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Currently Available Antimicrobial Agents and Their Potential for Use As Monotherapy L

Currently Available Antimicrobial Agents and Their Potential for Use As Monotherapy L

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REVIEW 10.1111/j.1469-0691.2008.02125.x

Currently available antimicrobial agents and their potential for use as monotherapy L. R. Peterson

Northwestern University’s Feinberg School of Medicine, Departments of Medicine and Pathology, Chicago, IL; Evanston Northwestern Healthcare, Department of Medicine, Division of Infectious Diseases and Department of Pathology and Laboratory Medicine, Division of Microbiology, Evanston, IL, USA

ABSTRACT Infectious diseases remain a serious and now re-emerging threat to human life, contributing to over ten million deaths per year. Treatment of major infectious diseases with antibacterial agents creates an ongoing and escalating public health issue that currently leads to more problems than solutions. By processes of adaptation and survival, bacteria consistently develop mechanisms to overcome the effects of the newest and most potent antibacterial compounds. Simultaneously, progressively fewer antibacterial agents are being developed by pharmaceutical and biotechnology companies. Although this dilemma is an inherent trade-off and has no imminent resolution, the most prudent paradigm to pursue is the judicious use of antibacterial agents in the most limited way possible to attain the desired treatment results. One straightforward approach to antimicrobial stewardship is to use a single agent as opposed to combination therapy, so as to subject bacteria to lower total exposure whenever feasible. This article reviews current trends in antibacterial drug development and describes a context for adherence to monotherapy with newer agents. Keywords Antibiotic resistance, antimicrobial stewardship, glycylcycline, monotherapy, tigecycline Clin Microbiol Infect 2008; 14 (Suppl. 6): 30–45

new antimicrobial agents is declining, while rates INTRODUCTION of morbidity and mortality, and the costs associ- A potential ‘post-antibiotic era’ is threatening ated with suboptimal treatment of infections present and future medical advances. According caused by resistant organisms, are rising [2]. The to the WHO, there is a global risk of creating an combination of the current worldwide increase in environment similar to that of the pre-antibiotic resistant bacteria and the downward trend in the era (i.e. before the middle of the 20th century), development of new has serious health when deaths from infectious diseases were much and economic implications [3–5]. Resistant bacte- more prevalent than they are currently, and ria dramatically reduce the possibility of treating modern implant and transplant surgery was infectious diseases effectively, increasing the risk impossible because of the risk of infection. Emer- of complications and fatal outcomes. gence of antimicrobial resistance is a natural Indeed, the pipelines of the world’s 15 largest phenomenon that is caused largely by antimicro- pharmaceutical companies reflect a notable de- bial use (and misuse). There is a global pandemic cline in the number of new antimicrobial agents of resistant organisms that requires changes in under development and recently introduced. A how we address the problem [1]. In parallel with survey by Spellberg et al. found that nine new escalating resistance, the rate of development of antibacterial agents were introduced between 1998 and 2003, a drop from 16 such agents introduced between 1983 and 1987 (the first Corresponding author and reprint requests: L. R. Peterson, period for which the authors obtained data), with Evanston Northwestern Healthcare, Walgreen Building, SB525, 2650 Ridge Avenue, Evanston, IL 60201, USA a steady decline during the intervening years up E-mail: [email protected] to the present [5]. Tigecycline, the first of the

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 Peterson Monotherapy of serious infection 31 glycylcyclines, a new class of semisynthetic tetra- treatment failure attributable to the emergence cyclines, was introduced in 2005, giving a current of resistance, the development of superinfection total of ten new antibacterials in the last decade; or overall disease mortality did not differ signi- most, tigecycline included, represent extensions ficantly between b-lactam monotherapy and com- of an existing class of compounds. The authors bination regimens containing a b-lactam and an contrasted this with the current trend in the aminoglycoside. Although generalization is prob- number of new molecular entities (NMEs) in ably unwise, the concept of monotherapy could other drug classes being developed by the same become one practical pillar of antimicrobial stew- companies, citing public disclosures of 23 NMEs ardship, involving only one antimicrobial agent for depression and anxiety, eight for bladder whenever possible while still covering the hyperactivity, and seven for osteoporosis, in breadth of likely infecting pathogens. contrast to only five antibacterial NMEs. Simi- The goals of this article are to: (i) discuss the larly, the world’s seven largest biotechnology antibiotics currently available for initial therapy; companies reported having a total 52 NMEs in (ii) summarize the mechanisms of resistance to development for indications in the areas of antimicrobials; and (iii) describe the microbiolog- oncology, inflammation ⁄ immunomodulation and ical and clinical profile of tigecycline, the first in a metabolism ⁄ endocrinology, but only one for anti- new group of broad-spectrum agents, the gly- bacterial therapy [5]. The challenge of new anti- cylcyclines, which provides a new, practical microbial development is one of the issues opportunity for increased use of monotherapy in addressed by the recent Infectious Diseases Soci- the seriously ill patient. ety of America (IDSA) policy document on anti- biotic resistance [1]. AVAILABLE AGENTS AND As few new antibacterials are being developed, TREATMENT GUIDELINES the global need for a cooperative effort to ensure their appropriate use is increasing, with the Since the discovery and development of antimi- objective of reducing the emergence of resistance. crobial agents in the 20th century, many novel There is a need in the drug development process agents have become available, including penicil- for a comprehensive approach that works in lins, , b-lactam–b-lactamase inhibitor concert with health, education, economic and combinations, extended-spectrum cephalospo- industrial policies. Containment of antibiotic rins, aminoglycosides, , oxazolidi- resistance will depend on coordinated interven- nones, fluoroquinolones, macrolides, and tions to optimize antibiotic consumption. The tetracyclines [7,8]. current rising trends in resistance to antimicrobial Many of these drugs have provided extended- agents suggest that the real problems are still spectrum anti-Gram-positive and anti-Gram-neg- ahead of us [2]. ative activity, but despite the availability of these In the interim, judicious use of existing anti- agents, resistance continues to disseminate among bacterials is paramount, but how to achieve this common pathogens (e.g. Staphylococcus aureus), practically is unclear. It is realistic to hypothesize while pathogens with new types of resistance that the fewer antibacterials used the better, with emerge and spread (e.g. CTX-M-producing Esc- less exposure to antimicrobials limiting the herichia coli and carbapenemase-producing Klebsi- opportunity for microbes to develop resistance ella pneumoniae strains). to these critical agents. Put another way, the fewer Because prevalence patterns of resistant organ- antibacterials used, the less the selection pressure isms vary widely and change continually, regio- on organisms that might develop resistance to nal, national and local resistance must be multiple agents when used together. However, considered in the selection of appropriate anti- the use of fewer antimicrobial agents is not bacterials to combat specific pathogens [3,4]. acceptable if it is accompanied by worse thera- Accordingly, the appropriate use of both older peutic outcomes. and newer agents is recommended through treat- Conceptually, the efficacy of monotherapy ment guidelines that address antibacterial use by must be proven, as was done by a meta-analysis geographical region and type of infection. Guide- of randomized, controlled studies in a report by lines for antibacterial use are most effective when Bliziotis et al. [6]. They showed that rates of they are evidence-based and focus on practical

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 32 Clinical Microbiology and Infection, Volume 14, Supplement 6, December 2008 recommendations that remain up to date through Table 2. Guideline summary for antibiotic selection rec- ongoing monitoring of published clinical studies. ommended for community-acquired intra-abdominal infections adapted from the Infectious Diseases Society of They should also focus on the level of risk for the America [9] individual patient, which typically is different for healthcare-associated and community-acquired –sulbactama – infections. –tazobactamb In the USA, the IDSA and the Surgical Infection or plus metronidazole Society (SIS) regularly update guidelines address- Ciprofloxacin and similar quinolones plus metronidazole plus metronidazole ing the diagnosis and management of skin and aLocal susceptibility profiles should be reviewed before soft tissue infections [8] and intra-abdominal use. infections [7,9]. Tables 1 and 2 summarize the bRecommended for serious infection. suggested available antibacterials for initial treat- ment of the most common of these infections as metronidazole, or a third ⁄ fourth-generation ceph- determined by the IDSA. Additionally, current alosporin (, , , cef- SIS guidelines recommend ampicillin–, tizoxime, or ) with an anti-anaerobe , , ertapenem, –cilast- drug for treatment of intra-abdominal infection. atin, , piperacillin– and In discussing the addition of a second agent, ticarcillin–clavulanic acid as single agents. For emphasis is placed upon achieving coverage of combination therapy, an aminoglycoside (amika- anaerobes. These guidelines highlight the in vitro cin, gentamicin, netilmicin, or tobramycin) plus activity afforded by carbapenems against routine an anti-anaerobe agent (clindamycin or metroni- isolates of Enterococcus spp. Although they do not dazole; the latter is preferred) can be considered, find a justification for routine coverage of entero- as well as aztreonam plus clindamycin, ce- cocci in community-acquired intra-abdominal furoxime plus metronidazole, ciprofloxacin plus infections, the current guidelines indicate the

Table 1. Guideline summary for antibiotic selection for skin and soft tissue infections adapted from the Infectious Diseases Society of America [8]

Antimicrobial therapy for skin and soft tissue infectiona

MSSA MRSA

Agent Comment Agent Comment

Nafcillin or Parental drug of choice; inactive For MSSA in -allergic against MRSA patients; parenteral drug of choice for treatment of infections caused by MRSA Cefazolin For penicillin-allergic patients, Linezolid Bacteriostatic; limited clinical except those with immediate experience; no cross-resistance hypersensitivity reactions with other antibiotic classes; expensive; may eventually replace other second-line agents as a preferred agent for oral therapy of MRSA infections Clindamycin Bacteriostatic; potential for Clindamycin Bacteriostatic; potential for cross-resistance and emergence cross-resistance and emergence of resistance in erythromycin- of resistance in erythromycin- resistant strains; inducible resistant strains; inducible resistance in MRSA resistance in MRSA Oral agent of choice for Bactericidal; do not use in patients -susceptible strains with lung involvement Cephalexin For penicillin-allergic patients, Doxycycline, Bacteriostatic; limited recent except those with immediate minocycline clinical experience hypersensitivity reactions Doxycycline, Bacteriostatic; limited recent Trimethoprim– Bactericidal; limited published minocycline clinical experience sulphamethoxazole efficacy data Trimethoprim– Bactericidal; efficacy poorly sulphamethoxazole documented

MSSA, methicillin-sensitive Staphylococcus aureus; MRSA, methicillin-resistant S. aureus. aAlso provides recommendations for treating impetigo caused by Streptococcus and Staphylococcus spp.; dicloxacillin, cephalexin, erythromycin (cautionary note that some strains of S. aureus and Streptococcus pyogenes may be resistant), clindamycin, amoxycillin–clavulanate and mupirocin ointment are listed as recommended treatments.

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 Peterson Monotherapy of serious infection 33 importance of such initial therapy for the higher- resistance to the b-lactam antibiotics and DNA risk patient with an infection of suspected health- gyrase mutations that alter the effectiveness of the care-associated origin [7]. fluoroquinolones. Enzymatic degradation of anti- Tellado et al. [10] have published the Spanish biotics is a mechanism that is usually associated Guidelines under the auspices of the Sociedad with Gram-negative bacteria, and in the case of Espan˜ola de Quimioterapia and other Spanish b-lactam resistance, it is due to b-lactamase surgical and infectious disease societies. These production. authors summarize appropriate initial treatment The fluoroquinolones block DNA synthesis by of intra-abdominal infections in light of IDSA, SIS inhibiting DNA gyrase and topoisomerase IV, and other published guidelines, including those which are responsible for the DNA folding and of the Societe´ Franc¸aise d’Anesthe´sie et de Re´an- supercoiling required for replication. Glycopep- imation [11], and the Consejo Europeo. Table 3 tide antibiotics (e.g. vancomycin) form complexes summarizes the activity profiles of currently with the that prevent binding of available antibacterials published in the Spanish the transpeptidases that are responsible for ter- Guidelines. minal cross-linking. Metronidazole causes DNA damage that ultimately leads to cell death. The sulphonamides, trimethoprim–sulphamethox- MECHANISMS OF ACTION AND azole and iclaprim (discussed elsewhere in this RESISTANCE issue) block the metabolism of bacteria by inhib- Antibacterial agents prevent bacterial growth by iting the enzymes needed for the synthesis of folic disrupting the function of a wide variety of acid. molecular targets located within bacteria and at Many antibiotics, including the aminoglyco- the cell surface [12]. Fig. 1 summarizes the mech- sides, macrolides, oxazolidinones, streptogra- anisms of action of the most commonly used mins, lincosamides, and tetracyclines, interact antibacterials. The , and with bacterial ribosomes at various sites to inhibit carbapenems all target synthesis by protein synthesis. In particular, the tetracyclines inhibiting the transpeptidases required for pepti- and glycylcyclines bind to the 30S subunit to doglycan formation and cross-linking in the cell inhibit binding of aminoacyl-tRNA to the A site of wall. Examples of drug target site modifications the ribosome and prevent the transfer of amino occurring in drug-resistant bacteria include pen- acids to newly forming protein chains (Fig. 1). icillin-binding protein alterations that confer Glycylcyclines are a new class of semisynthetic

Table 3. Activity profiles of anti- Escherichia Bacteroides Enterococcus Staphylococcus Pseudomonas microbial agents listed for empirical colia fragilis faecalis aureusb aeruginosa therapy in the Spanish guidelines [10] Amoxycillin–clavulanic acidc ++ +++ +++ +++ – Piperacillin–tazobactam +++ +++ +++ +++ +++ Cephamycinsd +++ ++ – ++ – Cefotaxime–ceftriaxone +++ – – +++ – Cefepime +++ – – +++ ++ Carbapenemse +++ +++ ++f +++ +++g Ciprofloxacin ++ – – + ++ Metronidazole – +++ – – – Clindamycin – ++ – ++ – Aminoglycosides +++ – + + +++h Ampicillin + – +++ – – Glycopeptides – – +++ +++i – Linezolid – – +++ +++i – Aztreonam +++ – – – ++

+, activity for approximately 50% of isolates; ++, activity for approximately 75% of isolates; +++, activity for more than 90% of isolates. aActivity against Klebsiella spp., Proteus spp., and Enterobacter spp. bMethicillin-susceptible S. aureus only. cThe activity of ampicillin–sulbactam is superior to that of amoxycillin–clavulanic acid. dCephamycins: cefotaxime, , and cefminox. eCarbapenems: imipenem, meropenem, and ertapenem. fMeropenem and ertapenem both have little activity against Enterococcus sp. g % ⁄ The activity of imipenem in Spain is 86.2 , and ertapenem (MIC90 >16 mg L) is less active than imipenem. hAmikacin and tobramycin. iGlycopeptides: ; vancomycin and linezolid are active against resistant strains of methicillin-resistant S. aureus.

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 34 Clinical Microbiology and Infection, Volume 14, Supplement 6, December 2008

Fluoroquinolones β Metronidazole – -lactams Cell wall Cephalosporins synthesis Carbapenems – – Sulfonamides TMP-SMX Topo-– DNA replication ~ isomerase – DNA- Protein gyrase mRNA (mutations) Nucleotide biosynthesis Protein RNA synthesis transcription –– mRNA ––

– Peptide Cytoplasmic Rifampin Glycylcyclines antibiotics membrane integrity Aminoglycosides Macrolides Oxazolidinones Streptogramins Lincosamides Tetracyclines

Fig. 1. Schematic diagram of various mechanisms of bacterial resistance. Adapted from reference [12]. tetracyclines developed with the intention of choice of antimicrobial therapy. These include circumventing both efflux- and target modifica- ease of drug administration [13], potential tion-mediated resistance to tetracyclines [12]. adverse events, the complex dosing schedules Bacteria that have developed tetracycline resis- necessary with combination therapy, which can tance have commonly acquired the ability to carry an increased risk of drug interactions, the protect the bacterial target (the ribosome) or to need to monitor blood levels of some agents, produce efflux pumps that extrude the drug complicated dosing adjustments in selected pa- molecule from the cell; both mechanisms are tients with renal disease or hepatic dysfunction, evaded by tigecycline, the first glycylcycline, due and treatment cost [6]. However, it is important to to a bulky substituent. Thus, the diverse resis- understand that the most critical aspect of therapy tance mechanisms affecting the antimicrobial leading to a positive clinical outcome is early agents described should not have an effect on treatment with an effective agent. tigecycline, indicating that cross-resistance to this new agent, due to these mechanisms, should not The role of monotherapy be expected in otherwise multidrug-resistant bac- teria. The intuitive benefit of monotherapy is that it subjects bacteria to less exposure to antimicrobial agents than combination therapy and thus might SELECTION OF EMPIRICAL lead to a slowing of resistance development. ANTIMICROBIAL THERAPY Additional benefits include less complexity of Several decisions are important in selecting initial drug administration and typically a lower overall antimicrobial therapy, most importantly in sur- therapeutic cost. Clinical evidence supports the mising what the likely infecting pathogen is hypothesis that certain antibacterials used as (based on the clinical presentation) and in choos- monotherapy are as efficacious as regimens that ing the adequate regimen on the basis of knowl- involve the addition of one or more drugs. As edge of the local antibiotic susceptibility of the noted earlier, a meta-analysis by Bliziotis et al. [6], expected pathogen, as well as of the pharmaco- incorporating eight studies published between kinetics of the chosen therapeutic agent. Other 1983 and 1995, revealed that b-lactam monother- ancillary factors can also impact on the overall apy was not associated with a greater emergence

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 Peterson Monotherapy of serious infection 35 of resistance than was aminoglycoside–b-lactam Food and Drug Administration (FDA) in June combination therapy (OR 0.90; 95% CI 0.56– 2005, and is the first new tetracycline analogue 1.47). Importantly, b-lactam monotherapy was since the introduction of minocycline over associated with fewer superinfections (OR 0.62; 30 years ago [15–17]. The chemical structures of 95% CI 0.42–0.93) and treatment failures tetracycline, minocycline and tigecycline are (OR 0.62; 95% CI 0.38–1.01). Also, all-cause mor- shown in Fig. 3. As a glycylamido derivative of tality during treatment (OR 0.70; 95% CI 0.40– minocycline [16,17], tigecycline binds to the 30S 1.25) and mortality due to infection (OR 0.74; ribosomal subunit [16–18]. Tigecycline possesses 95% CI 0.46–1.21) did not differ significantly an expanded spectrum of in vitro activity [17], between the two regimens. and overcomes tetracycline resistance by retain- Another study, by Cometta et al., found that the ing the ability to bind to bacterial ribosomes that addition of vancomycin therapy did not improve are protected by the Tet(M) protein, a mechanism the time to defervescence or lower mortality in that compromises all available tetracyclines [16– piperacillin–tazobactam-treated, persistently feb- 18]. Tigecycline also evades the Tet(A–E) efflux rile neutropenic patients with cancer (Fig. 2) [14]. pumps, which account for most of the acquired The outcome of this prospective, randomized, resistance to tetracycline and minocycline in double-blind, multicentre trial (34 centres of the Enterobacteriaceae and Acinetobacter spp., as well EORTC-IATG), which included adults and chil- as the Tet(K) pumps, which occur widely in dren (aged ‡2 years) in Europe, the Middle East staphylococci and confer resistance to tetracy- and North America, and had as a primary cline, although not to minocycline or doxycycline objective the assessment of whether or not the [16]. It has been shown that overproduction of the addition of a glycopeptide would reduce the time AcrAB multidrug efflux pump is probably a key to defervescence in neutropenic patients who had factor leading to decreased tigecycline suscepti- persistent fever, was that there was no benefit bility when found in E. coli [19]. over monotherapy. Summary of in vitro activity TIGECYCLINE: A NEW The results of the Tigecycline Evaluation and MONOTHERAPY OPTION Surveillance Trial (TEST) in vitro study published Tigecycline (Wyeth, formerly GAR-936) is the first by Hoban et al. [20] demonstrated that tigecycline glycylcycline antibacterial agent to be available is highly active against the majority of commu- for clinical use. It was approved for use by the US nity- and healthcare-associated Gram-positive

1

Vancomycin Placebo

0.8

Placebo (n = 79) 0.6 median 4.3 days (95% CI 3.5–5.1)

0.4 Vancomycin (n = 86) median 3.5 days Fig. 2. Comparison of time to (95% CI 2.7–4.4) defervescence in patients with per- 0.2 sistent fever 48–60 h after initiation Proportion of patients with fever of empirical piperacillin–tazobactam monotherapy randomized to receive 0 in addition either vancomycin or placebo. Median days (95% CI). 02468101214 p >0.5. Adapted from reference [14]. Days

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 36 Clinical Microbiology and Infection, Volume 14, Supplement 6, December 2008

Tetracycline

Minocycline 9-tert-butyl-glycylamido side chain added to the D ring at the 9th position

Tigecycline Fig. 3. Chemical structures of tetra- cycline, minocycline, and tigecycline. Adapted from references [16–18]. bacterial isolates. Table 4 presents the in vitro ated with cross-resistance to other drug classes, activities of tigecycline and other commonly and tigecycline and imipenem demonstrated sim- prescribed antimicrobials against over 2000 ilar activity against 285 ESBL-producing isolates Gram-positive isolates from 40 study centres in from Spain (community and healthcare-associ- 11 countries, as of December 2004. This study ated Enterobacteriacea), exhibiting the lowest ⁄ ⁄ included important antibiotic-resistant strains MIC90 values (1.0 mg L for tigecycline; 0.5 g L such as methicillin-resistant S. aureus (MRSA) for imipenem) of all agents tested (Table 6) [22]. [20]. The global in vitro susceptibility data The most commonly observed ESBLs were CTX- showed that tigecycline is highly active against M-type enzymes (in >58% of both nosocomial the majority of Gram-positive isolates tested, and community isolates), and these were typically including MRSA. The clinical trial data published associated with cross-resistance to other antimi- by Florescu et al. demonstrated that the in vitro crobials, including aminoglycosides, fluoroqui- activity was matched by the clinical treatment nolones, sulphonamides, and trimethoprim [22]. results [21]. Similarly, although the numbers of An additional study conducted in Spain by isolates were smaller, 100% of the vancomycin- Sorlo´zano et al., which used the breakpoint for resistant enterococcal isolates tested were suscep- tigecycline established by the FDA in 2005 for tible to tigecycline. The TEST study also showed Enterobacteriaceae (MIC £2mg⁄ L), demonstrated that tigecycline is highly active against Enterobac- that 100% of the ESBL-producing E. coli isolates teriaceae, with activity similar to that of imipenem, were susceptible to tigecycline, and all of the and superior to that of numerous comparator isolates tested were inhibited by a concentration agents, including ceftazidime and piperacillin– of £0.75 mg ⁄ L, regardless of the type of ESBL tazobactam (Table 5). In other studies, tigecycline produced [23]. Although the long-term success of has demonstrated potent activity against Entero- the strategy of using a new agent (e.g. tigecycline) bacteriaceae, including extended-spectrum b-lac- for monotherapy will depend on clinical tamase (ESBL)-, CTX-M-9-, SHV-producing E. coli response, the initial blinded, randomized clinical [22,23] and non-ESBL-producing K. pneumoniae trials showing the efficacy of tigecycline are [24]. encouraging [25,26]. Of note, Morosini et al. reported the in vitro Antibacterial resistance is often thought to activity of nine antibacterials against organisms begin in intensive-care units in patients with with ESBL phenotypes characteristically associ- infection, and resistance among specific Gram-

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 Peterson Monotherapy of serious infection 37

Table 4. Tigecycline in vitro activity: Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE)

Percentage susceptible

Enterococcus Enterococcus Enterococcus Enterococcus Streptococcus faecium faecium faecalisa,b faecalis S. aureusa,b MRSAb,c agalactiaeb (non-VRE) (VRE) (non-VRE) (VRE) (n = 489) (n = 348) (n = 328) (n = 68) (n = 77) (n = 333) (n = 11)

Tigecyclinec 99.8 98.9 100 95.6 100 99.1 100 Ampicillin 16.2 – 99.4 35.3 – 98.5 – Ceftriaxone 89.2 – 98.8 NR – NR Levofloxacin 82.2 17.0 97.0 26.5 0 58.9 9.1 Linezolid 100 100 100 98.2 99.1 98.2 100 Minocycline 99.2 96.8 NR 72.1 62.3 38.1 36.4 Vancomycin 100 99.7 100 NR – NR –

Adapted from reference [20]. NR, not reported. aClinical efficacy has been demonstrated for susceptible strains in complicated intra-abdominal infections. bClinical efficacy has been demonstrated for susceptible strains in complicated skin and soft tissue infections. cBreakpoint for susceptibility is £0.5 mg ⁄ L for S. aureus, and £0.25 for Streptococcus spp. (other than Streptococcus pneumoniae) and Enterococcus sp.

Table 5. Global in vitro activity of antimicrobial agents expected, tigecycline proved to be ineffective against 3201 clinical isolates of Enterobacteriaceae ⁄ against P. aeruginosa strains (MIC90 16 mg L), ⁄ % % Antimicrobial MIC90 (mg L) susceptible although 93.3 of 171 Acinetobacter baumannii isolates tested were susceptible to tigecycline Tigecycline 1 96.7 Amikacin 4 99.0 (susceptibility breakpoint of £2mg⁄ L) [29]. Also Amoxycillin–clavulanate >32 51.0 Ampicillin >32 17.0 reported was the alarming finding of a high level Cefepime 2 95.9 of vancomycin resistance among enterococci, Ceftazidime 32 86.5 b Ceftriaxone 16 88.8 ESBL-mediated -lactam resistance, fluoroquino- Imipenem 1 98.7 lone resistance among Enterobacteriaceae, and Levofloxacin 8 87.2 Minocycline 8 86.0 resistance among P. aeruginosa and Piperacillin–tazobactam 16 90.7 Acinetobacter spp. Tigecycline showed consistently Adapted from reference [20]. good activity against these organisms with the indicated resistance phenotypes, except against P. aeruginosa [24]. negative non-fermenters is viewed as a particular Waites et al. reported additional data from the threat in this setting. Tigecycline is active (in vitro) TEST program in 2006 [24] that demonstrate the against many non-fermenting Gram-negative bac- efficacy of tigecycline against A. baumannii as teria (e.g. Acinetobacter spp. and Stenotrophomonas well as ESBL-producing and non-producing maltophilia), with the important exception of K. pneumoniae. Susceptibility was determined . The recent publication of according to the testing methods and interpretive a systematic review and an open-label trial criteria of the CLSI. For tigecycline, the FDA- suggests that the in vitro activity of tigecycline approved criteria were applied to those organ- translates into effective clinical response when isms that are listed in the package insert. Among this new agent is used in the therapy of serious a total of 1460 strains of K. pneumoniae screened, infection due to these difficult-to-treat pathogens 126 (8.6%) were confirmed ESBL producers. [27,28]. In a large in vitro trial, Sader et al. [29] Tigecycline activity was unaffected by ESBL tested the susceptibility of 9093 non-fermenting production, and was the only compound to Gram-negative isolates from bloodstream which more than 90% of ESBL-producing isolates (68.5%), respiratory tract (13.6%), skin ⁄ soft tissue were susceptible. Livermore [16] points out that (5.5%) and urinary tract (2.0%) infections in many carbapenemase-producing A. baumannii intensive-care unit patients between 2000 and isolates are resistant to all available agents except 2004. Tigecycline and trimethoprim–sulphameth- the , which, in addition to their oxazole were the most active against Acinetobacter in vitro antibacterial activity, have the drawbacks spp. and Stenotrophomonas maltophilia among all of toxicity and poor penetration into respiratory £ ⁄ the antibacterials tested (MIC90 2mg L). As secretions. Because tigecycline is active against

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 38 Clinical Microbiology and Infection, Volume 14, Supplement 6, December 2008

Table 6. In vitro activity of tigecycline against 285 ex- These findings confirm those of earlier tigecy- b tended-spectrum -lactamase-producing Enterobacteriaceae cline pharmacokinetic studies, which have shown

MIC (mg ⁄ L) that multiple doses of a 30-min infusion of 50 mg % of tigecycline every 12 h produce a linear phar- Antimicrobial Range 50% 90% Mode susceptible macokinetic course, with a maximum plasma ⁄ Piperacillin–tazobactam £0.5 ⁄ 4–‡128 ⁄ 416⁄ 416⁄ 416⁄ 493 concentration (Cmax) of 0.87 mg L, whereas a Cefotaxime 0.5–512 256 256 256 0 Ceftazidime 0.12–256 4 256 256 0 single 100-mg dose of tigecycline produces a Cefepime 1–64 64 64 64 0 terminal t1 ⁄ 2 of 27 h. The minimum serum con- Aztreonam 0.5–256 64 128 128 0 Imipenem £0.06–2 0.5 0.5 0.5 100 centration (Cmin) observed with tigecycline is Ciprofloxacin £0.12–8 1 8 £0.12 64.9 0.13 mg ⁄ L, and the area under the serum con- Minocycline 0.5–128 4 32 2 69.5 Tigecycline 0.12–4 0.5 1 0.5 97.5 centration–time curve from 0 to 24 h (AUC0–24 h) ⁄ Adapted from reference [22]. is 4.7 mg h L. The average steady-state apparent volume of distribution (Vss) is 639 L, which indicates that tigecycline has extensive distribu- most carbapenemase-producing A. baumannii tion beyond the plasma volume, with deposition strains (MICs £2mg⁄ L), it may provide a useful into human tissues [31–33]. Tigecycline skin alternative or adjunct to polymyxins, with a tissue penetration has been demonstrated in a comparable potency [29]. study by Sun et al.; they used the ratio between the tigecycline area under the blister fluid con- centration–time curve (AUC ) in experimen- Pharmacokinetics and dosing 0–12 h tally induced blisters and the serum equivalent In three phase 1 studies of single and multiple after a total of seven 50-mg intravenous doses in doses ranging from 12.5 to 300 mg in healthy healthy subjects, and found a mean rate of subjects, tigecycline exhibited linear pharmacoki- tigecycline penetration into the blister fluid of netics at steady state, a large apparent volume of 74% [34]. distribution (7–10 L ⁄ kg), and a long elimination A single-dose (100 mg, intravenous) study by half-life (t1 ⁄ 2), ranging from 37 to 67 h [30]. Rodvold et al. in patients undergoing elective Systemic clearance ranged from 0.2 to 0.3 L ⁄ h ⁄ kg. surgery or medical procedures yielding tissue Food intake afforded a higher tolerability of a for drug extraction found that the concentration single dose (between 100 and 200 mg), but the of tigecycline exceeded that found in serum duration of infusion did not affect tolerability. 23-fold in gall bladder tissue, two-fold in lung Nausea and vomiting were the most common side tissue, and 2.6-fold in colon tissue [35]. Another effects observed in these studies, and appeared to recent study, by Ji et al., demonstrates the impor- be dose-related. tance of the assay technique, as it was shown that

Vancomycin Tigecycline Imipenem-cilastatin plus aztreonam 100 87 89 87 87

80

Cure 60 rate (%) 40

20 Fig. 4. Clinical cure rates in compli- cated skin and soft tissue infection (cSSTI) and complicated intra- 0 abdominal infection (cIAI) phase 3 n = 422 n = 411 n = 685 n = 679 studies of tigecycline and compara- Complicated skin and Soft-tissue Complicated intra-abdominal tors. Adapted from references infection (cSSTI) infection (cIAI) [25,26].

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 Peterson Monotherapy of serious infection 39 tigecycline concentration in bone exceeded that in mild ⁄ moderate hepatic disease [33]. Also, the serum several-fold when careful drug extraction pharmacokinetic parameters of tigecycline do not was performed [36]. differ significantly between sexes, or across age The standard dosage of tigecycline is 100 mg groups (healthy subjects aged 18–50, 55–75 and administered intravenously, followed by 50 mg >75 years); therefore, no dosage adjustment is every 12 h; importantly, no dosing adjustments necessary according to age or sex [37], thus are needed in cases of renal impairment or simplifying its use.

Studies 3074A1-300-US/CA and 305-WW Total subjects screened n = 1153

Did not pass screening n = 24

ITT: All Randomised subjects n = 1129

No study drug received n = 13 Tigecycline = 4, V/A = 9

mITT: At least 1 dose of study drug n = 1116 Tigecycline = 566, V/A = 550

Did not meet severity criteria n = 59 Tigecycline = 128, V/A = 31

Clinical mITT Clinical mITT n = 1057 n = 1057 Tigecycline = 538, V/A = 519 Tigecycline = 538, V/A = 519

Did not meet evaluability criteria No baseline pathogen n = 224 n = 288 Tigecycline =116, V/A = 108 Tigecycline = 143, V/A = 145

Clinically evaluable Microbiologic mITT n = 833 n = 769 Tigecycline = 422, V/A = 411 Tigecycline = 395, V/A = 374

No baseline and/or susceptible pathogen n = 293 Tigecycline = 143, V/A = 150

Microbiologically evaluable n = 540 Tigecycline = 279, V/A =261

Fig. 5. Schema of patients in studies of tigecycline vs. vancomycin–aztreonam (V ⁄ A) in the treatment of skin and skin structure infections. ITT, intent-to-treat; mITT, modified intent-to-treat. Adapted from reference [26].

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 40 Clinical Microbiology and Infection, Volume 14, Supplement 6, December 2008

Tigecycline is not extensively metabolized, and more applicable to b-lactams), citing a clinically ⁄ is eliminated primarily by the biliary–faecal route. derived exposure–response AUC0–24 MIC ratio of In healthy male volunteers receiving [14C]tigecy- 17.9 for tigecycline [39]. This pharmacodynamic cline, tigecycline was the primary 14C-labelled measure was validated in a pulmonary pharma- material recovered in urine and faeces, but a cokinetic study by Conte et al. [40], which dem- ⁄ glucuronide, an N-acetyl metabolite and a tigecy- onstrated therapeutically favourable Cmax MIC90 % ⁄ cline epimer (each at no more than 10 of the and AUC MIC90 ratios for tigecycline activity administered dose) were also present. The recov- against Streptococcus pneumoniae, Chlamydia pneu- ery of total radioactivity in faeces and urine moniae, Mycoplasma pneumoniae, Moraxella catarrh- following administration of [14C]tigecycline indi- alis and Haemophilus influenzae. Time above the % % cates that 59 of the dose is eliminated by biliary– MIC90 was 100 for all five of these respiratory % faecal excretion, and 33 is excreted in the urine, pathogens. The tigecycline AUC0–12 h (134 mg with approximately 22% of the total dose being h ⁄ L) in alveolar cells was approximately 78-fold excreted as unchanged tigecycline in urine [38]. higher than the AUC0–12 h in serum, and the ⁄ In vitro studies in human liver microsomes AUC0–12 h (2.28 mg h L) in epithelial lining indicate that tigecycline is not metabolized by, fluid was approximately 32% higher than the and does not inhibit or induce, cytochrome enzy- AUC0–12 h in serum. mes, including cytochrome P450 isoforms 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4. Thus, it has a low Clinical trial data for complicated skin and soft potential for interactions with drugs that inhibit or tissue infections and for complicated induce the activity of these cytochrome P450 iso- intra-abdominal infections forms [33]. The only cautionary note regarding drug–drug interactions is based on phase 1 safety In clinical studies, tigecycline has a demonstrated data that show increases in warfarin Cmax and AUC efficacy profile in the treatment of both compli- when this drug is administered with tigecycline. cated skin and soft tissue infections (cSSTIs) and However, warfarin did not affect the pharmacoki- complicated intra-abdominal infections (cIAIs) netic profile of tigecycline [33]. [21,25,26,28]. Tigecycline has been evaluated in four large phase 3, double-blind, randomized, multicentre, active-comparator clinical studies in Clinical implications of pharmacodynamic hospitalized patients with cSSTI or cIAI, in which measures it was not inferior at the 15% level (cure vs. One pharmacodynamic variable affecting the failure) at test-of-cure assessments in either the broad-spectrum efficacy of an antibacterial agent cSSTI studies (p <0.0001) or the cIAI studies is the measurable ratio between pharmacokinetic (p <0.0001). Fig. 4 summarizes the clinical cure parameters and bacterial susceptibility. Ambrose rates for each of the two pooled study pairs. In ⁄ et al. recently reported that the AUC0–24 MIC the cSSTI studies used for drug approval, similar ratio is the appropriate clinically derived phar- clinical cure rates were obtained with tigecycline macokinetic–pharmacodynamic target for tigecy- and vancomycin–aztreonam (87% vs. 89%); rates cline (in contrast to time above the MIC, which is were also similar for patients with monomicrobial

Tigecycline Vancomycin plus aztreonam 100 100 91 92 91 89 88 89 90 83 80 80 78 76 Fig. 6. Cure rates by pathogen in Cure 60 the microbiologically evaluable rate population of the complicated skin (%) 40 and skin structure studies (tigecy- cline vs. vancomycin–aztreonam). 20 MSSA, methicillin-susceptible Staph- ylococcus aureus; MRSA, methicillin- resistant S. aureus. aStreptococcus 0 134 120 32 33 16 24 56 47 29 30 8 5 spp. includes S. anginosus, S. inter- MSSA MRSA Enterococcus Streptococcus Escherichia Bacteroides medius, and S. constellatus. Adapted faecalis spp.a coli fragilis from reference [26].

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 Peterson Monotherapy of serious infection 41 and polymicrobial infections [26]. Fig. 5 pre- inferiority was demonstrated in all treatment sents the study design and disposition for this subsets. Fig. 6 summarizes the results from the pooled analysis. Tigecycline monotherapy was microbiologically evaluable populations in these shown to be as effective as vancomycin–aztreo- studies [26]. nam for treating cSSTIs. Cure rates with respect In the cIAI studies used for drug approval, to pathogens were similar for the two treatment tigecycline gave clinical cure rates similar to groups (e.g. 78% vs. 76% for MRSA), and non- imipenem (each 86%), and rates were also similar

Studies 3074A1-301 and 306 Total subjects screened n = 1759

Did not pass screening n = 101

ITT: All Randomised subjects n = 1658

No study drug received n = 16 Tigecycline = 9, I/C = 7

mITT: At least 1 dose of study drug n = 1642 Tigecycline = 817, I/C = 825

Did not meet minimal disease criteria n = 41 Tigecycline = 16, I/C = 25

Clinical mITT Clinical mITT n = 1601 n = 1601 Tigecycline = 801, I/C = 100 Tigecycline = 801, I/C = 100

Did not meet evaluability criteria No baseline isolate n = 219 n = 339 Tigecycline =116, I/C = 103 Tigecycline = 170, I/C = 169

Clinically evaluable Microbiologic mITT n = 1382 n = 1262 Tigecycline = 685, I/C = 697 Tigecycline = 631, I/C = 631

No baseline or susceptible isolate n = 357 Tigecycline = 173, I/C = 184

Microbiologically evaluable n = 1025 Tigecycline = 512, I/C =513

Fig. 7. Schema of patients in studies of tigecycline vs. imipenem–cilastatin (I ⁄ C) in the treatment of complicated intra- abdominal infections. ITT, intent-to-treat; mITT, modified intent-to-treat. Adapted from reference [25].

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 42 Clinical Microbiology and Infection, Volume 14, Supplement 6, December 2008

Tigecycline Imipenem-Cilastatin Complicated Gastric/Duodenal Complicated appendicitis perforations Peritonitis cholecystitis 100 Intra-abdominal 92 92 89 89 90 88 97 95 abscess Perforated Complicated intestine 78 78 diverticulitis 80 Other 75 73 72 71 67 60 60 Cure rate (%) 40

20

0 n = 263 262 69 74 51 45 51 40 32 42 25 25 18 20 3 5

Fig. 8. Cure rates by diagnosis in the microbiologically evaluable population of the complicated intra-abdominal infection studies (tigecycline vs. imipenem–cilastatin) Adapted from reference [25]. for patients with monomicrobial and polymicro- events at the test-of-cure visit in these tigecycline bial infections. Fig. 7 presents the study design phase 3 studies. and disposition for this pooled analysis. Tigecy- cline monotherapy was shown to be as effective as BENEFITS OF SINGLE VS. MULTIPLE imipenem–cilastatin for treating cIAIs [25]. Cure AGENTS rates according to diagnosis were also similar for the two treatment groups (e.g. 88% vs. As the provision of healthcare becomes ever more 89% for complicated appendicitis), and non- complex, the administration of a single agent inferiority was demonstrated in all treatment becomes more attractive, even if it is a new, subsets. Fig. 8 summarizes the results from the potent antibiotic that historically might have been microbiologically evaluable populations in these reserved in order to prevent the development of studies. resistance to the new compound. At the current stage of emerging resistance, it is important to reconsider entrenched habits and assess whether Summary of tigecycline safety data in phase 3 simplified forms of antimicrobial stewardship cSSTI and cIAI studies will improve the treatment of infectious diseases. On the basis of 1415 tigecycline-treated and 1382 An additional argument in favour of monother- comparator-treated patients, nausea, vomiting apy, considering also that reduced antibiotic use and hyperbilirubinaemia were reported as ad- should result in reduced antimicrobial resistance, verse events significantly more often with tigecy- is the lower risk of toxicity and therapy-related cline than with the comparator agents: 29.5% vs. adverse events when only a single agent is 15.8%, 19.7% vs. 10.8%, and 2.3% vs. 0.9%, prescribed. respectively [32,33]. Most cases of nausea and vomiting were mild to moderate, and treatment CONCLUSION discontinuation rates due to adverse events were similar between tigecycline and comparator treat- Resistance to virtually all classes of antimicrobial ment groups for cSSTIs (20 (3.5%) for tigecycline; agents is increasing, which highlights the fact that 29 (5.3%) for vancomycin–aztreonam (p 0.188)) past practices during the last half-century and [26] and for cIAIs (21 (2.6%) for tigecycline; 12 beyond have not been sufficient to prevent the (1.5%) for imipenem–cilastatin (p 0.116)) [25]. development and spread of resistant pathogens. Table 7 summarizes commonly reported adverse The inescapable conclusion from history is that

2008 The Author Journal Compilation 2008 European Society of Clinical Microbiology and Infectious Diseases, CMI, 14 (Suppl. 6), 30–45 Peterson Monotherapy of serious infection 43

emerging resistance is intrinsic to antibacterial therapy itself, and that treatment, in the long – – 0 0.2 – – – – 0.4 0.2 term, leads to resistance in the very pathogens that it is intended to eradicate [17]. New strategies to slow the emergence of resistance require a paradigm shift in our use of antimicrobial agents. Increasing worldwide resistance in key pathogens patients discontinued due to – – 0.1 0.4 – – – – % AEs 0.2 0.1 (MRSA, enterococci, and enteric Gram-negative organisms) requires a reassessment of how we make the initial choice of treatment for likely infection, whenever the offending pathogen will 0.673 0.568 – – <0.001 0.760 0.719 0.019 p-value 0.010 0.008 remain unknown for several days. For example, rising MRSA infection rates will lead to an increased use of combination therapy unless a monotherapy with a suitable agent is adopted. Data from many published studies argue that, as = 1382) Tigecycline Comparator 3.4 2.8 5.5 6.4 4.0 n – – 13.2 ( 19.0 14.3 Comparator a general rule, combination therapy offers no advantage over monotherapy with an antimicro- bial agent with a suitable spectrum of activity [5,13,41–43]. Although exclusive use of monother-

cIAI patients apy is a clinically unrealistic objective, expanded = 1415) 2.9 3.3 6.0 2.0 n – 10.2 – 13.8 % 24.4 19.2 Tigecycline ( prescription of a single agent, wherever it is likely to provide effective treatment, can lower the pressure for further development of resistant pathogens, and help to maintain the therapeutic foothold against an ever-worsening global prob- – – – – – 1.1 – – 0.2 0 lem concerning both community and healthcare- associated resistant bacterial infections.

ACKNOWLEDGEMENTS patients discontinued due to – – – – – 0.2 – % AEs – Tigecycline Comparator 1.1 0.4 L. R. Peterson thanks H. Alimohammadi, Upside Endeavors, Sanatoga, USA for editorial support with the manuscript.

TRANSPARENCY DECLARATION 0.003 <0.001 – – – 0.113 <0.001 p-value <0.001 <0.001 0.032 Over the past three years, L.R. Peterson has received research grants from Cepheid, Evanston Northwestern Healthcare, BD-

a GeneOhm, Johnson and Johnson, MicroPhage, Nanogen, Nanosphere, Roche, 3M, Washington Square Health Founda- tion, and Wyeth Pharmaceuticals. He has also provided = 550) n 5.1 6.2 – 3.1 – – 5.8 Comparator 8.2 3.6 ( 5.1 consultations and/or received speaking honoraria from Cep- heid, BD-GeneOhm, MicroPhage, Nanogen, Nanosphere, Roche, 3M and Wyeth.

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