSA treat infection with this bacterium could premature infants and individuals who infection, but glycopeptide resistance is be useful; some immune globulin prep- have undergone surgery, are undergoing emerging, with documented resistant, arations that might impact virulence are dialysis, or have prosthetic devices. Nos- heteroresistant, and intermediately sus- under study. In addition, methods to pre- ocomial infection caused by S. aureus ceptible isolates recovered from persons vent infection before it occurs are also prolongs hospital stay, leads to increased with clinical infection [85]. Newer par- critically important. Several companies hospitalization-related costs, and sub- enteral antibiotic agents for severe MRSA are investigating antistaphylococcal im- stantially increases the rate of in-hospital infection include linezolid and dapto- munoglobulin (table 3). Success in this death [79]. mycin; rare strains resistant to these challenging area would be welcome. After the discovery of penicillin and newer drugs have been encountered. Ti- the tetracyclines and their introduction gecycline was recently granted marketing DISCUSSION into the clinical setting, S. aureus rapidly authorization by the FDA, and dalbavan- acquired resistance to these agents. A cin (a lipoglycopeptide) was submitted to Ensuring the continued availability of similar scenario evolved, albeit more the FDA for review in December 2004. novel antimicrobials to combat existing slowly, with the penicillinase-resistant These 2 compounds offer alternatives for and emerging pathogens, especially path- penicillins. MRSA is now the etiologic therapy of MRSA infection. ogens expressing resistance to currently pathogen for the majority of health care– Mupirocin has been shown to be ef- available therapies, is a critical public associated infections [80], and it creates fective as topical therapy for cutaneous health issue. Published inventories of a huge burden on the health care system, MRSA infection. However, mupirocin- drugs in development have taken a class- as evidenced by a rate of 3.95 MRSA in- resistant strains have been isolated and specific focus. Although this perspective is fections per 1000 discharges [81]. Nos- associated with therapeutic failures [86]. useful, the AATF believes that a pathogen- ocomial MRSA infection is associated The needs for drug development. driven analysis better highlights the with higher morbidity, mortality, and As can be seen in table 2, multiple anti- strengths and weaknesses of the product medical costs than infection caused by MRSA compounds are in late-stage de- pipeline. methicillin-susceptible S. aureus [82, 83]. velopment, and others, such as Paratek’s Our review of the current state of the The emergence of community-associ- compound PTK 0796, may be forthcom- pipeline reveals some variability in the ated MRSA has raised additional concern ing [80]. However, the apparent plethora number of development candidates from [84]. Strains of community-associated of available antibiotics for MRSA infec- organism to organism, with some, such as MRSA, which are readily transmitted tion is somewhat misleading. A critical MRSA, receiving substantial attention

Anti-Infective Development Pipeline • CID 2006:42 (1 March) • 665 from major pharmaceutical companies make their needs known via IDSA’s ad- velopment of new antimicrobial drugs: a po- tential serious threat to public health. Lancet and others, such as A. baumannii, Asper- vocacy efforts, as found on the IDSA Infect Dis 2005; 5:115–9. gillus species, ESBL-producing E. coli and Web site (available at: http://www 5. Wenzel RP. The antibiotic pipeline—chal- Klebsiella species, and P. aeruginosa, re- .idsociety.org). lenges, costs, and values. N Engl J Med 2004; 351:523–6. ceiving much less. The pipeline reflects ac- Acknowledgments 6. DeMaria A. Challenges of sexually transmitted tive decisions by these companies about disease prevention and control: no magic bul- where they are investing research dollars We wish to express appreciation to the following let, but some bullets would still be appreciated. on behalf of their shareholders. Unfor- colleagues for providing insight into the devel- Clin Infect Dis 2005; 41:804–7. opment pipeline: Drs. Michael Alekshun (Para- 7. Projan SJ. Why is big Pharma getting out of tunately, many of the problem pathogens tek), Helen Boucher (Cubist and Tufts–New En- antibacterial drug discovery? Curr Opin Mi- we have identified are characterized by gland Medical Center), Karen Bush (Johnson & crobiol 2003; 6:427–30. commercial markets that are relatively Johnson), Ian Critchley (Replidyne), James Ge 8. Shlaes DM, Projan SJ, Edwards JE. Antibiotic (Cerexa), and George Jacoby (Harvard Medical discovery: state of the state. ASM News small, as well as unpredictable; these fac- School). We also thank Mr. Robert Guidos, Ms. 2004; 70:275–81. tors have deterred major pharmaceutical Diana Olson, and Mr. Mark Leasure of the Infec- 9. Bush K. Why it is important to continue an- companies from investing in these unmet tious Diseases Society of America for their support tibacterial drug discovery. ASM News 2004; 70:282–7. needs. Fortunately, the economic equation in the Antimicrobial Availability Task Force efforts. Financial support. The Antimicrobial Avail- 10. Powers JH. Development of drugs for anti- for smaller companies differs from that for ability Task Force has received no financial support microbial-resistant pathogens. Curr Opin In- larger companies, in that compounds as- from outside sources for any of its activities, in- fect Dis 2003; 16:547–51. 11. Sheridan C. Antiinfective biotechs face part- sociated with lower revenues may be fi- cluding preparation of this manuscript. Potential conflicts of interest. G.H.T. cur- nering gap. Nat Biotechnol 2005; 23:155–6. nancially attractive. Nonetheless, the ques- rently serves as an advisor for Actelion, Advancis, 12. Powers JH. Antimicrobial drug develop- tion remains as to whether novel, Array, Cerexa, Cubist, Cumbre, ICOS, Mpex, Os- ment—the past, the present, and the future. Clin Microbiol Infect 2004; 10(Suppl 4): early-stage compounds developed by cient, Replidyne, Sanofi-Aventis, Serenex, Ther- avance, ViroPharma, and Wyeth. J.B. provides his 23–31. smaller companies will see the light of day, stipend and research support to Children’s Hos- 13. Bad bugs, no drugs: as antibiotic R&D stag- given the high cost of late-stage (especially pital San Diego and affiliates for general Infectious nates, a public health crisis brews. Alexandria, VA: Infectious Diseases Society of America, phase 3) clinical development. Diseases Division support; serves on the advisory boards of Actelion, Astra-Zeneca, Elan, and John- 2004. What can be done to address this prob- son & Johnson; and receives research support from 14. The Protecting America in the War on Terror lem? The IDSA has proposed a number Astra-Zeneca, Elan, GlaxoSmithKline, Merck, and Act of 2005. 109th Cong. (24 January 2005): S3. of solutions that could be implemented by Novartis. J.E.E. serves on the scientific advisory boards of Pfizer, Merck, Vicuron, and Gilead; has 15. The Biodefense and Pandemic Vaccine and the FDA and other federal agencies, such participated in educational programs regarding Drug Development Act of 2005. 109th Cong. as the National Institutes of Health [13]. fungal infections funded by Pfizer, Merck, and As- (17 October 2005): S 1873. In addition, measures to address current tellas; has received research laboratory support 16. The Project BioShield II Act of 2005. 109th from Pfizer, Merck, and Gilead; and has partici- Cong. (28 April 2005): S 975. financial disincentives for the develop- pated in the Bristol-Myers Squibb Freedom to Dis- 17. The Infectious Diseases Research and Devel- ment of anti-infective agents could be leg- covery research program. D.G. serves on the opment Act of 2005. 109th Cong. (30 June islated [13]; indeed, some of the IDSA’s speakers’ bureau of Abbott Laboratories, Bayer, 2005): H 3154. GlaxoSmithKline, Lilly, Merck, Pfizer, Roche, Sch- 18. American Society for Microbiology. Program proposed remedies have been included in ering-Plough, and Wyeth. M.S. serves on advisory and abstracts of the 44th Interscience Con- legislation recently introduced into the boards of Pfizer, Cubist, and GlaxoSmithKline and ference on Antimicrobial Agents and Che- House of Representatives and the Senate. serves on speakers’ bureaus of these same com- motherapy [on CD-ROM]. 2004. panies, plus those of Schering-Plough and Bristol- 19. Bush K, Macielag M, Weidner-Wells M. Tak- The discovery and development of new Myers Squibb. J.G.B. serves on the HIV advisory ing inventory: antibacterial agents currently at antimicrobials is an expensive and time- boards for Bristol-Myers Squibb, Abbott Labora- or beyond phase 1. Curr Opin Microbiol consuming process requiring a long-term tories, and GlaxoSmithKline. 2004; 7:466–76. 20. Farr-Jones S, Boggs AF. Antibacterial drug dis- commitment to maintaining a substantial References covery and development: a 2004 snapshot. and sophisticated infrastructure. Once dis- Waltham, MA: Decision Resources, 19 May mantled, such programs cannot be re- 1. Smolinski MS, Hamburg MA, Lederberg J, 2004. 21. Page MGP. Cephalosporins in clinical devel- started in weeks or months. Clinicians and eds. Microbial threats to health: emergence, detection, and response. Washington, DC: The opment. Expert Opin Investig Drugs 2004; 13: public health officials, working in collab- Institute of Medicine, 2003. 973–85. oration with the pharmaceutical industry, 2. Diekema DJ, BootsMiller BJ, Vaughn TE, et 22. Alekshun MN. New advances in antibiotic dis- must act now to ensure a robust pipeline al. Antimicrobial resistance trends and out- covery and development. Expert Opin Investig break frequency. Clin Infect Dis 2004; 38: Drugs 2005; 14:117–34. of compounds for the next decade. IDSA’s 78–85. 23. Gaynes R, Edwards JR. Overview of nosoco- membership, including specifically those 3. Spellberg B, Powers JH, Brass EP, Miller LG, mial infections caused by gram-negative ba- clinicians who serve on the front line car- Edwards JE Jr. Trends in antimicrobial drug cilli. National Nosocomial Infection Surveil- development: implications for the future. Clin lance System Clin Infect Dis 2005; 41:848–54. ing for patients with nosocomial infection Infect Dis 2004; 38:1279–86. 24. Davis KA, Moran KA, McAllister K, Gray PJ. due to multidrug-resistant pathogens, can 4. Norrby SR, Nord CE, Finch R. Lack of de- Multidrug-resistant Acinetobacter extremity

666 • CID 2006:42 (1 March) • Talbot et al. infections in soldiers. Emerg Infect Dis 41. Walsh TJ, Fiberg RW, Arndt C, et al. Lipo- intensive care unit: report from the SENTRY 2005; 11:1218–24. somal amphotericin B for empirical therapy Antimicrobial Surveillance Program (North 25. Garzoni C, Emonet S, Legout L, et al. Atypical in patients with persistent fever and neutro- America, 2001). Int J Antimicrob Agents infections in tsunami survivors. Emerg Infect penia. N Engl J Med 1999; 340:764–71. 2004; 24:111–8. Dis 2005; 11:1591–3. 42. Walsh TJ, Teppler H, Donowitz GR, et al. Cas- 55. National Nosocomial Infections Surveillance 26. Gales AC, Jones RN, Forward KR, Linares J, pofungin versus liposomal amphotericin B for (NNIS) System Report, data summary from Sader HS, Verhoef J. Emerging importance of empirical antifungal therapy in patients with January 1992 through June 2004, issued Oc- multi-drug resistant Acinetobacter species and persistent fever and neutropenia. N Engl J tober 2004. Am J Infect Control 2004; 32: Stenotrophomonas species as pathogens in se- Med 2004; 351:1391–402. 470–85. riously ill patients: geographic patterns, epi- 43. Walsh TJ, Pappas P, Winston D, et al. Vori- 56. Schwaoer MJ, Navon-Venezia S, Schwartz D, demiological features, and trends in the SEN- conazole compared with liposomal ampho- Carmeli Y. High levels of antimicrobial co- TRY antimicrobial surveillance program tericin B for empirical antifungal therapy in resistance among extended-spectrum b-lac- (1997–1999). Clin Infect Dis 2001; 32(Suppl patients with neutropenia and persistent fever. tamase–producing Enterobacteriaceae. Anti- 2):S104–13. N Engl J Med 2002; 346:225–34. microb Agents Chemother 2005; 49:2137–9. 27. Landman D, Quale JM, Mayorga D, et al. Ci- 44. Meyer KS, Urban C, Eagan JA, Berger BJ, Ra- 57. Bradford PA, Bratu S, Urban C et al. Emer- tywide clonal outbreak of multresistant Aci- hal JJ. Nosocomial outbreak of Klebsiella in- gence of carbapenem-resistant Klebsiella netobacter baumannii and Pseudomonas aeru- fection resistant to late generation cephalo- species possessing the class A carbape- ginosa in Brooklyn, NY: the preantibiotic era sporins. Ann Intern Med 1993; 119:353–8. nem–hydrolyzing KPC-2 and inhibitor-resis- has returned. Arch Intern Med 2002; 162: 45. Wiener J, Quinn JP, Bradford PA, et al. Mul- tant TEM-30 b-lactamases in New York City. 1515–20. tiple antibiotic-resistant Klebsiella and Esche- Clin Infect Dis 2004; 39:55–60. 28. Quale J, Bratu S, Landman D, Heddurshetti richia coli in nursing homes. JAMA 1999; 281: 58. Woodford N, Teerno PM, Young K et al. Out- R. Molecular epidemiology and mechanisms 517–23. break of Klebsiella pneumoniae producing a of carbapenem resistance in Acinetobacterbau- 46. Paterson DL, Ko W-C, Gottberg AV, et al. In- new carbapenem-hydrolyzing class A b-lac- mannii endemic in New York City. Clin Infect ternational prospective study of Klebsiella tamase, KPC-3, in a New York medical center. Dis 2003; 37:214–20. pneumoniae bacteremia: implications of ex- Antimicrob Agents Chemother 2004; 48: 29. Falagas ME, Kasiakou SK. Colistin: the revival tended-spectrum b-lactamase production in 4793–9. of polymixins for the management of multi- nosocomial infections. Ann Intern Med 59. Murray BE. Vancomycin-resistant enterococ- drug-resistant gram-negative bacterial infec- 2004; 140:26–32. cal infections. N Engl J Med 2000; 342:710–21. tions. Clin Infect Dis 2005; 40:1333–41. 47. Paterson DL, Ko W-C, Gottberg AV, et al. An- 60. Wisplinghoff H, Bischoff T, Tallent SM, Seifert 30. Li J, Nation RL, Milne RW, Turnidge JD, Coul- tibiotic therapy for Klebsiella pneumoniae bac- H, Wenzel RP, Edmond MB. Nosocomial thard K. Evaluation of colistin as an agent teremia: implications of production of ex- bloodstream infections in US hospitals: anal- against multi-resistant gram-negative bacteria. tended spectrum b-lactamases. Clin Infect Dis ysis of 24,179 cases from a prospective na- Int J Antimicrob Agents 2005; 25:11–25. 2004; 39:31–7. tionwide surveillance study. Clin Infect Dis 31. Bradford PA, Weaver-Sands DT, Petersen PJ. 48. Decre´ D, Burghoffer B, Gautier V, Petit J-C, 2004; 39:309–17. In vitro activity of tigecycline against isolates Arlet G. Outbreak of multi-resistant Klebsiella 61. Zaas AK, Song X, Tucker P, Perl TM. Risk from patients enrolled in phase 3 clinical trials oxytoca involving strains with extended spec- factors for the development of vancomycin- of treatment for complicated skin and skin trum b-lactamases and strains with extended resistant enterococcal bloodstream infection structure infection and complicated intra-ab- spectrum activity of chromosomal b-lacta- in patients with cancer who are colonized with dominal infections. Clin Infect Dis 2005; mase. J Antimicrob Chemother 2004; 54: vancomycin-resistant enterococci. Clin Infect 41(Suppl 5):S315–32. 881–8. Dis 2002; 35:1139–46. 32. Clark TA, Hajjeh RA. Recent trends in the 49. Kang C-I, Kim S-H, Park WB, et al. Blood- 62. D’Agata EMC, Green WK, Schulman G, Li H, epidemiology of invasive mycoses. Curr Opin stream infections due to extended-spectrum Tang Y-W, Schaffner W. Vancomycin-resistant Infect Dis 2002; 15:569–74. b-lactamase–producing Escherichia coli and enterococci among chronic hemodialysis pa- 33. Connolly JE Jr, McAdams HP, Erasmus JJ, et Klebsiella pneumoniae: risk factors for mor- tients: a prospective study of acquisition. Clin al. Opportunistic fungal pneumonia. J Thorac tality and treatment outcome, with special em- Infect Dis 2001; 32:23–9. Imaging 1999; 14:51–62. phasis on antimicrobial therapy. Antimicrob 63. Bhavani SM, Drake JA, Forrest A, et al. A 34. Denning DW. Invasive aspergillosis. Clin In- Agents Chemother 2004; 48:4574–81. nationwide, multicenter, case-control study fect Dis 1998; 26:781–803. 50. Quale JM, Landman D, Bradford PA, et al. comparing risk factors, treatment, and out- 35. Denning DW. Aspergillosis in “nonimmu- Molecular epidemiology of a city-wide out- come for vancomycin-resistant and -suscep- nocompromised” critically ill patients. Am J break of extended-spectrum b-lacta- tible enterococcal bacteremia. Diagn Micro- Respir Crit Care Med 2004; 170:580–1. mase–producing Klebsiella pneumoniae infec- biol Infect Dis 2000; 36:145–58. 36. Talbot GH, Huang A, Provencher M. Invasive tion. Clin Infect Dis 2002; 35:834–41. 64. DiazGranados CA, Zimmer SM, Klein M, Jer- aspergillus rhinosinusitis in patients with acute 51. Bush K. New b-lactamases in gram-negative nigan JA. Comparison of mortality associated leukemia. Rev Infect Dis 1991; 13:219–32. bacteria: diversity and impact on selection of with vancomycin-resistant and vancomycin- 37. Ohmagari N, Raad II, Hachem R, et al. In- antimicrobial therapy. Clin Infect Dis 2001; susceptible enterococcal bloodstream infec- vasive aspergillosis in patients with solid tu- 32:1085–9. tions: a meta-analysis. Clin Infect Dis 2005; mors. Cancer 2004; 101:2300–2. 52. Jacoby GA, Munoz-Price LS. The new b-lac- 41:327–33. 38. Maschmeyer G, Ruhnke M. Update on anti- tamases. N Engl J Med 2005; 352:380–91. 65. Carmeli Y, Eliopoulos G, Mozaffari, E, Samore fungal treatment of invasive Candida and As- 53. Biedenbach DJ, Moet GJ, Jones RN. Occur- M. Health and economic outcomes of van- pergillus infections. Mycoses 2004; 47:263–76. rence and antimicrobial resistance pattern comycin-resistant enterococci. Arch Intern 39. Boucher HW, Groll AH, Chiou CC, Walsh TJ. comparisons among bloodstream infection Med 2002; 162:2223–8. Newer systemic antifungal agents: pharma- isolates from the SENTRY Antimicrobial Sur- 66. Maschmeyer G, Braveny I. Review of the in- cokinetics, safety, and efficacy. Drugs 2004; 64: veillance Program (1997–2002). Diagn Micro- cidence and prognosis of Pseudomonas aeru- 1997–2020. biol Infect Dis 2004; 50:59–69. ginosa infections in cancer patients in the 40. Johnson MD, Perfect JR. Caspofungin: first 54. Streit JM, Jones RN, Sader HS, Fritsche TR. 1990s. Eur J Clin Microbiol Infect Dis 2000; approved agent in a new class of antifungals. Assessment of pathogen occurrences and re- 19:915–25. Expert Opin Pharmacother 2003; 4:807–23. sistance profiles among infected patients in the 67. Garau J, Gomez L. Pseudomonas aeruginosa

Anti-Infective Development Pipeline • CID 2006:42 (1 March) • 667 pneumonia. Curr Opin Infect Dis 2003; 16: dhqp/pdf/nnis/2003NNISReport_AJIC.PDF. JI, Solomon SL, Jernigan DB. Methicillin-re- 135–43. Accessed 20 January 2005. sistant Staphylococcus aureus hospitalizations, 68. Foca MD. Pseudomonas aeruginosa infections 75. Obritsch MD, Fish DN, MacLaren R, Jung R. United States. Emerg Infect Dis 2005; 11: in the neonatal intensive care unit. Semin Per- National surveillance of antimicrobial resis- 868–72. inatol 2002; 26:332–9. tance in Pseudomonas aeruginosa isolates ob- 82. Cosgrove SE, Sakoulas G, Perencevich EN, et 69. Rajan S, Saiman L. Pulmonary infections in tained from intensive care unit patients from al. Comparison of mortality associated with patients with cystic fibrosis. Semin Respir In- 1993 to 2002. Antimicrob Agents Chemother methicillin-resistant and methicillin-suscepti- fect 2002; 17:47–56. 2004; 48:4606–10. ble Staphylococcus aureus bacteremia: a meta- 70. Livermore DM. Multiple mechanisms of an- 76. Micek ST, Lloyd AE, Ritchie DJ, Reichley RM, analysis. Clin Infect Dis 2003; 36:53–9. timicrobial resistance in Pseudomonas aeru- Fraser VJ, Kollef MH. Pseudomonas aeruginosa 83. Engemann JJ, Carmeli Y, Cosgrove SA, et al. ginosa: our worst nightmare? Clin Infect Dis bloodstream infection: importance of appro- Adverse clinical and economic outcomes at- 2002; 34:634–40. priate initial antimicrobial treatment. Anti- tributable to methicillin resistance amongsub- microb Agents Chemother 2005; 49:1306–11. jects with Staphylococcus aureus surgical site 71. Gales AC, Jones RN, Turnidge J, Rennie R, 77. Conway SP, Brownlee KG, Denton M, Peck- infection. Clin Infect Dis 2003; 36:592–8. Ramphal R. Characterization of Pseudomonas ham DG. Antibiotic treatment of multidrug- 84. Vandenesch F, Naimi T, Enright MC, et al. aeruginosa isolates: occurrence rates, antimi- resistant organisms in cystic fibrosis. Am J Community-acquired methicillin-resistant crobial susceptibility patterns, and molecular Respir Med 2003; 2:321–32. Staphylococcus aureus carrying Panton-Val- typing in the global SENTRY Antimicrobial 78. Smith AW. Biofilms and antibiotic therapy: is entine leukocidin genes: worldwide emer- Surveillance Program, 1997–1999. Clin Infect there a role for combating bacterial resistance gence. Emerg Infect Dis 2003; 9:978–84. Dis 2001; 32(Suppl 2):S146–55. by the use of novel drug delivery systems? Adv 85. Fridkin SK, Hageman J, McDougal LK, et al. 72. Walsh TR, Toleman MA, Poirel L, Nordmann Drug Deliv Rev 2005; 57:1539–50. Epidemiological and microbiological charac- P. Metallo–b-lactamases: the quiet before the 79. Noskin GA, Rubin RJ, Schentag JJ, et al. The terization of infections caused by Staphylococ- storm? Clin Microbiol Rev 2005; 18:306–25. burden of Staphylococcus aureus infections on cus aureus with reduced susceptibility to van- 73. Poole K. Efflux-mediated resistance in Pseu- hospitals in the United States. Arch Intern comycin, United States, 1997–2001. Clin domonas aeruginosa. Clin Microbiol Infect Med 2005; 165:1756–61. Infect Dis 2003; 36:429–39. 2004; 10:12–26. 80. Deresinski S. Methicillin-resistant Staphylo- 86. Walker ES, Vasquez JE, Dula R, Bullock H, 74. Nosocomial Infections Surveillance (NNIS) coccus aureus: an evolutionary, epidemiologic, Sarubbi FA. Mupirocin-resistant, methicillin- System report, data summary from January and therapeutic odyssey. Clin Infect Dis resistant Staphylococcus aureus: does mupiro- 1992 through June 2003, issued August 2003. 2005; 40:562–73. cin remain effective? Infect Control Hosp Ep- Available at: http://www.cdc.gov/ncidod/ 81. Kuehnert MJ, Hill HA, Kupronis BA, Tokars idemiol 2003; 24:342–6.

668 • CID 2006:42 (1 March) • Talbot et al. ERRATUM

An article in the 1 March 2006 issue of the journal (Talbot able letter from FDA June 2005” (not “Approved by FDA in GH, Bradley J, Edwards JE, Jr., Gilbert D, Scheld M, Bartlett June 2005”). The journal regrets this error. JG. Bad bugs need drugs: an update on the development pipe- Second, the Acknowledgments section incorrectly listed Cub- line from the Antimicrobial Availability Task Force of the In- ist as an affiliation for Helen Boucher. Dr. Boucher is not af- fectious Diseases Society of America. Clin Infect Dis 2006;42: filiated with Cubist Pharmaceuticals; her only affiliation is with 657–68) contained 2 errors. First, in table 1, the text in the Tufts–New England Medical Center. The authors regret this “Comments” column for posaconazole should read “Approv- error.

Clinical Infectious Diseases 2006;42:1065 2006 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2006/4207-0041$15.00

ERRATUM • CID 2006:42 (1 April) • 1065