investigational new drugs for the treatment of resistant pneumococcal infections

Review

10.1517/13543784.14.8.973 © 2005 Ashley Publications Ltd ISSN 1354-3784 973

Ashley Publicationswww.ashley-pub.com

Monthly Focus: Anti-infectives

Investigational new drugs for the treatment of resistant pneumococcal infectionsHolly L Hoffman-Roberts†, Emily C Babcock & Isaac F Mitropoulos†College of Pharmacy, 1110 North Stonewall 206, PO BOX 26901, Oklahoma City, OK 73190, USA

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 β-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.

Keywords: ceftobiprole, dalbavancin, faropenem, garenoxacin, investigational antibiotics, oritavancin, pneumonia, resistance, RWJ-442831, sitafloxacin, Streptococcus pneumoniae

Expert Opin. Investig. Drugs (2005) 14(8):973-995

1. Introduction

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.

Colonisation with pneumococci occurs in the nasopharynx and generally occursin 5 – 10% of healthy adults and 40 – 50% of healthy children < 2 years of age.Asymptomatic carriage rates fluctuate throughout the year and generally peakduring winter months.

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

1. Introduction

2. Cephalosporins

3. Penems

4. Quinolones

5. Glycopeptides

6. Glycylcyclines

7. Ketolides

8. Conclusion

9. Expert opinion

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Investigational new drugs for the treatment of resistant pneumococcal infections

974 Expert Opin. Investig. Drugs (2005) 14(8)

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.

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 > 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 > 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 > 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 < 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].

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 theβ-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 β-lactams do nothave activity against atypical respiratory tract pathogens, suchas Mycoplasma pneumoniae, Chlamydophilia pneumoniae andLegionealla pneumophila. Therefore, a β-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.

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

(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 aβ-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 β-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.

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 β-lactam allergy is present, then trimetho-prim–sulfamethoxazole or a macrolide can be considered. Inchildren with mild or moderate sinusitis with recent anti-biotic exposure, high-dose amoxicillin–clavulanate remainsthe preferred choice. Therapy for adults with sinusitis issimilar; however, doxycycline or a fluoroquinolone can alsobe used.

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, trimethoprim–sulfamethoxazole and macrolidesshould be avoided due to the risk of cross-resistance.

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.

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.

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Hoffman-Roberts, Babcock & Mitropoulos

Expert Opin. Investig. Drugs (2005) 14(8) 975

2. Cephalosporins

2.1 IntroductionHistorically, β-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).

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 differentβ-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.

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 β-lactamases producedby Gram-positive and -negative pathogens, thus providing abroad spectrum of activity [15,16].

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 µgl and 72.2 µg, respectively. Ceftobiprolemedocaril was converted by plasma esterases to ceftobiprolein < 30 min. Ceftobiprole was ∼ 38% protein bound, andthe free drug was renally excreted at a rate that approximatedglomerular filtration. In the urine, > 70% of the drug wasexcreted in its active form. In addition, the half-life, volume

of distribution at steady state and clearance were ∼ 3 h, 19 land 6 l/h, respectively.

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 > 40% of the dosage interval, andthat the MIC of the pneumococcal and MRSA isolates were< 2 and 4 µg/ml, respectively. The corresponding, provisionalsusceptible breakpoint used for MRSA and S. pneumoniae was4 µg/ml.

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].

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.

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 µg/ml, bactericidaleffects were reported with all isolates following exposure toceftobiprole concentrations of 4 µg/ml. Bactericidal activitywas observed regardless of penicillin susceptibility.

2.3.5 In vivoCeftobiprole was compared with benzylpenicillin, ceftriax-one and meropenem in an experimental murine septicae-mia model [15]. S. pneumoniae isolates susceptible andresistant to penicillin and ceftriaxone were evaluated.Ceftobiprole had the lowest effective dose necessary toachieve a clinical response in 50% of the test subjects(ED50) compared with ceftriaxone, meropenem andbenzylpenicillin.

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Ceftobiprole was also compared with ceftriaxone in amurine model of pneumococcal pneumonia using clinicalisolates with penicillin and ceftriaxone resistance [24]. Thedifference in the survival rate between the two groups wasnot statistically significant, although the dose of ceftobiprolewas considerably lower than the dose of ceftriaxone requiredto achieve similar survival rates among mice infected with apenicillin- and cephalosporin-resistant pneumococcal strain.Both agents provided complete bacterial clearance of lungtissue by the end of the third and final day of treatment.Additionally, no regrowth occurred with either drug andblood cultures remained negative until the end of the study.The time that serum concentrations remained above theMIC of the isolate and ranged from 9 to 18% in the ceftobi-prole-treated mice, compared with 30 – 50% in the ceftriax-one-treated mice. Although the time above the MIC was lessfollowing administration of ceftobiprole, adequate bacterialkilling was achieved. This may be attributed to the lowerserum protein binding in ceftobiprole, which is < 60%,compared with ceftriaxone which is > 80%.

In summary, ceftobiprole demonstrated in vitro activityagainst penicillin-resistant pneumococci. Additionally,ceftobiprole was at least comparable with ceftriaxone for thetreatment of penicillin- and cephalosporin-resistantpneumococcal pneumonia in animal studies.

2.3.6 SafetyOverall, ceftobiprole had a good safety profile in preliminarystudies. One episode of syncope was reported but it was notattributed to the study drug [20]. No other serious adverseevents were reported. Headache, nausea and a caramel-liketaste were the most common adverse events that werereported [17,18]. The caramel–like taste disturbance was

attributed to the release of diacetyl during the conversion ofthe prodrug to active cephalosporin [15,17,25]. No changes inelectrocardiogram (ECG) or vital signs were observed [17,18].A mild-to-moderate increase in alanine aminotransferase wasreported in three patients receiving multiple doses of ceftobi-prole 750 mg [18]. It is unlikely that any of these adverseevents will significantly limit the use of ceftobiprole. Addi-tional studies with larger populations will provide moreinformation regarding adverse events with ceftobiprole.

2.4 RWJ-544282.4.1 IntroductionRWJ-54428 from Johnson & Johnson has just completedPhase I clinical trials. RWJ-54428 has in vitro activity againstresistant Gram-positive organisms including vancomycin-resistant enterococci (VRE), MRSA and penicillin-resistantS. pneumoniae [15,16,21,23]. It is available as both a parenteralform and an aspartyl prodrug (RWJ-442831) for oral admin-istration. There is less in vitro and in vivo data available withRWJ-54428 compared with ceftobiprole; however, the datathat has been published will be summarised.

2.4.2 Pharmacokinetics and pharmacodynamicsAs RWJ-54428 has just completed Phase I clinical trials, thepublished pharmacokinetic data are limited to animal data. In amurine model, a single dose of RWJ-54428 10 or 50 mg/kg s.c.was rapidly absorbed, and the time until maximum concentra-tion (Tmax) ranged from 0.12 to 0.31 h [26]. The volume of dis-tribution, half-life and Tmax increased with the dose, whereasclearance decreased. The Cmax values after a does of 50 and10 mg/kg were 22.1 and 5.6 mg/l, respectively.

Another murine study reported that 90% of the watersoluble-prodrug RWJ-442831 was converted to the active

Table 1. Comparison of in vitro activity of ceftobiprole against selected Streptococcus pneumoniae isolates.

Drug/resistance type Number of isolates MIC range (µg/ml) MIC50 (µg/ml) MIC90 (µg/ml)

Penicillin PCN susceptible [15,16,21]

PCN intermediate [16,21]

PCN resistant [15,16,21]

Macrolide susceptible [21]

Macrolide resistant [21]

310205343147152

≤ 0.015 – 0.060.12 – 12 – > 160.016 – 40.016 – 16

≤ 0.0030.5422

0.061444

Ceftobiprole PCN susceptible [15,16,21]





310205343147152

0.008 – 0.03≤ 0.008 – 10.015 – 40.08 – 10.008 – 4

≤ 0.0150.060.250.250.5

≤ 0.0150.1210.51

Ceftriaxone–cefotaximePCN susceptible [15,16,21]





310205343147152

≤ 0.008 – 0.12≤ 0.008 – 80.012 – 80.016 – 40.016 – 32

0.060.25111

≤ 0.0151424

MIC: Minimum inhibitory concentration; PCN: Penicillin.

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form RWJ-54428 within 30 min [27]. RWJ-54428 was theonly detected metabolite of RWJ-442831 [28]. Over 70% ofthe prodrug was degraded within 1 h by liver homogenates ofanimal and human serum [28]. Human serum degraded 35%of RWJ-442831 over 1 h compared with 84% degradation inrat serum at 1 h. These data suggest that RWJ-442831 is con-verted rapidly and specifically to the active drug RWJ-54428in vivo.

A neutropoenic murine thigh infection model was used toevaluate the pharmacodynamic parameters with RWJ-54428against penicillin-susceptible and -resistant isolates [29]. Asobserved with other cephalosporins, the pharmacodynamicparameter that best correlated with clinical efficacy inRWJ-54428 was significantly above the MIC. The maximalreductions in tissue colony counts occurred when RWJ-54428concentrations were above the MIC of the infectingS. pneumoniae strain for 25 – 30% of the dosing interval.

2.4.3 In vitroAs illustrated in Table 2, RWJ-54428 had more potent in vitroactivity compared with ceftriaxone or cefotaxime against pen-icillin-susceptible, -intermediate and -resistant pneumococcalisolates [30-32]. However, in all of the cases, the MIC90 ofRWJ-54428 increased as penicillin resistance increased. Thistrend has been observed with other cephalosporins and ismost likely to be a result of similar mechanisms of resistanceof the cephalosporins and penicillins.

Competition assays that included four strains of S. pneumo-niae with varying penicillin susceptibility demonstrated anincreased binding affinity to PBP2a with RWJ-54428 comparedwith penicillin [33]. The authors concluded that this increasedbinding affinity to PBP2a may in part account for the increasedactivity of RWJ-54428 against pneumococci and other Gram-positive pathogens. Additional studies are needed to determineif the increased binding affinity of RWJ-54428 to PBP2a willhave any clinical advantage for the treatment of infectionscaused by PNSP.

2.4.4 In vivoA pneumococcal-pneumonia murine model was used tocompare RWJ-54428 with cefotaxime and penicillin [26]

using strains of S. pneumoniae that were susceptible to allantibiotics. In comparing equivalent doses, RWJ-54428 wassuperior to cefotaxime and penicillin in reducingS. pneumoniae colony counts in the lungs. More animaldata are needed to determine if the increased potency allowsfor an advantage in treating infections caused by S. pneumo-nia isolates that are resistant to penicillin and other drugclasses. It would be expected that RWJ-54428 will havesimilar activity to cefotaxime and ceftriaxone against peni-cillin-resistant S. pneumoniae, but the increased potencycombined with a higher affinity to PBP2a may provide aclinical advantage.

2.4.5 ResistanceResistance with β-lactam antibiotics in S. pneumoniae occurfrom stepwise mutations in the PBPs. In S. pneumoniae, fivePBPs exist including PBP1 (1a and 1b) and PBP2 (2a, 2b and2x). The most common mutations with cephalosporin resist-ance involve PBPs2x and PBP2b. RWJ-54428 has a high affin-ity for all of the PBPs in penicillin-susceptible, -intermediateand -resistant isolates of S. pneumoniae. The binding ofRWJ-54428 to PBPs was equivalent or superior to thatobserved with penicillin [33]. Additionally, ceftobiprole has astrong affinity for PBP2a and PBP2x [15]. The stepwise accu-mulation of PBP mutations implies that resistance withβ-lactams is not an all-or-none occurrence but isconcentration dependant. High-dose amoxicillin has becomethe drug of choice for pneumococcal otitis media and sinusi-tis. As the binding affinity of RWJ-54428 is at least the sameor superior to penicillin, and ceftobiprole also has a strongaffinity for PBP2a and PBP2x, increased doses of these cepha-losporins should theoretically be effective against cepha-losporin-resistant pneumococci. Further clinical trials willneed to determine if this concept correlates with improvedclinical outcomes.

3. Penems

3.1 FaropenemThe penems are a new distinct class of antibiotics that are ahybrid of the penicillins and cephalosporins. Several investiga-tional penems including ritipenem, sulopenem and faro-penem (Figure 1) are at various stages of clinical development.However, faropenem appears to have the most data and,therefore, will be discussed in greater detail.

Faropenem daloxate (an ester) is in Phase III clinical trialsand a new drug application (NDA) submission is scheduledfor late 2005 [201]. Replidyne acquired faropenem daloxatein March 2004 from Daiichi Suntory Pharmaceuticals(Tokyo, Japan). Faropenem will probably be marketed foracute bacterial sinusitis, acute exacerbations of chronicbronchitis and CAP.

Faropenem has a broad spectrum of activity includingmany Gram-positive and -negative pathogens as well as sev-eral anaerobes. It has a spectrum of activity that includes themost common community-associated respiratory tract patho-gens and is stable to β-lactamases. As with other β-lactams,faropenem does not have any activity against atypicalrespiratory tract pathogens [34].

3.1.1 Mechanism of actionThe penems, like other β-lactams, bind to PBPs and inhibitcell wall synthesis. It appears that faropenem binds to PBPswith a higher affinity than other β-lactam drugs [35]. The freeacid is the active form of the drug and results from in vivohydrolysis of the ester prodrug.

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3.1.2 Pharmacokinetics and pharmacodynamicsFaropenem daloxate has an oral bioavailability of 70 – 80% [34].Linear pharmacokinetics were observed in healthy volunteersfollowing the administration of faropenem 300 – 1200 mg/dayfor 8 days [36]. However, among the patients who received faro-penem 1200 mg b.i.d., the Cmax values at night on days 7 and 8were lower than the values obtained during the day. This sug-gests that the metabolism of the drug may occur via a differentmechanism at higher doses. No accumulation of faropenemwas observed following multiple doses. Additionally, faropenemcan be administered without consideration to meal intake [37].

Among healthy volunteers, no difference in faropenempharmacokinetic parameters were observed between elderlyindividuals (> 65 years of age) compared with a younger popu-lation (19 – 45 years of age) [38]. No differences were observedin the Cmax and Tmax values between the elderly and youngerindividuals; however, a slight increase in the area under thecurve (AUC0-∞) and half-life was observed in the elderly com-pared with the younger population. As faropenem will be dosedevery 12 h and the half-life is short, ranging from 0.8 to 1.32 h,the accumulation of the drug is not likely to occur and a doseadjustment will probably not be necessary in elderly individu-als. Furthermore, following a single dose of faropenem 300 mg,no gender-related differences in pharmacokinetic parameterswere observed [38].

Plasma samples evaluated in Phase I studies did not find anyevidence of active metabolites of faropenem [39]. Lung tissueconcentrations for faropenem were estimated to be 40% of theserum levels [40]. Protein binding was high and ranged from 95to 98% [41]. In a rabbit model, faropenem demonstrated alower antigenic cross-reactivity to penicillins compared withother β-lactam antibiotics [42]. However, it is unlikely that faro-penem will be a treatment option among patients with a severepenicillin allergy.

3.1.3 In vitro activityAs illustrated in Table 3, faropenem has good in vitro activityagainst S. pneumoniae. However, among isolates that are not

susceptible to penicillin, the MIC values of faropenem areelevated compared with penicillin-susceptible isolates [43].Conversely, the MIC values of faropenem do not appear tobe elevated among isolates that are resistant to macrolides,tetracycline, levofloxacin or trimethoprim–sulfamethoxazole[44]. Faropenem also has good in vitro activity against Hae-mophilus influenzae and Moraxella catarrhalis, thus making ita favourable drug for empirical therapy for respiratory tractinfection.

Faropenem was bactericidal against S. pneumoniae at 4 hfollowing drug exposure at concentrations 5 – 10 times theMIC [41]. Using an in vitro model, concentrations that simu-lated serum concentrations following faropenem doses of300 – 1200 mg resulted in bactericidal activity againstS. pneumoniae and H. influenzae.

3.1.4 In vivo animal dataA neutropoenic murine thigh infection model was used toevaluate the in vivo pharmacodynamic activity of faropenemagainst penicillin- and macrolide-resistant S. pneumoniae iso-lates [45]. The time that the free-drug concentrations of faro-penem were above the MIC of the S. pneumoniae isolate bestcorrelated with microbiological cure. Penicillin- and macro-lide-resistant strains required a slightly longer time above theMIC for microbiological cures. These results suggested thatfree serum levels should be above the MIC for ≥ 15% of thedosage interval for effective microbiological outcomes.

3.1.5 In vivo human dataA prospective, multinational, double-blinded comparativestudy of patients with acute bacterial maxillary sinusitis com-pared faropenem daloxate 300 mg b.i.d. with cefuroxime axe-til 250 mg b.i.d. for 7 days [46]. Patients included in the studyhad both clinical signs and radiographic evidence of acutesinusitis. Cure rates were similar between faropenem andcefuroxime at the 7 – 16 day post-therapy assessment (92.6versus 94.9%, confidence interval [CI] -6.9 and +1.2%,respectively). In addition, similar bacteriological success rates

Table 2. Comparison of in vitro activity of RWJ-54428 against selected Streptococcus pneumoniae isolates.


Penicillin [30,31,114]

PCN susceptible PCN intermediate PCN resistant

6510781

≤ 0.008 – 0.060.125 – 12 – > 8

0.0612

0.0614

RWJ-54428 [30,31,114]


6510781

≤ 0.008 – 0.060.015 – 0.250.125 – 1

≤ 0.0150.1250.5

≤ 0.0150.251

Ceftriaxone–cefotaxime [30,31,114]


6510781

≤ 0.06 – 0.5≤ 0.06 – 80.5 – > 32

≤ 0.120.51

0.2514


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were observed between faropenem and cefuroxime in the136 patients in whom causative pathogens were identified(91.5 versus 90.8%, CI -9.2 and +9.5%, respectively).S. pneumoniae was identified in 47.1% of the recoveredpathogens, and faropenem and cefuroxime therapy resulted inthe eradication or presumed eradication in 97.3 and 96.3% ofthe cases, respectively. The bacteriological response rate inboth groups was not affected by the penicillin susceptibility ofS. pneumoniae. More clinical data are needed to determine iffaropenem is more effective than other available β-lactamantibiotics for the treatment of infections caused by resistantpneuococci. However, based on this study, faropenem is atleast as effective as cefuroxime against respiratory tractinfections caused by S. pneumoniae.

3.1.6 Safety and impact on normal floraFaropenem was well tolerated and the side effects were similarto other β-lactams. The most common adverse events withfaropenem include gastrointestinal side effects (0.7 – 2.2%),such as diarrhea, nausea and vomiting. In addition, abdo-minal pain, skin reactions (1.5%) and headache have alsobeen reported [38,46].

A pharmacokinetic dose-escalation study in healthyvolunteers compared the endogenous gut and oropharyngealflora before treatment and 1 – 2 weeks following 8 days oftreatment with faropenem 300 and 600 mg b.i.d. [36]. Fol-lowing therapy, an increase in recovery of Enterococcus fae-cium and a decrease in Clostridium spp. was observed.Although this has been observed with other β-lactams, more

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Doripenem Faropenem Tigecycline

Cethromycin Sitafloxacin Garenoxacin

RWJ-54428

BAL-9141

BAL-5788

Figure 1. Chemical structures of investigational drugs for the treatment of resistant pneumococcal infections.

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studies will need to be conducted to see if thebroad-spectrum activity of faropenem has negativeconsequences on normal microbial flora.

4. Quinolones

4.1 IntroductionThe quinolone class has established its utility in treating awide variety of infectious diseases with the advantages ofexcellent oral bioavailability, convenient dosing schedules andfavourable adverse-event profiles. The newer quinolones haveactivity against the common respiratory bacterial pathogensincluding isolates with resistance to other classes of anti-biotics. Several new quinolones are in investigational trialsdue to a response of the emergence of multi-drug resistantS. pneumoniae.

Structural modifications, such as the presence of pyrroli-dinyl derivatives at position C-7 and halides at position C-8for sitafloxacin (DU-6859A), or the removal of the C-6 fluo-rine, des-F(6), in garenoxacin (BMS-284756), differentiatethe newer agents from earlier fluoroquinolones. Currently, theinvestigational quinolones with the most data includegarenoxacin (Schering-Plough) and sitafloxacin (Daiichi).

4.2 Mechanism of actionFluoroquinolones inhibit topoisomerases II (DNA gyrase)and IV in bacteria. Both enzymes have a very similar proteinstructure, each composed of two subunits. In the replicationfork, two quinolone molecules self-assemble to form a dimer

structure. They bind to the complex by electrostatic forces,which stabilise the intermediate stage in this reaction step.Replication can no longer occur and the process is effectivelylocked. Exonucleases then degrade the DNA, leading toirreversible damage and, finally, to the death of the cell.

4.3 Garenoxacin4.3.1 IntroductionSchering Plough has recently completed Phase III clinicaltrials with garenoxacin and is expecting to file a NDA withthe FDA in 2005. Garenoxacin is a novel des-F(6) qui-nolone that was shown to be effective in vitro against a widerange of clinically important pathogens, including Gram-positive and -negative aerobes and anaerobes, as well asatypical respiratory tract pathogens.

4.3.2 Pharmacokinetics and pharmacodynamicsGarenoxacin is well absorbed following oral administrationand may be taken without regard to meals [47]. The serumprotein binding of garenoxacin is ∼ 75% [48]. Amonghealthy male volunteers, the mean Cmax of garenoxacin fol-lowing a single 600-mg dose was 10.4 µg/ml and the Tmax

was 1.5 h [49]. The mean plasma half-life of garenoxacin was9.8 h, allowing for once-daily dosing. Garenoxacin is likelyto require dosage adjustment in severe renal insufficiency as∼ 30 – 50% of the drug is renally excreted as unchangeddrug [50].

Healthy volunteers received garenoxacin 100 – 1200 mg/dayp.o. for 14 days [50]. A linear dose response was observed with

Table 3. Comparison of in vitro activity of faropenem against selected Streptococcus pneumoniae isolates.


Penicillin [43]

AllPCN susceptiblePCN intermediatePCN resistant

472530781154493

≤ 0.03 – > 4≤ 0.03 – 0.06≤ 0.12 – 12 – > 4

≤ 0.03≤ 0.030.52

2≤ 0.0314

Faropenem [43]

AllPCN susceptiblePCN intermediatePCN resistant

472530781154493

≤ 0.004 – 2≤ 0.004 – 0.12≤ 0.004 – 1≤ 0.004 – 2

0.008≤ 0.0040.120.5

0.250.0080.251

Penicillin [44]

ermBmefAtetMLevofloxacin resistantTMP–SMX

157582402550

≤ 0.015 – > 8≤ 0.015 – 2≤ 0.015 – 4≤ 0.015 – 2≤ 0.015 – > 8

21222

21222

Faropenem [44]

ermBmefAtetMLevofloxacin resistantTMP–SMX

157582402550

0.008 – 0.50.004 – 0.50.004 – 0.50.008 – 0.50.004 – 0.5

0.060.0150.0150.060.015

0.250.1250.250.250.125

MIC: Minimum inhibitory concentration; PCN: Penicillin; TMP–SMX: Trimethoprim–sulfamethoxazole.

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garenoxacin doses ranging from 100 to 400 mg, but concentra-tions increased in a non-linear manner with doses > 800 mg.After 14 days of therapy, the mean elimination half-lifeappeared to be independent of the dose and ranged from 13.3to 17.8 h.

In addition, the population pharmacokinetic parametersfrom three Phase II clinical trials with garenoxacin400 mg/day for 5 – 10 days were determined [51]. Absorp-tion and elimination was best described by a one-compart-ment model. Clearance was dependent on creatinineclearance, ideal body weight, age and obesity. The volumeof distribution was dependent on weight and gender.Patients had a ∼ 16 or 26% decrease in clearance with mildor moderate renal dysfunction, respectively, thus suggest-ing that garenoxacin maintenance doses may need to belowered with severe renal insufficiency.

Like other quinolones, garenoxacin is secreted in breastmilk [52]. A mean of 0.07% of a single 600-mg dose wasrecovered within 120 h following administration. However,garenoxacin was undetectable in the breast milk in themajority of the subjects within 84 h after dosing.

In a murine thigh infection model, the AUC–MIC ratiowas determined to be the pharmacodynamic parameter thatbest correlated with efficacy [53]. The mean 24 h AUC–MICratio was calculated for successful therapy with S. pneumoniaeinfections and found to be 33 ± 18. The AUC–MIC ratiorequired for effective therapy was not altered based onpenicillin or ciprofloxacin resistance.

4.3.3 In vitroAs observed with other respiratory quinolones, garenoxacinhas good in vitro activity against penicillin-resistantS. pneumoniae (Table 4) [54]. In a multi-step selection study,12 strains of S. pneumoniae developed resistance to quino-lones [55]. Of all of the quinolones tested, garenoxacin retainedthe most activity including activity against isolates selectedwith garenoxacin. Among pneumococcal strains resistant tociprofloxacin, the garenoxacin MIC90 was ≤ 1 µg/ml, whereasthe MIC90 values for levofloxacin and moxifloxacin were 16and 4 µg/ml, respectively. In a similar study of S. pneumoniaestrains resistant to ciprofloxacin, garenoxacin retained the bestactivity with ranges of 0.03 – 1 µg/ml, compared with gati-floxacin and moxifloxacin with ranges of 0.5 – 8 and 0.06 –2 µg/ml, respectively [56]. The increased potency observedwith garenoxacin may allow this drug to be a useful additionto the treatment of respiratory tract infections caused byS. pneumoniae resistant to other drug classes. It is also possiblethat the increased potency observed with garenoxacin mayallow for less selection of resistant isolates as it would retainactivity against any single-step mutants that could occur in abacterial population.

4.3.4 In vivo animal dataSeveral rabbit meningitis models have been used to evaluatethe efficacy of garenoxacin. The penetration of garenoxacin

into the cerebrospinal fluid (CSF) was favourable and achievedconcentrations well above the MIC for S. pneumoniae within30 min, which remained elevated for ~ 24 h [57]. In anotherexperimental meningitis model, garenoxacin exhibited a killingrate at 8 h superior to the combination of ceftriaxone and van-comycin against penicillin-resistant pneumococci [58]. Further-more, against nine S. pneumoniae isolates resistant to bothpenicillin and quinolones, garenoxacin was bactericidal within8 h. Additionally, garenoxacin has demonstrated activityagainst a vancomycin-tolerant S. pneumoniae strain [59].Although quinolones are not routinely used for the treatmentof meningitis, these animal data warrant further studies todetermine if garenoxacin may have a role in the treatment ofpneumococcal meningitis, particularly for those isolates thatare resistant to penicillin or other antimicrobial classes.

4.3.5 In vivo human dataData were combined from three Phase II clinical trials ofgarenoxacin among patients who were administered400 mg/day for 5 – 10 days [51]. Patients received garenoxacinfor the treatment of CAP, acute exacerbations of chronic bron-chitis or sinusitis. A total of 96 patients had cultures positivefor S. pneumoniae. The clinical and bacteriological responserates among patients with positive S. pneumoniae cultures were91 and 90%, respectively. Using Bayesian estimates from pop-ulation pharmacokinetics, the garenoxacin fraction unboundAUC0-∞–MIC ratio was determined to be > 200 for 99% ofthe patients infected with S. pneumoniae. Similar finding werereported with H. influenzae, H. parainfluenzae and M. catarrh-alis. These findings suggest that garenoxacin is likely to beeffective for the treatment of respiratory tract infections causedby S. pneumoniae. More clinical data are needed to evaluate theefficacy of garenoxacin for infections caused by antibiotic-resistant S. pneumoniae. Based on in vitro studies, garenoxacinis likely to have activity against S. pneumoniae isolates withreduced susceptibility to penicillin.

4.3.6 Safety and toxicityAdverse effects with garenoxacin include abdominal pain,diarrhoea, fatigue, lethargy, somnolence, headache, sorethroat, vomiting and discolouration of the tongue [50].Garenoxacin has no clinically significant effects on ECGs(including QTc prolongation) or evaluations of the CNSfunction [50].

No signs of chondrotoxicity were observed in immature ratsor juvenile beagle dogs treated with garenoxacin [60,61].However, high doses of garenoxacin administered daily for5 days in Winstar rats that were 4 weeks old resulted in adverseeffects on the Achilles tendon [62]. Achilles tendon specimenswere studied by electron microscopy in comparison with vehi-cle-treated controls and ultrastructural changes were detectablein all of the samples from the garenoxacin-, ofloxacin- or cipro-floxacin-treated rats. Degenerative changes such as multiplevacuoles and large vesicles in the cytoplasm of tenocytes wereobserved. The degree of changes increased with higher doses of

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quinolones. These findings suggest a possible risk in paediatricpatients treated with garenoxacin or the other quinolones.Additional studies are necessary to determine if garenoxacincan be safely used in the paediatric population.

4.4 Sitafloxacin4.4.1 IntroductionSitafloxacin, similar to garenoxacin, is also in Phase III clinicaltrials. Sitafloxacin has a broad spectrum of activity, includingmany Gram-negative and -positive pathogens includingMRSA, Pseudomonas aeruginosa, Bacteroides species, as well asthe most common respiratory tract pathogens

4.4.2 Pharmacokinetics and pharmacodynamicsLinear pharmacokinetics were observed in healthy volunteersadministered sitafloxacin 25 – 200 mg [63]. The Cmax after sin-gle doses of 25 and 200 mg were 0.29 and 1.86 µg/l, respec-tively. A bi-phasic decline was observed in serum drug levelsindependently of the dose, and the half-life was 4 – 5 h. Thevolume of distribution ranged from 1.5 to 1.9 l/kg, and serumprotein binding ranged from 46 to 55%. Dose reductions willbe necessary in renal insufficiency as suggested by ∼ 70% ofthe orally administered dose being recovered as unchangeddrug in the urine. Administration with food had no signifi-cant impact on pharmacokinetic parameters and multiple-dose pharmacokinetic parameters were consistent with thoseobserved after single doses.

Another pharmacokinetic study compared the intravenousand oral administration of sitafloxacin [64]. The absolute bio-availability of sitafloxacin was 80 – 89%. Renal clearance washigher than the glomerular filtration rate, suggesting that thedrug underwent active tubular secretion. Small differences inpharmacokinetic parameters were observed between gendersbut these were accounted for by differences in body weight.

The authors concluded that no dose adjustment was necessaryfor gender. Other pharmacokinetic parameters were similar tothose reported in previous studies.

4.4.3 In vitroThe in vitro activity of sitafloxacin is summarised in Table 5.Sitafloxacin was more potent in vitro compared with cipro-floxacin, levofloxacin, cefotaxime, imipenem and vancomycinagainst penicillin-susceptible and -resistant S. pneumoniae iso-lates [65]. The sitafloxacin MIC90 was 0.064 µg/ml with all ofthe pneumococcal strains regardless of penicillin susceptibil-ity. It was the most rapidly bactericidal agent among its com-parators, with bactericidal activity against all of the strainsafter 6 h following exposure to concentrations eight times theMIC and after 12 h with concentrations twice the MIC.

Sitafloxacin has more potent in vitro activity against peni-cillin-resistant S. pneumoniae compared with other fluoro-quinolones [66-68]. In all of the cases, the sitafloxacin MIC wasnot affected by penicillin susceptibility.

Sitafloxacin also demonstrated activity in vitro against qui-nolone-resistant pneumococci [69]. Daporta and colleaguestested the in vitro activity of sitafloxacin compared to severalother quinolones against a ciprofloxacin-resistantS. pneumoniae strain. The resistant strain was selected in vitroand did not have a topoisomerase mutation, but expressedhigh-level efflux activity. The MIC values increased three- tosixfold with norfloxacin, ciprofloxacin and levofloxacin com-pared with a twofold increase with moxifloxacin and sita-floxacin. These results suggest that the activities ofsitafloxacin and moxifloxacin in vitro are less affected by high-level efflux in S. pneumoniae compared with other quinolo-nes. Therefore, sitafloxacin may retain its activity against clin-ical isolates of S. pneumoniae that contain the efflux-mediatedresistance mechanism.

Table 4. Comparison of in vitro activity of garenoxacin against selected Streptococcus pneumoniae isolates.


GarenoxacinPCN susceptible [54,115]


PCN resistant [54,115]

Quinolone resistant [115]

2889810528

≤ 0.016 – 0.06≤ 0.016 – 0.06≤ 0.016 – 0.060.03 – 1

0.060.060.060.25

0.120.120.121

Ciprofloxacin [43]

PCN susceptible [54,115]




2889810528

≤ 0.125 – 40.5 – 20.5 – 18 – 64

11116

22264

LevofloxacinPCN susceptible [54,115]




2889810528

0.25 – 20.5 – 10.25 – 21 – 32

1118

11116


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4.4.4 In vivo human dataSitafloxacin has shown clinical efficacy in respiratory tractinfections. A randomised, open-label, multi-centre studycompared sitafloxacin safety and efficacy with that of imi-penem–cilastatin in the treatment of hospitalised patientswith pneumonia [70]. A total of 65 hospitalised adults withclinical evidence of bacterial pneumonia that warranted treat-ment with intravenous therapy were evaluated. Patients wererandomised to receive sitafloxacin 400 mg/day or imipenem–cilistatin 500 mg t.i.d. for 7 – 14 days. A total of four patientsin the sitafloxacin group and five in the imipenem–cilistatingroup had pneumococcal pneumonia. At the first and secondfollow-up assessments, 94% of the sitafloxacin patients and97% of imipenem/cilistatin patients had clinical cures. In thebacteriologically evaluable population (n = 42), the treatmentresponse was satisfactory at the second follow-up for 95% ofthe patients in the sitafloxacin group and 100% of thepatients in the imipenem–cilistatin group. In this preliminarytrial, sitafloxacin had clinical and bacteriological efficacy simi-lar to imipenem–cilistatin for the treatment of respiratorytract infections. Although only a small percentage of partici-pants had positive cultures for S. pneumoniae, sitafloxacin waseffective for the treatment of pneumonia in these individuals.

In a multi-centre study, the clinical efficacy of sitafloxacinwas evaluated in the treatment of mild-to-moderate pneumo-nia, chronic lower respiratory tract infection and acute upperrespiratory tract infection [71]. Patients received sitafloxacin 50or 100 mg p.o. b.i.d. for 3 – 15 days. The clinical efficacyrates for pneumonia, chronic lower respiratory tract infection,acute upper respiratory tract infection and other respiratoryinfections were 95% (62/65 patients), 83% (94/113 patients),92% (33/36 patients) and 80% (8/10 patients), respectively.The overall clinical efficacy rate was 88% (197/224 patients).S. pneumoniae was eradicated from all of the 26 patients fromwhom it was isolated. No susceptibility data were available forthese S. pneumoniae isolates. However, based on these results,

sitafloxacin is effective for the treatment of mild-to-moderatepneumonia, chronic lower respiratory tract infection andacute upper respiratory tract infections. Based on in vitrodata, sitafloxacin is also likely to be clinically effective for thetreatment of respiratory tract infections caused bypenicillin-resistant S. pneumoniae.

4.4.5 SafetyIn a randomised trial, sitafloxacin was reported to have asafety profile similar to the combination of ciprofloxacin andmetronidazole for the treatment of intra-abdominal infections[72]. Mild transient increases in alanine aminotransferase andalkaline phosphatase were reported among patients in aPhase II clinical trial receiving sitafloxacin 400 mg/day for thetreatment of pneumonia [70]. Another trial for the treatmentof VRE or MRSA reported a maculopapular rash in fourpatients and diarrhoea in nine patients [72]. In addition, atransient seizure was reported in one patient; however, thispatient was also taking propofol. The only side effect reportedin a sitafloxacin pharmacokinetics and tolerability study wasmild, transient soft stool or diarrhoea [63].

Results from a preliminary in vitro study on hepatocytessuggested that sitafloxain may have less hepatotoxicity thantrovofloxacin; however, further studies are needed [73]. A mag-netic resonance spectroscopy study of the hepatic accumula-tion of sitafloxacin in healthy volunteers showed noaccumulation of the drug [74].

The phototoxicity of sitafloxacin was compared with thatof sparfloacin, enoxacin and levofloxacin in a randomised,placebo-controlled, investigator-blinded clinical trial [75]. Lev-ofloxacin failed to show a phototoxic effect. Sitafloxacin wasassociated with mild phototoxicity among Caucasian subjects,but to a lesser extent than that observed with enoxacin orsparfloxacin. No phototoxicity was observed among individu-als from the Far East. Phototoxicity subsided within 48 h ofsitafloxacin discontinuation.

Table 5. Comparison of in vitro activity of sitafloxacin against selected Streptococcus pneumoniae isolates.


SitafloxacinPCN susceptible [66,68]

PCN intermediate [66,68] PCN resistant [66,68]


2661641875

≤ 0.008 – 0.50.015 – 0.50.015 – 0.50.25 – 1

0.060.060.06NR

0.120.120.12NR

Ciprofloxacin PCN susceptible [66,68]

PCN intermediate [66,68] PCN resistant [66,68]


288981055

0.03 – > 160.5 – > 160.25 – > 168 – 64

222NR

444NR

LevofloxacinPCN susceptible [66,68] PCN intermediate [66,68] PCN resistant [66,68]


288981055

0.12 – > 160.5 – 80.5 – 168 – 32

111NR

222NR

MIC: Minimum inhibitory concentration; NR: Not reported; PCN: Penicillin.

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The proarrhythmic effects of sitafloxacin were evaluatedusing in vivo models [76]. Delayed ventricular repolarisationand torsades de points were observed in animals with com-plete atrioventricular block following gatifloxacin and moxi-floxacin; however, this was not observed following sitafloxacinadministration. Additional clinical studies are necessary toevaluate the proarhythmia effects observed with sitafloxacin.

4.5 Resistance with quinolonesLike previous quinolones, these agents target topoisomeraseIV and DNA gyrase, effectively blocking DNA replicationand resulting in cell destruction. Amino acid substitutions inthe quinolone resistance-determining regions (QRDR) giverise to S. pneumoniae mutants with variable resistance to thequinolone antibiotics. Although a single mutation in the gyrAor parC gene, which code for DNA gyrase andtopoisomerase IV, respectively, often leads to low-level quino-lone resistance. Further step-wise point mutations in theseregions lead to the development of strains significantly lesssusceptibile to the quinolones. Theoretically, the activity ofnewer agents such as garenoxacin and sitifloxacin, which willtarget both DNA gyrase and topoisomerase IV without a pref-erence, may make the agents more active among bacterialstrains harbouring low-level quinolone resistance. So far, theseresults remain to be seen in human populations.

In vitro selection rates using garenoxacin and sitafloxacinfor quinolones-resistant S. pneumoniae were found to be lowerthan that recovered using other quinolones [55,69]. Like theirpredecessors, these agents seems to lose their activity in just afew selective steps from the same point mutations that occurin the gyrA and parC genes. The increased potency ofgarenoxacin and sitafloxacin may postpone the inevitable riseof resistant S. pneumoniae strains in clinical practice.

5. Glycopeptides

5.1 IntroductionVancomycin has remained the empirical treatment of choicefor suspected cephalosporin-resistant isolates of S. pneumo-niae. Other glycopeptide antibiotics have been developed toexpand the choices for drug therapy. Currently, oritavancinfrom Eli Lilly and dalbavancin from Pfizer are in clinicaldevelopment (Figure 2). Oritavancin is a semi-synthetic glyc-opeptide developed from a naturally occurring glycopeptidethat is similar to vancomycin. Presently, most of the suscep-tibility data with oritavancin against S. pneumoniae (Table 6)has been limited to in vitro data. Both oritavancin anddalbavancin have long elimination half-lifes allowing forweekly dosing. Given the duration of treatment of mostGram-positive infections, only two doses may be necessaryto complete a treatment course. Both of these investigationalglycopeptides are being studied for their utility in treatingenterococcal, staphylococcal and streptococcal infectionswith activity against VRE, MRSA and multi-drug-resistantS. pneumoniae.

5.2 Mechanism of actionGlycopeptides bind to the D-Ala-D-Ala subunits in the bacte-rial cell membrane, blocking them from the active site oftranspeptidase, the enzyme responsible for crosslinkingpeptidoglycans and building a stable, supportive membrane.This compromises the integrity of the cell wall and eventuallycauses the cell to lyse.

5.3 Oritavancin5.3.1 Pharmacokinetics and pharmacodynamicsThe pharmacokinetics were linear following the administra-tion of intravenous oritavancin ranging from 0.02 to0.325 mg/kg in healthy volunteers [77]. After infusion, plasmaconcentrations followed a multiexponential decline. Renalclearance was ∼ 0.46 ml/min and < 5% of the drug wasrecovered in the urine after 7 days. Oritavancin demonstrateda terminal half-life of ∼ 196 h. However, the authors con-cluded that this may be an underestimation of the true termi-nal half-life of the drug based on sampling issues. In all of thesubjects, plasma concentrations decreased to < 10% of theCmax in 24 h. These data suggest rapid tissue accumulationand a prolonged retention of oritavancin.

Oritavancin pharmacokinetics in plasma and skin blister fluidwere studied in healthy subjects [78]. Subjects received orita-vancin 200 or 800 mg/day i.v. for 3 days. After the third day ofthe 200-mg/day regimen, the mean plasma Cmax was46.2 µg/ml. A single does of oritavancin 800 mg achieved amean plasma Cmax of 137 µg/ml. The mean AUCblister

fluid/AUC plasma ratios were ∼ 0.2 regardless of the dosing regimen.

5.3.2 In vitroOritavancin had potent in vitro activity against penicillin-resistant clinical isolates of S. pneumoniae [79,80]. Oritavancindemonstrated the most potent activity compared with vanco-mycin and cefuroxime or ceftriaxone. Although the MIC val-ues slightly increased in penicillin-resistant S. pneumoniaeisolates, the increase was not as substantial as that observedwith the β-lactams. In all of the isolates, the MIC90 was ≤ 0.01and 0.5 µg/ml with oritavancin and vancomycin, respectively.

In an in vitro pharmacodynamic model, the activity of ori-tavancin against two multi-drug-resistant pneumococcal iso-lates was compared with that of vancomycin [81]. Bothpneumococcal strains were penicillin-, macrolide- and cipro-floxacin-resistant. For both strains, the MIC of oritavancinwas < 0.015 and 0.5 µg/ml for vancomycin. Oritavancindisplayed rapid bactericidal activity with concentrationssimulating a loading dose of 5 mg/kg followed by a4 mg/kg/day maintenance dose. Oritavancin decreased bacte-rial burden 4 log10 CFU/ml in < 1 h. Vancomycin required24 h to achieve the same result.

Another in vitro study reported oritavancin activity againstmulti-drug-resistant clinical pneumococcal isolates [82].Strains resistant to penicillin, cefotaxime and erythromycinwere included. The MIC90 of oritavancin and teicoplanin was≤ 0.01 µg/ml regardless of the resistance to other antibiotics.

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The MIC90 of vancomycin for penicillin-susceptible and-intermediate strains was 0.25 and 0.5 µg/ml, respectively.Oritavancin was more potent and achieves bactericidal con-centrations in less time compared with vancomycin. In vivostudies are needed to determine if this will provide anyclinical advantage.

5.3.3 In vivoA rabbit model of meningitis was used to evaluate the activityof oritavancin against a penicillin-susceptible S. pneumoniaeisolate in CNS infections [83]. Oritavancin penetration intothe CSF was estimated to be 1 – 5% of the plasma concentra-tions. Similar reductions in bacterial burden were observedwith oritavancin and ceftriaxone.

A second study in rabbits evaluated the activity oforitavancin alone and in combination with ceftriaxone ordexamethasone in the treatment of cephalosporin- and peni-cillin-resistant pneumococcal meningitis [84]. Oritavancinalone was bactericidal 6 h after its administration. Orita-vancin in combination with ceftriaxone was also bactericidalby 6 h but no synergy was detected with the combination ofthe two drugs. The lack of synergy may be because of therapid decrease in bacterial concentrations. The addition ofdexamethasone did not provide any additional benefit. Theauthors concluded that oritavancin may be a good alternativein the treatment of penicillin- and cephalosporin-resistantpneumococcal meningitis, but combination with dexametha-sone should be avoided. Based on these animal studies, orita-vancin does not appear to have any advantage compared toceftriaxone and vancomycin for the treatment of pneumo-coccal meningitis. The oritavancin penetration into the CNSis low, which will not favour its use empirically for thetreatment of suspected resistant S. pneumoniae meningitis.Additional studies evaluating the concentration in respiratorytissues are needed to determine if oritavancin will have a rolein therapy for the treatment of antibiotic-resistantpneumococcal respiratory tract infections.

5.3.4 SafetyIn healthy volunteers, asymptomatic, transient elevations inhepatic transaminase occurred in 5/11 patients followingoritavancin administration. [77] A Phase III clinical trial for

skin and skin-structure infections stated that fewer patients inthe oritavancin group reported adverse events compared withintravenous vancomycin followed by oral cephalexin (47 ver-sus 58%) [85]. Additionally, 1.8% of the patients in the orita-vancin group discontinued therapy due to adverse eventscompared with 4.8% in the vancomycin/cephalexin group. Adetailed report of adverse events in this study was not availa-ble. A second Phase III clinical trial of short-course orita-vancin versus vancomycin followed by oral cephalexin in thetreatment of complicated skin and skin-structure infectionsreported that adverse events were similar between treatmentgroups [86]. The adverse effects with oritavancin appear to besimilar to those seen with vancomycin and are not likely tolimit therapy to a significant extent.

5.4 Dalbavancin5.4.1 Pharmacokinetics and pharmacodynamicsLinear pharmacokinetics were reported in a Phase I study ofhealthy volunteers that received dalbavancin doses ranging from140 to 1120 mg [87]. Following a single infusion of dalbavancin500 mg, the Cmax was 133 mg/l and the half-life of dalbavancinranged from 149 to 198 h. Steady state was generally achievedin multiple-dose regimens 2 to 3 days after the initial dose, andthe mean volume of distribution at steady state was 10 l. Highconcentrations were observed in blister fluids with the ratio ofblister fluid to plasma levels ranging from 0.83 to 1.11. Of thedose, ∼ 33% was eliminated as unchanged drug in the urine.This suggests that, unlike other glycopeptides, non-renal routesaccount for most of the drug’s elimination. Dose adjustmentdoes not appear to be required in patients with mild-to-moder-ate hepatic impairment or renal impairment [88,89]. The longhalf-life of dalbavancin will allow the option of weekly dosing.Additional data evaluating concentrations in respiratory tissuesand the CNS are needed to determine if dalbavancin may haveany advantages over vancomycin for the treatment ofantibiotic-resistant pneumococcal infections.

5.4.2 In vitroIn vitro susceptibility testing demonstrated dalbavancin activ-ity against penicillin-resistant S. pneumoniae clinical isolates[90,91]. The dalbavancin MIC90 was 0.03 µg/ml regardless ofpenicillin susceptibility. Dalbavancin was approximately

Table 6. Comparison of in vitro activity of oritavancin against selected Streptococcus pneumoniae isolates.


Oritavancin [79,80,82]


123146144

≤ 0.01 – 0.12≤ 0.01 – 0.06≤ 0.01 – 0.12

≤ 0.01≤ 0.01≤ 0.01

≤ 0.01≤ 0.01≤ 0.01

Vancomycin [79,80,82]


123146144

0.06 – 0.5≤ 0.01 – 0.50.06 – 0.5

0.250.50.5

0.50.50.5

MIC: Minimum inhibitory ocncetration; PCN: Penicillin.

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fivefold more potent than vancomycin againstpenicillin-resistant S. pneumoniae clinical isolates [90].

5.4.3 In vivoA rat model was used to compare dalbavancin and penicillinfor the treatment of penicillin-susceptible and -resistantpneumococcal pneumonia [92]. Against the penicillin-sus-ceptible isolates, the highest dose of dalbavancin reducedbacterial load significantly more than the lower dalbavancindoses or penicillin. However, all of the drugs had similarreductions in bacterial burden by the end of treatment.Among the rats infected with penicillin-resistant S. pneumo-niae, the highest dose of dalbavancin was significantly moreefficacious than the other regimens in reducing bacterialcounts. No mortality was observed in rats receiving eitherdose of dalbavancin. In contrast, there were no survivorsamong mice that received penicillin for the treatment ofpenicillin-resistant pneumococci.

Another in vitro study compared linezolid and dalbavancinin a rat pneumonia model against penicillin-resistant S. pneu-moniae [93]. Dalbavancin was administered as a one-timeintravenous dose whereas oral linezolid was administeredtwice daily for 3 days. At the end of treatment, both treatmentgroups were equally effective at reducing the bacterial burdenin the lungs. These preliminary data warrant additional stud-ies to evaluate dalbavancin for penicillin-resistantpneumococcal respiratory tract infections.

5.4.4 SafetyIn a pharmacokinetics and tolerability study, dalbavancin waswell tolerated and treatment-emergent adverse events weresimilar to placebo, with pyrexia and headache being the mostcommon [87]. One patient experienced mild, transient,asymptomatic elevations in alanine aminotransferase andaspartate aminotransferase. These events did not vary with thedose of dalbavancin that was administered. No serious adverseevents or deaths were reported, and no audiological changeswere evident in any of the subjects.

5.5 ResistanceAntibiotic tolerance is thought to be the precursor to resistance.Glycopeptide tolerance in S. pneumoniae may be due to muta-tions in vncSR, a two-component system responsible for trigger-ing pathways that ultimately lead to cell death. Tolerant strainsare expected to survive longer in the presence of lytic antibiotic,which increases the likelihood of resistance developing. It is notyet known if this laboratory phenomenon of vancomycin toler-ance in pneumococci will become more commonly observed inthe clinic. Dalbavancin or oritavancin resistance in S. pneumoniaehas not been reported.

6. Glycylcyclines

6.1 TigecyclineTigecycline (Figure 1) is a new and novel antibiotic developed toovercome the tetracycline-resistance mechanisms of efflux andribosomal protection. It is a structural analogue of minocycline,a semi-synthetic tetracycline that is active against most of thecommon Gram-positive and -negative organisms found in res-piratory tract infections. In addition, tigecycline targets MRSA,drug-resistant S. pneumoniae and VRE. This drug was recentlyapproved in the US for the treatment of skin and soft-structureinfections and complicated intra-abdominal infections.

6.2 Mechanism of actionLike the tetracyclines, tigecycline binds to the 30S ribosomalsubunit and inhibits protein synthesis by preventing tRNAfrom interacting with the ribosome. Analysis of the structure–activity relationship has revealed that a modification at posi-tion 9 of the tetracycline molecule restored activity againstbacterial cells with efflux and/or ribosomal protective traits.This agent is primarily bacteriostatic but may exhibitbactericidal activity at higher concentrations.

6.3 Pharmacokinetics and pharmacodynamicsTigecycline pharmacokinetics were evaluated in healthyvolunteers that received single and multiple intravenous doses

Table 7. Comparison of in vitro activity of tigecycline against selected Streptococcus pneumoniae isolates.


TigecyclinePCN susceptible [100,101,117]

PCN intermediate [100,101,117]


Tetracycline susceptible [102]

Tetracycline resistant [102]

12522882691392

0.008 – 0.06≤ 0.015 – 0.12≤ 0.015 – 0.120.12 – 0.50.06 – 0.5

≤ 0.12≤ 0.12≤ 0.120.250.12

≤ 0.12≤ 0.12≤ 0.12NRNR

Tetracycline PCN susceptible [100,101,117]

PCN intermediate [100,101,117]


Tetracycline susceptible [102]

Tetracycline resistant [102]

12522882691392

≤ 0.06 – 640.12 – 320.12 – > 80.25 – 28 – 128

4440.564

> 8> 8> 8NRNR


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of tigecycline ranging from 12.5 to 300 mg [94]. Followingsingle does of 12.5 and 300 mg, the Cmax values were 109 and2817 ng/ml, respectively. Mean drug clearance was 0.2 –0.3 l/h/kg for all of the doses and half-life was ∼ 40 – 60 h fortigecycline doses > 100 mg. Of the dose, ∼ 13% was excretedunchanged in the urine. Administration of tigecycline withfood had no significant effect on pharmacokinetic parameters[95]. Due to an increased frequency of gastrointestinal adverseevents, the individuals who received multiple-dose tigecycline> 100 mg were unable to complete therapy. Therefore, a load-ing dose of 100 mg followed by 50 mg every 12 h was used insubsequent clinical trials.

Tigecycline has good lung tissue penetration [96]. In epi-thelial lining fluid, the Cmax, AUC and half-life were ∼ 0.5-,1.3- and 2.5-times the serum values, respectively. The alveolarcell Cmax, AUC and half-life were 21-, 77- and 1.5-fold higherthan serum values, respectively. In alveolar cells, Cmax/MIC90,AUC/MIC90 and the percentage of time above the MIC90 were507, 4467 and 100% for S. pneumoniae, respectively. The highconcentrations of tigecycline in the lung are likely to be anadvantage for pneumococcal lower respiratory tract infections.

In patients with end-stage renal disease (ESRD), slightlyhigher Cmax and AUC values were obtained following aninfusion of tigecycline 100 mg i.v. [97]. The AUC and Cmax

were ∼ 60 and 21% higher in ESRD patients compared tohealthy patients, respectively. However, the elevation did notaffect the agent’s safety or tolerability, therefore, dose adjust-ments may not be necessary in renal impairment. Tigecyclineis not dialysable.

Tigecycline pharmacokinetics are similar between the gen-der and age groups [98]. Tigecycline undergoes significant tis-sue distribution and penetrates well into polymorphonuclearneutrophils, suggesting that it may be useful in the treatmentof intracellular pathogens [95,99]. The drug is likely to beexcreted in bile. [94] Due to poor oral bioavailability,tigecycline is currently limited to parenteral administration.

6.4 In vitroThe in vitro susceptibility of tigecycline is illustrated inTable 7. Tigecycline is active against S. pneumoniae regardlessof penicillin susceptibility [100,101]. Additionally, tigecyclinemay possess activity against multi-drug-resistant pneumococci[102]. Against tetracycline-resistant strains, tigecycline (MIC50

0.12 µg/ml) was 64- to 512-fold more potent thantetracycline (64 µg/ml) or minocycline (8 µg/ml).

6.5 In vivoTigecycline was evaluated alone and in combination withvancomycin (Figure 2) in a rabbit meningitis model against ahighly penicillin-resistant S. pneumoniae isolate [103]. Resultsdemonstrated that high doses of tigecycline alone are bacteri-cidal against penicillin-resistant pneumococci. In addition,the combination of vancomycin and tigecycline may also havean additive effect against penicillin-resistant S. pneumoniae.Although tigecycline is unlikely to have a role empirically for

the treatment of pneumococcal meningitis, additional studiesare required to determine if tigecycline can be used for thetreatment of infections caused by penicillin-resistantS. pneumoniae strains.

6.6 SafetyGastrointestinal adverse events were the most common sideeffect with tigecycline [94,96,99,105]. The most commonadverse events were nausea (49%) and vomiting (29%), bothof which increased with increasing doses of tigecycline. Onesubject developed a rash, and no relevant changes in clinicallaboratory parameters, blood pressure or ECG wereobserved [94,99].

A study of varying infusion rates and times reported no sig-nificant decrease in gastrointestinal adverse events with pro-longed infusion times or slower rates of drug administration[94]. However, tolerability improved when patients were fedprior to drug administration.

7. Ketolides

7.1 CethromycinIn response to the increased frequency of macrolide resistanceamong pneumococci, a new class of agents, the ketolides(3-keto-substituted macrolide antibiotics), were developed totarget penicillin- and macrolide-resistant pneumococci.Ketolides are semisynthetic derivatives of the 14-memberedmacrolide erythromycin. Currently, macrolides are consideredamong the first-line agents for the treatment of community-acquired respiratory tract infections, and this increasing drugresistance poses a risk of losing macrolides as a valuabletreatment option.

In April 2004, telithromycin became the first ketolideapproved by the FDA for use in respiratory tract infec-tions. Cethromycin (formerly ABT-773) is currently inPhase III clinical trials and is being developed to targetresistant respiratory tract infections. It differs from tel-ithromycin by an O-quinolinyl propylene chain in place ofthe OCH3 at position 6, and lacks a substituent on theC11, C12 carbamate.

7.2 Mechanism of actionKetolides restrict protein synthesis at the 23S component ofthe 50S ribosomal subunit. Macrolides and ketolides bothbind to domain V of the 23S component, but ketolides bindwith more affinity. Ketolides also bind to domain II of the23S component. Although macrolides are known to inhibitthe formation of the 30S subunit, ketolides inhibit both 30Sand 50S formation, which may account for their enhancedactivity against macrolide-resistant S. pneumoniae.

The structure of ketolides differs from macrolides in thesubstitution of a 3-keto group for the L-cladinose moiety.Currently, it is speculated that this substitution reduces thelikelihood of ribosomal resistance because of its interactionwith domain II of 23S rRNA.

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7.3 Pharmacokinetics and pharmacodynamicsThe pharmacokinetics were evaluated in healthy volunteersfollowing administration of cethromycin ranging from 100 to1200 mg [105]. The half-life ranged from 3.6 to 6.7 h and themean Tmax increased from 0.9 to 5.1 h following the 100- and

1200-mg doses, respectively. Mean Cmax was 141 and1174 ng/ml following the administration of 100 and1200 mg, respectively. Cmax consistently increased in directproportion to the dose but AUC0-∞ kinetics were nonlinearfor doses < 400 mg.

Figure 2. Chemical structures of oritavancin and dalbavancin.

Cl

NH

NH

NH

NH

NH

NH

O

O O

O O

O

OO

OO O

O

O

NH2

OH

NH2

NH

Cl

Cl

OH

OH

OHOH

HHH

H

HOH

O

NHH

OH

OO

OH

OHOH

H

NH

NH

NH

NH

NH

NH

O

O

O

O

O

O

O

O

O

O

O

OO

OH

NH

OH

Cl NH

OH

Cl

OH

OH

N

OHOHOH

OH

HH

H

H

H

H

H

ONH

O

OHOH

OH

H

O

Oritavacin

Dalbavancin

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The plasma, lung epithelial lining fluid (ELF) and alveolarcell pharmacokinetics and pharmacodynamics of cethromycinat steady state were studied in healthy volunteers [106]. In theELF, Cmax, AUC and half-life were 0.9 µg/ml, 11.4 µg.h/ml and6.43 h, respectively, with the 150 mg dose, and 2.7 µg/ml,24.15 µg.h/ml and 5.26 h, respectively, with the 300 mg dose.Cmax, AUC and half-life in alveolar cells were 12.7 µg/ml, 160.8µg.h/ml and 10 h, respectively, with the 150 mg dose, and 55.4µg/ml, 636 µg.h/l and 11.6 h, respectively, with the 300 mgdose. When a S. pneumoniae MIC90 of 0.008 µg/ml wasassumed, the AUC/MIC90 ratios in ELF following a 150- and300-mg dose were 1425 and 3224, respectively. TheAUC/MIC90 ratios for pneumococci in alveolar cells followinga 150- and 300-mg dose were 20,106 and 95,050, respectively.The extensive lung penetration and prolonged intrapulmonaryhalf-life of cethromycin suggest that it is likely to have a role forpneumococcal lower respiratory tract infections.

A murine pneumococcal pneumonia model was used tostudy cethromycin pharmacodynamics against macrolide-resist-ant strains including both mefA- and ermB-positive isolates[107]. Cethromycin demonstrated bactericidal activity inS. pneumoniae regardless of macrolide susceptibility. Based onsigmoid maximum efficacy (Emax) models, thepharmacodynamic parameters that best correlated with theactivity of cethromycin were AUCfree/MIC and Cmax free/MIC.An AUCfree/MIC ratio of 50 or a Cmax free/MIC of 1 wasassociated with bacteriostatic activity, whereas an AUCfree/MICratio of 1000 or a Cmax free/MIC of 100 was required formaximal bactericidal activity.

7.4 In vitroCethromycin has in vitro activity against penicillin- andmacrolide-resistant S. pneumoniae (Table 8). An in vitro study

evaluated the activity of cethromycin in penicillin- and mac-rolide-resistant S. pneumoniae isolates recovered from themiddle ear of children with otitis media [108]. Cethromycinwas active against 97% of the penicillin-resistant S. pneumo-niae isolates with concentrations of ≤ 0.125 µg/ml. Cethro-mycin inhibited 100% of the erythromycin-susceptibleisolates requiring concentrations of ≤ 0.125 µg/ml. The activ-ity of cethromycin was also evaluated among S. pneumoniaeisolates from the Canadian Respiratory Organism Surveil-lance Study (CROSS) 1999 – 2002 [109]. The MIC50/90 for allof the S. pneumoniae isolates recovered was 0.004 and0.008 µg/ml, respectively, with all of the isolates havingcethromycin MIC values of ≤ 1 µg/ml.

7.5 In vivoIn a murine respiratory infection model, cethromycin dis-played greater activity against a penicillin-resistant strain ofS. pneumoniae than its comparators, including telithromycinand levofloxacin [110]. Mice in the cethromycin group had thelowest bacterial burden at the end of treatment among all ofthe drugs that were studied.

The efficacy of cethromycin was compared with othermacrolides in an animal pneumococcal pneumonia model[111]. Penicillin-resistant and macrolide-resistant (includingmefA- and ermB-resistant determinants) S. pneumoniae iso-lates were included. Cethromycin activity was not affectedby penicillin resistance. Also, cethromycin demonstratedimproved efficacy in rodents infected with mefA- or ermB-mediated macrolide-resistant S. pneumoniae compared withother macrolide antibiotics. The cethromycin MIC valuesfor mefA S. pneumoniae isolates were slightly higher com-pared with the ermB isolates [112,113]. Ketolides are notknown to act as efflux substrates. Although the clinical

Table 8. Comparison of in vitro activity of cethromycin against selected Streptococcus pneumoniae isolates.


Cethromycin [118]

PCN susceptiblePCN resistant

16040

≤ 0.01 – 0.03≤ 0.01 – 0.06

≤ 0.010.03

≤ 0.010.06

Azithromycin [118]

PCN susceptiblePCN resistant

16040

≤ 0.01 – 0.120.03 – 128

0.061

0.124

CethromycinMacrolide susceptible [119]

Macrolide resistant [112,119]

ermB [112,119]

mefA [112,113]

ermB and mefA [112,113]

5923515610713

≤ 0.03≤ 0.008 – 0.5≤ 0.008 – > 2≤ 0.008 – 20.25 – 1

≤ 0.03≤ 0.03≤ 0.008≤ 0.008NR

≤ 0.030.120.50.125NR

AzithromycinMacrolide susceptible [113]


ermB [112,113]

mefA [112,113]

ermB and mefA [112,113]

5918015610713

NR2 – > 1284 – > 1281 – 32> 8

NR16> 1288NR

NR> 128> 12816NR


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impact of this is unknown, this should be considered whenusing ketolides as mefA-mediated macrolide resistance is themost common type of macrolide resistance in S. pneumoniaein the US.

7.6 SafetySafety data regarding cethromycin is limited. In an ascendingsingle-dose study, oral cethromycin was well tolerated. Themost common adverse effect reported was mild-to-moderategastrointestinal disturbance [105].

8. Conclusion

None of these new antimicrobials will significantly alter themanagement of antibiotic-resistant pneumococcal infections,but instead, will offer more treatment choices. A recent USreport indicates that penicillin, macrolides and tetracyclineresistance in S. pneumoniae has remained stable over the lastfew years. In contrast, fluoroquinolone resistance is becomingmore prevalent [120]. A dramatic transformation in resistancepatterns with S. pneumoniae has been observed over the last20 years. Resistance patterns will probably continue to evolve,thus making it difficult to predict future antibiotic suscepti-bility. Nonetheless, with more antibiotics and altered resist-ance patterns, the therapy choices for infections caused by thispathogen will probably become more complex in the future.

9. Expert opinion

Ceftobiprole and RWJ-54428 are likely to have a role in thetreatment of PNSP. Although decreased activity wasobserved with ceftobiprole and RWJ-54428 against penicil-lin-resistant pneumococci, both of these drugs appear to bemore potent in vitro than ceftriaxone. More clinical studiesare needed to determine if the increased potency andenhanced binding to PBPs with these cephalosporins willhave any clinical advantage. Higher doses of amoxicillin canbe administered for the treatment of pneumococcal respira-tory tract infections as resistance at the PBP is a concentra-tion-dependent phenomenon. This same concept has notbeen evaluated for cephalosporins; however, if ceftobiproleand RWJ-54428 bind better to the PBPs, this could be apotential benefit. In addition, the concentrations of thesenew cephalosporins in the lung and CSF need to be deter-mined to establish if there is any further advantage com-pared with the currently available cephalosporins for thetreatment of pneumococcal infections. Also, both drugs arelikely to have an oral and intravenous formulation thatallows for convenient dosing regemins.

Faropenem appears to have good in vitro data againstS. pneumoniae including drug-resistant pneumococci. It isalso active against M. catarrhalis and H. influenzae, and sta-ble against β-lactamases, which would allow for its empiricaluse in respiratory tract infections. However, it is not activeagainst atypical pathogens. Therefore, as with other

β-lactams, combination therapy with a macrolide would benecessary empirically. Faropenem may not be a treatmentoption among patients with a severe penicillin allergy; how-ever, the cross-reactivity may be lower than that observedwith other β-lactams. This drug will probably have a role intreating respiratory tract infections in the out-patient settingor among hospitalised patients who do not require intra-venous therapy. The lack of an intravenous formulationwould not allow faropenem to be used among hospitalisedpatients with more severe CAP, or as initial empirical ther-apy in suspected meningitis. The broad-spectrum activitythat includes many enteric Gram-negative pathogens as wellas anaerobic species may warrant limiting its use to prevent‘collateral damage’, which has been reported with the use ofbroad-spectrum cephalosporins and the quinolones.

Both sitafloxacin and garenoxacin have good activityagainst penicillin-resistant pneumococci as well as the othermost common causes of respiratory tract infections. Likeother respiratory quinolones, these drugs will probably havean empirical role for the treatment of respiratory tract infec-tions. Additionally, both quinolones are more potent thanother available quinolones and have lower MIC valuesagainst quinolone-resistant S. pneumoniae. More data areneeded to see if the increased potency provides a clinicaladvantage for sitafloxacin or garenoxacin. Both investiga-tional quinolones are likely to have oral and intravenousformulations. Adverse effects with sitafloxacin andgarenoxacin appear to be similar to the currently availablequinolones. Animal data with garenoxacin demonstratedgood penetration into the CNS and additional studies arewarranted to determine if it may have a role for thetreatment of meningitis.

Oritavancin and dalbavancin (Figure 2) both have a longhalf-life that may be advantageous for compliance but maynot be necessary for the treatment of pneumococcal infec-tions. Typically, when S. pneumoniae is suspected in meningi-tis, vancomycin is added to the empirical regimen until resultsfrom susceptibility testing are available. In most of the cases,vancomycin is discontinued a few days later as cephalosporin-resistant pneumococci are rare. Therefore, with these newglycopeptides, if therapy was initiated, patients would main-tain therapeutic levels for extended periods of time, even iftherapy was determined to be unnecessary. No clinical dataare available comparing vancomycin with ortivancin or dalba-vancin. If the concentrations of either of these new glyco-peptides were higher in the lung or CNS and this correlatedto improved outcomes compared to vancomycin, then thesedrugs may have a role for pneumococcal infections. Currently,vancomycin continues to have good activity against penicillin-resistant pneumococci and much more clinical data areavailable with this drug.

Although tigecycline has activity against multi-drug-resist-ant pneumococci, it is associated with high gastrointestinalside effects and is unlikely to be used as initial empiricaltherapy. It is only available as an intravenous form and,

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therefore, its use would be limited to meningitis orhospitalised patients with respiratory tract infections.

Cethromycin, like telithromycin, is likely to have a role intreating macrolide- and penicillin-resistant pneumococcalrespiratory tract infections. Cethromycin appears to havegood activity against the most common pathogens inrespiratory tract infections including H. influenzae,

M. catarrhalis and atypical pathogens, thus allowing forempirical usage. Unfortunately, cethromycin will only beavailable as an oral formulation, which limits its use in thehospital setting. However, recently, Abbott has made anagreement with Advanced Life Sciences to develop ABT-210,a novel second-generation ketolide that may be amenable tointravenous administration.

BibliographyPapers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

1. SCHUCHAT A, ROBINSON K, WENGER JD et al.: Bacterial meningitis in the United States in 1995. Active Surveillance Team. N. Engl. J. Med. (1997) 337(14):970-976.

2. JORGENSEN JH, DOERN GV, MAHER LA, HOWELL AW, REDDING JS: Antimicrobial resistance among respiratory isolates of Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae in the United States. Antimicrob. Agents Chemother. (1990) 34(11):2075-2080.

3. SPIKA JS, FACKLAM RR, PLIKAYTIS BD, OXTOBY MJ: Antimicrobial resistance of Streptococcus pneumoniae in the United States, 1979-1987. The Pneumococcal Surveillance Working Group. J. Infect. Dis. (1991) 163(6):1273-1278.

4. MASON EO, LAMBERTH L, LICHENSTEIN R, KAPLAN SL: Distribution of Streptococcus pneumoniae resistant to penicillin in the USA and in vitro susceptibility to selected oral antibiotics. J. Antimicrob. Chemother. (1995) 36(6):1043-1048.

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6. FELMINGHAM D: Evolving resistance patterns in community-acquired respiratory tract pathogens: first results from the PROTEKT global surveillance study. Prospective resistant organism tracking and epidemiology for the ketolide telithromycin. J. Infect. (2002) 44(Suppl. A):3-10.

7. KARCHMER AW: Increased antibiotic resistance in respiratory tract pathogens: PROTEKT US-an update. Clin. Infect. Dis. (2004) 39(Suppl. 3):S142-150.

8. MERA RM, MILLER LA, DANIELS JJ, WEIL JG, WHITE AR: Increasing prevalence of multidrug-resistant Streptococcus pneumoniae in the United States over a 10-year period: Alexander Project. Diagn. Microbiol. Infect. Dis. (2005) 51(3):195-200.

9. FELMINGHAM D, REINERT RR, HIRAKATA Y, RODLOFF A: Increasing prevalence of antimicrobial resistance among isolates of Streptococcus pneumoniae from the PROTEKT surveillance study, and compatative in vitro activity of the ketolide, telithromycin. J. Antimicrob. Chemother. (2002) 50(Suppl. S1):25-37.

10. HO PL, QUE TL, CHIU SS et al.: Fluoroquinolone and other antimicrobial resistance in invasive pneumococci, Hong Kong, 1995-2001. Emerg. Infect. Dis. (2004) 10(7):1250-1257.

11. SONG JH, JUNG SI, KO KS et al.: High prevalence of antimicrobial resistance among clinical Streptococcus pneumoniae isolates in Asia (an ANSORP study). Antimicrob. Agents Chemother. (2004) 48(6):2101-2107.

12. MANDELL LA, BARTLETT JG, DOWELL SF et al.: Update of practice guidelines for the management of community-acquired pneumonia in immunocompetent adults. Clin. Infect. Dis. (2003) 37(11):1405-1433.

•• Good summary of currently available drugs for the treatment of CAP. New guidelines will be published in late 2005 or early 2006.

13. ANON JB, JACOBS MR, POOLE MD et al.: Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol. Head Neck Surg. (2004) 130(Suppl. 1):1-45.

•• Recent guidelines for the treatment of bacterial rhinosinusitis. Provides a good summary of the treatment options and details of the pharmacokinetic and pharmacodynamic principles of commonly used antibiotics.

14. Diagnosis and management of acute otitis media. Pediatrics (2004) 113(5):1451-1465.

•• These guidelines provide more details on the choice of antibiotics in children with otitis media.

15. HEBEISEN P, HEINZE-KRAUSS I, ANGEHRN P et al.: In vitro and in vivo properties of Ro-639141, a novel broad-spectrum cephalosporin with activity against methicillin-resistant staphylococci. Antimicrob. Agents Chemother. (2001) 45(3):825-836.

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Website201. http://www.replidyne.com/pages/faropenem.

htmlFaropenem doloxate pipeline (2005).

AffiliationHolly L Hoffman-Roberts† PharmD, Emily C Babcock & Isaac F Mitropoulos†Author for correspondenceCollege of Pharmacy, 1110 North Stonewall 206, PO BOX 26901, Oklahoma City, OK 73190, USATel: +1 405 271 6878 ext. 47260; Fax: +1 405 271 6430

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