Investigational new drugs for the treatment of resistant pneumococcal infections

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<ul><li><p>Review</p><p>10.1517/13543784.14.8.973 2005 Ashley Publications Ltd ISSN 1354-3784 973</p><p>Ashley Publicationswww.ashley-pub.com</p><p>Monthly Focus: Anti-infectives</p><p>Investigational new drugs for the treatment of resistant pneumococcal infectionsHolly L Hoffman-Roberts, Emily C Babcock &amp; Isaac F MitropoulosCollege of Pharmacy, 1110 North Stonewall 206, PO BOX 26901, Oklahoma City, OK 73190, USA</p><p>Antibiotic resistance in Streptococcus pneumoniae is not only increasing withpenicillin but also with other antimicrobial classes including the macrolides,tetracyclines and sulfonamides. This trend with antibiotic resistance has high-lighted the need for the further development of new anti-infectives for thetreatment of pneumococcal infections, particularly against multi-drug resistantpneumococci. Several new drugs with anti-pneumococcal activity are at variousstages of development and will be discussed in this review. Two new cepha-losporins with activity against S. pneumoniae include ceftobiprole andRWJ-54428. Faropenem is in a new class of -lactam antibiotics called the pen-ems. Structurally, the penems are a hybrid between the penicillins andcephalosporins. Sitafloxacin and garenoxacin are two new quinolones that arelikely to have a role in treating pneumococcal infections. Oritavancin and dal-bavancin are glycopeptides with activity against methicillin-resistant S. aureusand vancomycin-resistant Enterococcus spp. as well as multi-drug resistantpneumococci. Tigecycline is the first drug in a new class of anti-infectives calledthe glycycyclines that has activity against penicillin-resistant pneumococci.</p><p>Keywords: ceftobiprole, dalbavancin, faropenem, garenoxacin, investigational antibiotics, oritavancin, pneumonia, resistance, RWJ-442831, sitafloxacin, Streptococcus pneumoniae</p><p>Expert Opin. Investig. Drugs (2005) 14(8):973-995</p><p>1. Introduction</p><p>Streptococcus pneumoniae is the most common bacterial pathogen in community-acquired meningitis, pneumonia, otitis media and sinusitis. Respiratory tractinfections, such as pneumonia, account for 10 million physician visits,600,000 hospitalisations and 45,000 deaths annually in the US. Pneumonia stillremains in the top 10 causes of death in developed countries and it is associatedwith significant healthcare costs. Additionally, S. pneumoniae accounts for 47%of bacterial meningitis in the US, and mortality ranges from 19 to 26% [1]. Cur-rently, respiratory tract infections still remain a leading cause of morbidity andmortality, and are among the most common reasons individuals seek medical care.</p><p>Colonisation with pneumococci occurs in the nasopharynx and generally occursin 5 10% of healthy adults and 40 50% of healthy children &lt; 2 years of age.Asymptomatic carriage rates fluctuate throughout the year and generally peakduring winter months.</p><p>1.1 Resistance with Streptococcus pneumoniaeIn the early 1980s, penicillin resistance rates in S. pneumoniae in the US were 3 5% and the majority of these isolates exhibited intermediate-level resistance[2,3]. By the early 1990s, the prevalence of penicillin-resistant S. pneumoniae(PRSP), which included penicillin intermediate and penicillin-resistant isolates,had increased to 16 18% [4]. Currently, penicillin non-susceptible</p><p>1. Introduction</p><p>2. Cephalosporins</p><p>3. Penems</p><p>4. Quinolones</p><p>5. Glycopeptides</p><p>6. Glycylcyclines</p><p>7. Ketolides</p><p>8. Conclusion</p><p>9. Expert opinion</p><p>Exp</p><p>ert O</p><p>pin.</p><p> Inv</p><p>estig</p><p>. Dru</p><p>gs D</p><p>ownl</p><p>oade</p><p>d fr</p><p>om in</p><p>form</p><p>ahea</p><p>lthca</p><p>re.c</p><p>om b</p><p>y M</p><p>cgill</p><p> Uni</p><p>vers</p><p>ity o</p><p>n 11</p><p>/03/</p><p>14Fo</p><p>r pe</p><p>rson</p><p>al u</p><p>se o</p><p>nly.</p></li><li><p>Investigational new drugs for the treatment of resistant pneumococcal infections</p><p>974 Expert Opin. Investig. Drugs (2005) 14(8)</p><p>S. pneumoniae (PNSP) resistant rates are 30 35% andvariation is observed based on geographical distribution [5,6].In addition, the percentage of PNSP isolates that are resist-ant to at least two other drug classes is also rising [7,8]. Themost common drug classes for cross-resistance include themacrolides, tetracyclines and sulfonamides.</p><p>Considerable geographical variation has been reportedregarding penicillin resistance rates in S. pneumoniae [9].Southeastern Asia generally reports the highest rates ofpenicillin and multi-drug resistance, where &gt; 71% ofS. pneumoniae isolates in South Korea are resistant to peni-cillin. In Europe, the resistance rates vary by country. BothFrance and Spain have the highest pneumococcal penicil-lin-resistance rates &gt; 40%, but little or no penicillin resist-ance is reported in the Netherlands. Recently, theS. pneumoniae resistance rates reported with macrolideshave continued to increase. Erythromycin resistance ratesare generally &gt; 30% with the highest resistance ratesreported in South Korea, France and Hungary, whichrange from 55 to 87%. However, the macrolide resistancerates are still low in Sweden where &lt; 5% of S. pneumoniaeisolates are resistant to erythromycin. Resistance to fluoro-quinolone antibiotics has remained low and is generallyaround 1%. Although the evidence of clonal spread hasoccurred in Asia, where 3.8 14.3% of all of the strains ofS. pneumoniae have been reported to be quinoloneresistant [9-11].</p><p>1.2 Current therapeutic optionsS. pneumoniae is the most common bacterial pathogen in allrespiratory tract infections. Therefore, when treating respira-tory tract infections, the increasing resistance rates must beconsidered. Respiratory tract infections, including sinusitis,otitis media and pneumonia, are commonly treated on anout-patient basis employing empiric antibiotic selection. Theantibiotic classes that are most commonly used for theempiric therapy of respiratory tract infections include the-lactams, macrolides and fluoroquinolones. Generally, theseantibiotic classes have activity against S. pneumoniae and othercommon respiratory pathogens, such as Haemophilus influen-zae and Moraxella catarrhalis. However, the -lactams do nothave activity against atypical respiratory tract pathogens, suchas Mycoplasma pneumoniae, Chlamydophilia pneumoniae andLegionealla pneumophila. Therefore, a -lactam is combinedwith a macrolide in more severely ill patients or if an atypicalpathogen is suspected. An advantage of the quinolone class isthat the most common pathogens are covered with a singledrug in community-acquired respiratory tract infections.</p><p>In 2003, the Infectious Diseases Society of America pub-lished guidelines for the treatment of community-acquiredpneumonia (CAP) in immunocompetent adults [12]. Cur-rent out-patient recommendations for CAP therapyinclude either a macrolide or doxycycline [12]. If the patienthas received recent antibiotic therapy within the last3 months, then a respiratory fluoroquinolone alone</p><p>(moxifloxacin, gatifloxacin, levofloxacin or gemifloxacin)or a combination of an advanced macrolide (clarithro-mycin or azithromycin) plus high-dose amoxicillin with orwithout clavulanate is recommended. If co-morbidities arepresent, such as chronic obstructive pulmonary disease,diabetes or heart failure, an advanced macrolide plus a-lactam or a respiratory fluoroquinolone is suggested evenif the patient has not had recent antibiotic exposure.Among patients who require hospitalisation, fluoroqui-nolones or an advanced macrolide plus a -lactam are therecommended therapy for CAP. In addition, obtaining cul-tures and susceptibility testing is advocated in an in-patient setting, which allows the tailoring of therapy basedon the resistance patterns of the pathogen.</p><p>As with pneumonia, sinusitis therapy is also often empiri-cal and the initial antibiotic selection must adequately coverpneumococci. Guidelines from a joint effort of the Ameri-can Academy of Otolaryngic Allergy, the American Acad-emy of Otolaryngology Head and Neck Surgery, and theAmerican Rhinologic Society published guidelines in 2004for the treatment of acute bacterial rhinosinusitis [13]. Inchildren, the initial therapy for mild sinusitis without recentantibiotic exposure includes amoxicillin with or without cla-vulanate. Cefpodoxime, cefuroxime and cefdinir are alsoalternatives. If a -lactam allergy is present, then trimetho-primsulfamethoxazole or a macrolide can be considered. Inchildren with mild or moderate sinusitis with recent anti-biotic exposure, high-dose amoxicillinclavulanate remainsthe preferred choice. Therapy for adults with sinusitis issimilar; however, doxycycline or a fluoroquinolone can alsobe used.</p><p>If antibiotic use is deemed appropriate in the treatment ofacute otitis media, then therapy should be initiated with high-dose amoxicillin with or without clavulanate [14]. Cefdinir,cefuroxime, cefpodoxime or advanced macrolides are alsoacceptable alternatives. If a patient fails to improve withamoxicillin, trimethoprimsulfamethoxazole and macrolidesshould be avoided due to the risk of cross-resistance.</p><p>S. pneumoniae is the most common bacterial cause ofmeningitis. In those cases in which S. pneumoniae is the sus-pected pathogen, vancomycin plus a third-generation cepha-losporin remains first-line empiric therapy. Carbapenamsand fluoroquinolones serve as possible alternatives.</p><p>1.3 Need for new agentsThe need for new antibacterial agents to treat infections causedby S. pneumoniae resistant to common therapeutic agents isincreasing. Recently, there have been several new antimicrobialagents developed that will have activity against antibiotic-resist-ant pneumococci. Some of these are new additions to the now-familiar drug classes, such as the fluoroquinolones, whereas oth-ers are the first of an entirely new class, such as the glycyl-cyclines and penems. This review will focus on the new andinvestigational agents that will have the greatest potential fortreating drug-resistant pneumococci.</p><p>Exp</p><p>ert O</p><p>pin.</p><p> Inv</p><p>estig</p><p>. Dru</p><p>gs D</p><p>ownl</p><p>oade</p><p>d fr</p><p>om in</p><p>form</p><p>ahea</p><p>lthca</p><p>re.c</p><p>om b</p><p>y M</p><p>cgill</p><p> Uni</p><p>vers</p><p>ity o</p><p>n 11</p><p>/03/</p><p>14Fo</p><p>r pe</p><p>rson</p><p>al u</p><p>se o</p><p>nly.</p></li><li><p>Hoffman-Roberts, Babcock &amp; Mitropoulos</p><p>Expert Opin. Investig. Drugs (2005) 14(8) 975</p><p>2. Cephalosporins</p><p>2.1 IntroductionHistorically, -lactams have been the drugs of choice forpneumococcal infections. Second- and third-generationcephalosporins are often used for the treatment of respiratorytract infections, including CAP, sinusitis and otitis media.Third-generation cephalosporins, generally in combinationwith vancomycin, are routinely used empirically for moresevere infections, including meningitis and bacteraemia. Twonew cephalosporins, ceftobiprole and RWJ-54428, have activ-ity against drug-resistant pneumococci and will be discussedin greater detail (see Sections 2.3 and 2.4).</p><p>2.2 Mechanism of actionCephalosporins inhibit the formation of the bacterial cellwall in actively growing cells. They exert their effects bybinding to the penicillin-binding proteins (PBPs) in themembrane and interfering with peptidoglycan crosslinking,which results in the subsequent lysis of the cell. The differ-ences in the binding affinity for the types of PBP by different-lactam antibiotics may account for the variations in bacte-ricidal activity among the cephalosporins. For example,PBP2x and PBP2b are the common targets of cephalosporinsin S. pneumoniae. Mosaic changes of these target sites resultin reduced affinity of the cephalosporin. An agent withhigher affinity for these PBPs may be more effective inovercoming target-site modifications.</p><p>2.3 Ceftobiprole2.3.1 IntroductionCeftobiprole medocaril (BAL-5788, Basilea Pharmaceuticals),the water-soluable prodrug that is rapidly hydrolysed to cefto-biprole (BAL-9141), represents a new cephalosporin with tar-geted activity against methicillin-resistant S. aureus (MRSA)and PRSP. Preliminary data for its anti-MRSA activity earnedthis drug fast-track status from the FDA. This drug is currentlyin Phase III clinical trials. Ceftobiprole is a pyrrodidinone-3-ylidenemehtyl cephalosporin with a strong affinity for staphy-lococci and pneumococci PBP2a and PBP2x [15]. In addition,ceftobiprole is resistant to many of the -lactamases producedby Gram-positive and -negative pathogens, thus providing abroad spectrum of activity [15,16].</p><p>2.3.2 Pharmacokinetics and pharmacodynamicsCeftobiprole displays linear kinetics in healthy volunteersfollowing single doses ranging from 125 to 1000 mg [17].Following administration of single-dose ceftobiprole 125and 1000 mg, the average maximum serum concentration(Cmax) was 9.87 gl and 72.2 g, respectively. Ceftobiprolemedocaril was converted by plasma esterases to ceftobiprolein &lt; 30 min. Ceftobiprole was 38% protein bound, andthe free drug was renally excreted at a rate that approximatedglomerular filtration. In the urine, &gt; 70% of the drug wasexcreted in its active form. In addition, the half-life, volume</p><p>of distribution at steady state and clearance were 3 h, 19 land 6 l/h, respectively.</p><p>The multiple-dose pharmacokinetics following the admin-istration of ceftobiprole 500 or 750 mg i.v. correlated wellwith those from the single-dose study [18]. Only negligibledose accumulation in the plasma was observed. The authorsconcluded that ceftobiprole has a stable pharmacokineticprofile following administration for 7 days at doses that yieldfavourable times above the minimum inhibitory concentra-tion (MIC) value. Monte-Carlo pharmacokinetic simulationswere used to determine that doses of 750 and 500 mg b.i.d.were sufficient for the treatment of MRSA and S. pneumoniaeinfections, respectively [19]. These simulations assumed thetime that the serum concentrations remained above the MICvalue for the organism was &gt; 40% of the dosage interval, andthat the MIC of the pneumococcal and MRSA isolates were&lt; 2 and 4 g/ml, respectively. The corresponding, provisionalsusceptible breakpoint used for MRSA and S. pneumoniae was4 g/ml.</p><p>The pharmacokinetics of ceftobiprole were also comparedbetween subjects with normal renal function and mild, moder-ate and severe renal dysfunction. The clearance of ceftobiprolewas found to be linearly related to creatinine clearance. Assum-ing a standard dose of 750 mg b.i.d., the authors proposed doseadjustments to 500 mg b.i.d. for patients with mild-to-moder-ate impairment, and 250 mg/day for patients with severe renalimpairment to achieve similar serum concentrations [20].</p><p>2.3.4 In vitroAlthough ceftobiprole does have activity against penicillin-susceptible S. pneumoniae isolates, less activity is observedagainst penicillin non-susceptible isolates compared to fullypenicillin susceptible isolates (Table 1) [15,16,21]. A lower MICis observed with ceftobiprole compared with other cepha-losporins, such as cefotaxime and ceftriaxone, thus suggestingthat it may be more potent. In vivo comparative studies arenecessary in determining if the increased potency results inbetter clinical outcomes.</p><p>An in vitro study of ceftobiprole demonstrated moderateconcentration-dependant killing and bactericidal activity[22,23]. Among those S. pneumoniae isolates with penicillinMIC values that ranged from 0.12 to 4 g/ml, bactericidaleffects were reported with all isolates following exposure toceftobiprole concentrations of 4 g/ml. B...</p></li></ul>

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