Lipopeptide Antibiotics - an overview

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8.1.56 2003

Daptomycin (a lipopeptide antibiotic) is introduced for the treatment of systemic and life-threatening infections caused by Gram-positive organisms (Raja et al., 2003).

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2 Natural antibacterial drugs approved by FDA

2.1 Daptomycin

Daptomycin (CUBICIN®) derived from Streptomyces roseosporus is a cyclic lipopeptide antibacterial. It was the first lipopeptide antibiotic approved by the US FDA (09/2003) in clinical use for the treatment of adult and pediatric patients with complicated skin and skin structure infections (cSSSIs) caused by Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae subsp. equisimilis, and Enterococcus faecalis (Dalbavancin FDA Label, 2018; Tally & DeBruin, 2000). The mode of action by which daptomycin kills bacteria was exactly described, including blockage of cell wall synthesis, membrane pore formation, and the generation of altered membrane curvature leading to aberrant recruitment of proteins (Fig. 2A) (Allen, Hobbs, & Alborn Jr., 1987; Canepari, Boaretti, Lleo, & Satta, 1990; Koller & Lohner, 2014; Muthaiyan, Silverman, Jayaswal, & Wilkinson, 2008; Zhang, Muraih, MacCormick, Silverman, & Palmer, 2014; Zweytick, Tumer, Blondelle, & Lohner, 2008). A recent study has confirmed that daptomycin inhibits cell envelope synthesis by interfering with fluid membrane microdomains (Müller et al., 2016). The latest research report indicated that daptomycin interferes with the lipid II biosynthesis cycle, binds to supported bilayers doped with cell wall lipid intermediates, forms a tripartite complex with lipid II and phosphatidylglycerol, and then finally kills bacteria (Grein & Müller, 2020). Clinical experiments demonstrated that daptomycin (6 mg per kilogram daily) is not inferior to standard therapy (gentamicin plus either an antistaphylococcal penicillin or vancomycin) for S. aureus bacteremia (SAB) and right-sided endocarditis (Fowler Jr. et al., 2006). High-dose daptomycin may be more effective than an adequate empiric regimen with glycopeptides or beta-lactams when a SAB is suspected, especially in the context of high local prevalence of MRSA (Bassetti et al., 2015). A non-comparative, observational, single-center cohort study that used high-dose daptomycin to treat 102 patients with infective endocarditis from 2007 to 2014 demonstrated that muscle toxicity is clinically negligible and that no significant renal toxicity occurs (Durante-Mangoni et al., 2016). Whether or not daptomycin plus beta-lactams improves the outcomes compared with beta-lactam monotherapy warrants additional validation experiments. Daptomycin is reversibly bound to human plasma proteins, and no metabolites are observed in plasma (Daptomycin FDA Label, 2018; Dvorchik & Damphousse, 2004). Daptomycin is excreted primarily by the kidneys (Woodworth, Nyhart Jr., Brier, Wolny, & Black, 1992) and excreted into human milk at a very low concentration (Buitrago, Crompton, Bertolami, North, & Nathan, 2009; Dei Cas, Casagni, Gambaro, Cesari, & Roda, 2019; Dvorchik, Brazier, DeBruin, & Arbeit, 2003). It does not cross the blood–brain barrier or penetrate the cerebrospinal fluid of healthy volunteers (Estes & Derendorf, 2010). Daptomycin does not inhibit or induce the activities of most of human CYP isoforms including CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 (Daptomycin FDA Label, 2018). Daptomycin has the activity against vancomycin-resistant enterococci (Desai, Wong, & Pasha, 2016). However, the emergence of resistance to daptomycin during therapy threatens its usefulness. This phenomenon is caused by concomitant alterations in genes (liaF and gdpD) encoding proteins that are probably involved in regulating the stress response to antimicrobial agents acting on the cell envelope and enzymes that are responsible for phospholipid metabolism in the cell membrane (Arias et al., 2011; Pader et al., 2016).

Fig. 2. Mechanism of actions of natural antibacterial drugs (A), natural antifungal drugs (B) and natural antiviral drugs (C) approved by FDA for nearly 20 years. (A) Antibacterial mechanism: inhibition cell wall and membrane synthesis; Inhibition DNA/RNA synthesis; Inhibition protein synthesis. (B) Antifungal mechanisms: interferes with fungal cell wall synthesis by inhibiting β-(1, 3)-D-glucan or/ and β-(1, 6)-D-glucan synthases. (C) Antiviral mechanisms: neuraminidase inhibitor; fusion inhibitor.

2.2 Fidaxomicin

Fidaxomicin (DIFICID®), derived from the fermentation product of the actinomycete Dactylosporangium aurantiacum, is a macrolide antibacterial approved by the US FDA (05/2011) for the treatment of Clostridium difficile-associated infection (CDI) over the last 25 years (Fidaxomicin FDA Label, 2020; Venugopal & Johnson, 2012). As a non-absorbed macrocyclic compound, fidaxomicin is not expected to be desired effective for the treatment of other types of infections (Louie, Emery, Krulicki, Byrne, & Mah, 2009; Tannock et al., 2010). Fidaxomicin inhibits bacterial RNA polymerase activity (Fig. 2A), thereby preventing bacterial protein synthesis (Artsimovitch, Seddon, & Sears, 2012). Fidaxomicin and its main metabolite OP-1118 formed by gastric acid hydrolysis or enzymatic activity of intestinal cells inhibit C. difficile toxin a- and b-mediated inflammatory responses by inhibiting NF-κB activity (Koon et al., 2018). The antibacterial activity against C. difficile of fidaxomicin in vitro is about two to eight fold more active than that of vancomycin (Goldstein et al., 2011; Hecht et al., 2007; Karlowsky, Laing, & Zhanel, 2008). Clinical studies indicated that fidaxomicin could be an alternative treatment for infection with C. difficile, with similar efficacy and safety to vancomycin (Cornely et al., 2012; Crook et al., 2012; Gentry et al., 2019). Recent studies have suggested that fidaxomicin is suited the best as a treatment for mild CDI during a patient’s first episode (Biggs, Iqbal, Holden, Clewer, & Garvey, 2019). Fidaxomicin and OP-1118 have minimal exposure at the therapeutic dose after oral administration (Shue et al., 2008). In addition, fidaxomicin is a P-glycoprotein (P-gp) substrate, an inhibitor of P-gp and major CYP enzymes expressed in the gastrointestinal (GI) tract (CYP3A4, CYP2C9, and CYP2C19) (Fidaxomicin FDA Label, 2020). Fidaxomicin demonstrates no in vitro cross-resistance with other classes of antibacterial drugs, and no developed resistance is observed during therapy in clinical trials (Freeman et al., 2018; Grant & Edward, 2011). The major reported adverse events of fidaxomicin include pyrexia, vomiting, abdominal pain, headache (Wolf et al., 2019).

2.3 Ertapenem sodium

Ertapenem sodium (INVANZ®), a new 1-beta-methyl carbapenem, was approved by the US FDA (11/2011) and indicated for the treatment of complicated intra-abdominal infections (cIAI), complicated skin and skin structure infections, community-acquired pneumonia, complicated urinary tract infections (cUTI), including pyelonephritis, and acute pelvic infections. Ertapenem sodium is active against most Gram-positive bacteria and a wide range of clinical isolates of Gram-negative and Gram-positive anaerobes (Ertapenem Sodium FDA Label, 2019; Falagas, Peppas, Makris, Karageorgopoulos, & Matthaiou, 2008). Ertapenem sodium also demonstrates great efficacy against a growing number of cephalosporin-resistant bacteria and is more effective than cefotetan in the prevention of surgical-site infection in patients undergoing elective colorectal surgery (Itani et al., 2006). The bactericidal activity of ertapenem is due to the inhibition of cell wall synthesis (Fig. 2A) and the binding to penicillin-binding proteins (PBPs), preferably to PBPs 2 and 3 (Kohler et al., 1999). The plasma concentrations of total ertapenem are similar whether given intramuscularly or intravenously, indicating that ertapenem is almost completely absorbed after intramuscular administration (Frasca et al., 2010). Ertapenem is neither an inhibitor of CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 nor a substrate of P-gp (Ertapenem Sodium FDA Label, 2019). Ertapenem is eliminated primarily by the kidneys, and the mean renal clearance of intact ertapenem is 12.8 mL/min compared with a total clearance of 28.4 mL/min (Nix, Majumdar, & DiNubile, 2004). The resistance rate to ertapenem among all Enterobacteriaceae isolates was 2.0%, 14.0% in Enterobacter spp., and 2.5% and 0.4% in Klebsiella pneumoniae and Escherichia coli, respectively (Chung, Yong, & Lee, 2016). The most common ertapenem-associated adverse events during therapy plus the 14-day follow-up period are diarrhea, infused vein complication, and nausea (Teppler et al., 2004).

2.4 Tigecycline

Tigecycline (TYGACIL®), a derivative of minocycline, is the first glycylcycline antibiotic approved by the US FDA (06/2005) for the treatment of a range of bacterial infections caused by many Gram-positive and -negative organisms, including MRSA, vancomycin-intermediate and -resistant enterococci, and extended-spectrum b-lactamase–producing E. coli and K. pneumoniae and many anaerobic bacteria (Stein & Craig, 2006; Wenzel, Bate, & Kirkpatrick, 2005). High-dose tigecycline is more effective than standard-dose tigecycline or its comparators for the treatment of hospital-acquired pneumonia (Xu et al., 2016). Tigecycline binds to the 30S ribosomal subunit and inhibits protein synthesis (Fig. 2A) (Lupien, Gingras, Leprohon, & Ouellette, 2015; Projan, 2000). Tigecycline exhibits linear pharmacokinetics and is rapidly distributed and has a large volume of distribution, indicating extensive tissue penetration (Muralidharan, Micalizzi, Speth, Raible, & Troy, 2005). Tigecycline is metabolized into a glucuronide, an N-acetyl metabolite, and a tigecycline epimer (each at no more than 10% of the administered dose) (Hoffmann et al., 2007). The primary route of elimination for tigecycline and its metabolites is biliary excretion (Alraish et al., 2020). The pharmacokinetics of tigecycline are also not affected by food, although tolerability is increased if the drug is administered following a meal (Meagher, Ambrose, Grasela, & Ellis-Grosse, 2005). Tigecycline is a substrate of P-gp in vitro but unknown in vivo. Tigecycline is not an inhibitor of P-gp, CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 (Tigecycline FDA Label, 2020). Tigecycline has steric hindrance afforded by the large D-ring substituent, resulting in insusceptibility to most of the common mechanisms of antibiotic resistance. Nevertheless, the resistance mechanisms to tigecycline in Enterobacteriaceae mainly involve the AcrAB efflux pump (Ye et al., 2017). The most frequently reported adverse effects associated with the use of tigecycline are nausea and vomiting, which are common to the tetracycline class of antimicrobial agents (Yamashita, Matschke, Gandhi, & Korth-Bradley, 2014). Tigecycline is expected to be used more often in approved indications and in off-combination regimens for the treatment of multidrug-resistant Gram-negative infections in routine clinical practice (Bassetti et al., 2013; Montravers, Dupont, Bedos, & Bret, 2014).

2.5 Retapamulin

Retapamulin (Altargo®), a derivative of the naturally occurring pleuromutilin, is the first pleuromutilin antibacterial approved by the US FDA (04/2007) for the treatment of impetigo primarily caused by S. aureus and uncomplicated secondarily infected traumatic skin lesion (Hu & Zou, 2009; Yang & Keam, 2008b). Clinical studies have shown that retapamulin ointment 1% is as effective as oral cephalexin in the treatment of patients with secondarily infected dermatitis (Parish et al., 2006). Topical retapamulin is effective and safe in the treatment of primary impetigo (Koning et al., 2008). Recent studies have indicated that retapamulin is highly active in vitro against Korean clinical isolates of high-level mupirocin and MRSA with different genetic backgrounds (Park, Kim, & Park, 2015). Retapamulin kills bacteria by binding to the bacterial ribosome with high affinity, inhibiting ribosomal peptidyl transferase activity (Fig. 2A), and partially inhibiting the binding of the initiator tRNA substrate to the ribosomal P-site (Yan et al., 2006). Retapamulin ointment (1%) is applied once daily to intact skin and to abraded skin, which results in the low systemic exposure of retapamulin. It is approximately 94% bound to human plasma proteins. In addition, the main metabolic pathways of retapamulin are mono-oxygenation and N-demethylation, which are mediated by CYP3A4. Retapamulin is neither an inducer nor an inhibitor of CYP3A4 (Retapamulin FDA Label, 2019). As a low-systemic-exposure drug, the elimination pathways of retapamulin have not been investigated. Reduced susceptibility to retapamulin may involve mutations in the retapamulin ribosomal binding site and a nonspecific efflux (Yang & Keam, 2008a). Retapamulin treatment is not associated with any serious adverse events (Free et al., 2006; Koning et al., 2008; Oranje et al., 2007).

2.6 Telavancin hydrochloride

Telavancin (VIBATIV® ), a semi-synthetic derivative of vancomycin, was approved by the US FDA (09/2009) for the treatment of adult patients with cSSSI caused by S. aureus (including methicillin-susceptible and -resistant isolates), S. pyogenes, S. agalactiae, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), or E. faecalis (vancomycin-susceptible isolates only), and hospital-acquired and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of S. aureus (both methicillin-susceptible and -resistant isolates) (Telavancin FDA Label, 2020). Telavancin has a dual mechanism of action: inhibits cell wall biosynthesis by binding to late-stage peptidoglycan precursors (Fig. 2A), including lipid II, binds to the bacterial membrane, and disrupts membrane barrier function, which portends a slow rate of resistance development (Lunde et al., 2009). Telavancin has a high level of protein binding (75.2% ~86.8%) (Matzneller et al., 2016). No metabolites of telavancin were detected in the liver mediated by CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP A4/5, and CYP4A11. Telavancin is primarily eliminated by the kidney (76%) and less by the bile acid (<1%). Telavancin does not inhibit the activities of CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 (Telavancin FDA Label, 2020). The pharmacokinetics of telavancin in adults is not affected by age alone, sex, or moderate hepatic impairment (Goldberg et al., 2010); Samara, Shaw, Barriere, Wong, & Worboys, 2012; Wong, Barriere, Kitt, & Goldberg, 2008). The most common adverse events of telavancin are taste disturbance, nausea, vomiting, and foamy urine (Barriere, 2010).

2.7 Ceftaroline fosamil

Ceftaroline fosamil (TEFLARO®), a fifth-generation cephalosporin, was approved by the US FDA (10/2010) for the treatment of adults and children with acute bacterial skin and skin structure in- fections (ABSSSIs) and community-acquired bacterial pneumonia (Lodise & Low, 2012). Ceftaroline fosamil is also frequently used off-label because of its broad spectrum of activity, good safety, and tolerability (Pani et al., 2019). Ceftaroline fosamil is the water-soluble prodrug of the bioactive ceftaroline. The bactericidal action of ceftaroline (Fig. 2A) is mediated through binding to essential PBPs and thus interfering with cell wall synthesis (Moisan, Pruneau, & Malouin, 2010). Ceftaroline binds to PBP 1–4 and has an especially high affinity for PBP2a (mecA), which is associated with methicillin resistance. This unique affinity for PBP2a distinguishes ceftaroline from other cephalosporins (Kosowska-Shick, McGhee, & Appelbaum, 2010). Compared with ceftriaxone, ceftaroline is > 16-fold more potent against MSSA (MIC90 0.25 mg/L vs. 4 mg/L) and ≥16-fold more potent against MRSA (MIC90 2 mg/L vs. > 32 mg/L) (Biedenbach, Iaconis, & Sahm, 2016). An international, randomized, controlled, double-blind, phase 3 trial demonstrated that ceftaroline fosamil (600 mg given every 12 h) is superior to ceftriaxone (2g given every 24 h) for the treatment of Asian patients with Pneumonia Outcomes Research Team risk class III–IV community-acquired pneumonia (Zhong et al., 2015). The plasma protein binding of ceftaroline is generally low (<20%) (Zhanel et al., 2009). Ceftaroline fosamil is transformed into bioactive ceftaroline in plasma by a phosphatase enzyme, and ceftaroline is hydrolyzed to form the inactive open-ring metabolite. Ceftaroline is neither a substrate, an inhibitor, nor an inducer of hepatic CYP enzymes (Ceftaroline Fosamil FDA Label, 2019). Ceftaroline and its metabolites are primarily eliminated by the kidneys (Maggiore, Pasquale, Cole, & Friedland, 2015). Ceftaroline has a low potential for the selection of resistance against drug-resistant Gram-positive organisms, including MRSA, VISA, hVISA, and VRSA isolates, S. pneumoniae, and Gram-negative respiratory pathogens (Clark, McGhee, Appelbaum, & Kosowska-Shick, 2011; Mushtaq & Livermore, 2010; Mushtaq, Warner, Ge, Kaniga, & Livermore, 2007).

2.8 Dalbavancin

Dalbavancin (DALVANCE®), a semisynthetic lipoglycopeptide synthesized from a fermentation product of Nonomuraea species, was approved by the US FDA (05/ 2014) for the treatment of Gram-positive bacteria associated with ABSSSIs (Anderson & Keating, 2008; Juul, Mullins, Peppard, & Huang, 2016). Dalbavancin inhibits cell wall synthesis by binding to the D-Ala-D-Ala terminus of pentapeptide peptidoglycan precursors and inhibiting cell wall peptidoglycan crosslinking (Fig. 2A) (Cheng et al., 2014). The spectrum of in vitro activity of dalbavancin is similar to that of available lipoglycopeptides, but dalbavancin is more potent than vancomycin against most pathogens (Candiani, Abbondi, Borgonovi, Romanò, & Parenti, 1999; Gales, Sader, & Jones, 2005; Goldstein et al., 2003; Lin, Smith, Ednie, & Appelbaum, 2005; Mushtaq, Warner, Johnson, & Livermore, 2004; Streit, Fritsche, Sader, & Jones, 2004; Streit, Sader, Fritsche, & Jones, 2005). The minimum inhibitory concentrations (MICs) of dalbavancin against more than 6000 Gram-positive pathogens range from ≤ 0.015μg/ml to > 32 μg/ml (Streit et al., 2004). Dalbavancin allows once-weekly intravenous dosing because of its extremely long half-life (Boucher et al., 2014). Dalbavancin is neither a substrate, an inhibitor, nor an inducer of CYP isoenzymes. A minor metabolite of dalbavancin (hydroxy-dalbavancin) has been observed in the human urine but not plasma (Dalbavancin FDA Label, 2018). Dalbavancin is mainly excreted by the kidneys (Azanza, Sádaba, & Reis, 2017). Resistance to dalbavancin has not been observed. The most common adverse reactions in patients treated with dalbavancin were nausea, headache, and diarrhea (Dunne, Talbot, Boucher, Wilcox, & Puttagunta, 2016).

2.9 Oritavancin

Oritavancin (ORBACTIV®), an analog of vancomycin that contains an additional unsubstituted sugar and an aromatic lipophilic side chain, was approved by the US FDA (08/2014) for the treatment of acute bacterial skin and skin structure infections (Markham, 2014). Oritavancin kills bacteria by binding to the stem peptide of peptidoglycan precursors (Münch et al., 2015), binding to the peptide bridging segments of the cell wall (Kim et al., 2008), thereby disturbing cell wall biosynthesis (Fig. 2A), and disrupting bacterial membrane integrity, resulting in depolarization, permeabilization, and cell death (Belley et al., 2009; Belley et al., 2010; Kim, Singh, & Schaefer, 2009). Due to the multiple mechanisms of action, oritavancin exerts activity against vancomycin-susceptible and -resistant organisms and biofilm-producing Gram-positive bacteria (Zhanel, Schweizer, & Karlowsky, 2012) (Jones, Turnidge, Moeck, Arhin, & Mendes, 2015). Oritavancin with a high plasma protein-binding rate (85%) (Oritavancin FDA Label, 2019) exhibits linear pharmacokinetics at a dose up to 1200 mg (Rose & Hutson, 2020). Oritavancin is not metabolized and slowly excreted unchanged in feces and urine (Bhavnani, Owen, Loutit, Porter, & Ambrose, 2004). Ritavancin is neither a substrate nor an inhibitor of the efflux transporter P-gp but is an inhibitor of CYP1A2, CYP2B6, CYP2D6, CYP2C9, CYP2C19, and CYP3A4 (Oritavancin FDA Label, 2019). Resistance to oritavancin was not observed in surveillance or clinical studies, but S. aureus and E. faecalis strains resistant to oritavancin were found in vitro (Karlowsky et al., 2017), although the mechanism of resistance to oritavancinremains unclear. The most common adverse reactions (≥3% ) of oritavancin in patients were headache, nausea, vomiting, limb and subcutaneous abscesses, and diarrhea (Corey et al., 2014; Corey et al., 2015).

2.10 Cetolozane/tazobactam

Ceftolozane/tazobactam (ZERBAXA®), a β-lactam/β-lactamase inhibitor combination, was approved by the US FDA (12/2014) for the treatment of adults with cIAI, HABP/VABP, and cUTI, including pyelonephritis (Ceftolozane/Tazobactam FDA Label, 2019; Liscio, Mahoney, & Hirsch, 2015). Ceftolozane kills bacteria by disturbing cell wall biosynthesis through binding to PBPs, thereby inhibiting peptidoglycan cross-linking (Fig. 2A) (Moyá, Zamorano, Juan, Ge, & Oliver, 2010). Tazobactam is an irreversible inhibitor of many beta-lactamases (Bonomo, Rudin, & Shlaes, 1997). Ceftolozane/tazobactam shows higher cure rates than colistin/aminoglycoside-based regimens for severe, resistant Pseudomonas aeruginosa infections (Vena, Giacobbe, Mussini, Cattelan, & Bassetti, 2020). Ceftolozane and tazobactam exhibit low protein binding (less than 10%) (Kratzer et al., 2019) and they are primarily eliminated by the kidneys (Miller, Hershberger, Benziger, Trinh, & Friedland, 2012). Tazobactam is hydrolyzed to form the pharmacologically inactive open-ring metabolite (Miller et al., 2012; Nishimori et al., 1994). Ceftolozane is neither a substrate nor an inhibitor of CYP enzymes. Tazobactam is a substrate for OAT1 and OAT3 transporters but not OCT2 (Wen et al., 2018). Ceftolozane does not inhibit the transporters of P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, MRP, BSEP, OAT1, OAT3, MATE1, and MATE2-K. Neither tazobactam nor the tazobactam metabolite M1 inhibits P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, or BSEP transporters at therapeutic plasma concentrations (Ceftolozane/Tazobactam FDA Label, 2019).

2.11 Telithromycin

Telithromycin, the first of a new class of antibacterial drugs derived from macrolides, was approved by the US FDA (04/2004) for the treatment of acute bacterial sinusitis (ABS), acute bacterial exacerbations of chronic bronchitis (AECB), and mild-to-moderate community-acquired pneumonia (CAP) (Spiers & Zervos, 2004; Wellington & Noble, 2004). Telithromycin blocks protein synthesis with increased affinity for the binding sites on domains II and V of 23S rRNA of the 50S ribosomal subunit (Fig. 2A), resulting in increased activity against bacteria that are resistant to macrolides because of methylation- and efflux pump-mediated mechanisms (ermB and mefA, respectively) (Novotny, Jakobsen, Andersen, Poehlsgaard, & Douthwaite, 2004; Zuckerman, 2004). With 800 mg of telithromycin once daily, patients with CAP, AECB, or pharyngitis/tonsillitis caused by group A β-haemolytic streptococci achieve clinical cure rates of 86% to 94.8% (Fogarty et al., 2005; Fogarty, Patel, Dunbar, & Leroy, 2005; Norrby et al., 2001). Telithromycin displays nonlinear pharmacokinetics, with an absolute bioavailability of 57% (Perret et al., 2002) and a protein binding rate of 60%–70% (Yamazaki, Lamy, Ducelier, Bonnat, & Lenfant, 2003). Food does not affect the oral bioavailability of telithromycin (Bhargava et al., 2002). Approximately 70% of the telithromycin dose is metabolized, of which 50% is mediated by CYP3A4. Telithromycin is eliminated by multiple pathways, including biliary, intestinal, and renal excretion (Telithromycin FDA Label, 2015). It is a strong inhibitor of CYP3A4 (Kuramochi & Morita, 2006) and may be an inhibitor for OATP1B1 and OATP1B3 (Seithel et al., 2007). Telithromycin resistance is not accurately predicted. An international surveillance study shows that 10 of 13,874 pneumococci isolates are resistant to telithromycin. Of these 10 isolates, 7 has an MIC of 4 μg/mL and 3 has an MIC of 8 μg/mL (Farrell & Felmingham, 2004). In addition, production of Erm dimethyltransferases may cause telithromycin resistance in Gram-positive bacteria (Takaya, Sato, Shoji, & Yamamoto, 2013). However, telithromycin-associated hepatotoxicity, including frank liver failure, is acquired from market introduction and spontaneous reports (Brinker et al., 2009). Acute liver failure is 3.5 to 11 times as high for telithromycin as for other antibiotics marketed for similar indications (Graham, 2006). Like other macrolides, telithromycin can exacerbate myasthenia gravis (Perrot et al., 2006).

2.12 Doripenem

Doripenem (DORIBAX®), a parenteral antibiotic from the carbapenem class, was approved by the US FDA (2007) for the treatment of complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs), including pyelonephritis (Keam, 2008). Doripenem exerts its bactericidal activity by inactivating multiple essential penicillin-binding proteins (PBPs) (Fig. 2A)，thus inhibiting cell wall synthesis with subsequent cell death (Davies, Shang, Bush, & Flamm, 2008). Doripenem is metabolized into an inactive ring-opened metabolite via dehydropeptidase-1. The average binding of doripenem to plasma proteins is approximately 8.1% and it is independent of plasma drug concentrations. Doripenem is not substrate, an inhibitor, or an inducer of the major CYP450 isoenzymes (Doripenem FDA Label, 2015). Doripenem is primarily eliminated unchanged by the kidneys (Cirillo et al., 2008; Vermeir, 2008). The most common adverse reactions of doripenem are headache, nausea, diarrhea, rash, vomiting and phlebitis (Lucasti et al., 2008).

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6.6.3 Chemistry of the lipopeptides

6.6.3.1 Daptomycin

Overview. Daptomycin (structure 118 of Fig. 6.27) is a bactericidal lipopeptide antibiotic with clinical efficacy against gram-positive pathogens [236,313]. Its gross structure—consisting of a fatty acid at the N-terminus of a tripeptide handle attached to a cyclic decadepsipeptide—has some similarity to that of the gram-negative-acting polymyxins. Daptomycin and polymyxins both target the bacterial membrane. However, daptomycin is active against gram-positive bacteria, while the polymyxins target the lipopolysaccharide of gram-negative bacteria. A further distinction is a specific role for calcium ion binding to daptomycin to confer its biological activity [314]. The structure of the mechanistically relevant calcium–daptomycin complex is a focus of experimental study, especially with respect to the possibility that the structure may involve complexation with the undecaprenyl phosphate (and undecaprenyl pyrophosphate) structures in the bacterial membrane. Structure–activity studies demonstrate that daptomycin is highly optimized for its antibiotic function. Daptomycin was discovered in 1983. It was approved in 2003 as Cubicin, following a pause in its clinical development to optimize its dose regimen and to accommodate its transfer from its discovering company (Eli Lilly) to its final developing company (Cubist). Its developmental history is reviewed [315,316]. Daptomycin was approved for complicated skin infections and right-sided endocarditis caused by methicillin-sensitive S. aureus infection. Since its clinical introduction, its value as a systemically administered antibiotic has expanded to include infections by MRSA (approved in 2006), S. pneumoniae, and (as a first-line agent) Enterococcus spp. (including vancomycin-resistant strains) [317]. Daptomycin is currently being explored in combination (with β-lactams, fosfomycin, and linezolid) therapy against multidrug-resistant gram-positive bacteria and as a possibly advantageous step-down therapy for vancomycin in the chemotherapy of MRSA bacteremia [318–321]. Notwithstanding its established clinical value, daptomycin was removed from the 2019 Essential Medicines list (deprioritized in favor of linezolid) [322]. Daptomycin is now off-patent. The status of daptomycin with respect to its biosynthesis, chemistry, biochemistry, mechanism, and clinical use is reviewed [314,323–326].

Figure 6.27. Structures of daptomycin and other lipopeptides.

Synthesis. Daptomycin (118) is a product of nonribosomal peptide synthesis by Streptomyces roseosporus [313,327,328]. Its cyclic decapeptide segment has an ester linkage between the alcohol of the 4-threonine (Thr4) and the carboxylic acid of the kynurenine amino acid (Kyr13). Metabolic engineering of its producing strain of Streptomyces roseosporus improved its production titer from 17 mg L−1 to 113 mg L−1 [329]. Kynurenine is one of the six nonproteinogenic amino acids (the other five are the d-Asn2, d-Orn6, d-Ala8, d-Ser11, and the (2S,3R)-3-methylglutamate or l-MeGlu12). Replacement of the l-MeGlu residue with l-Glu significantly reduces antibiotic activity [330]. The combination of six nonproteinogenic amino acids within a complex cyclic depsipeptide challenged the chemical synthesis of daptomycin analogs. This challenge was met eventually by total synthesis [313,331–334] and by semisynthesis [335]. Notable features of daptomycin as an optimized antibacterial are summarized. N-Methylation of the Kyr13 aniline segment provided kynomycin (119), achieving several-fold improved potency against S. aureus and E. faecalis. This increase could have clinical value [336]. In contrast, N-methylation at the 1-position of the indole of Trp1 had a small effect with respect to the S. aureus strains but gave a several-fold improvement against E. faecalis, and N-methylation of Gly5 (120) improved the activity slightly against S. aureus but was disadvantageous with respect to E. faecalis [337]. Although Trp1 is not replaceable, its refinement in the form of tryptophan analogs having alkyl substituents at the 6-position of the indole gave analogs with several-fold improved activity against numerous S. aureus and E. faecium strains, exemplified by a decrease in the MIC for a daptomycin-resistant E. faecium (daptomycin, MIC 29 mg L−1) to 3 mg L−1 for a 6-(2E-pentenyl)indole Trp1 analog [335]. The preservation of the activity by this latter analog, in the absence of added calcium, is unprecedented. Since these latter analogs were accessed from daptomycin itself, their large-scale synthesis may be possible. Previous mechanistic studies indicated a significantly lower affinity of daptomycin for the membranes of gram-negative bacteria compared with the membranes of gram-positive bacteria. Siderophore substitution to the primary amine of d-Orn6 of daptomycin gave an analog (121, Mr = 1168) showing decreased gram-positive activity; no gain of activity against E. coli; but the acquisition of respectable activity (MIC < 1 mg L−1) against MDR strains of A. baumannii [338]. This unexpected outcome—confirmed with a second daptomycin–siderophore conjugate [339]—may reflect an unusual character to the membranes of A. baumannii, as further evidenced by the ability of this bacterium to alter the composition of its membranes as a resistance mechanism against the polymyxins [340].

Mechanism. The decanoyltryptophan terminus of daptomycin facilitates its entry into the gram-positive bacterial membrane. Within the membrane and in the presence of calcium, daptomycin engages in a concentration-dependent manner in multiple homooligomerization and heterooligomerization equilibria [341,342]. Its calcium-dependent affinity for the bacterial membrane correlates with the proportion of phosphatidylglycerol in the membrane [343–345]. This complexity challenged the identification of mechanistically relevant equilibria. The enantiomer of daptomycin obtained by total synthesis gave clarification. This enantiomer is 85-fold poorer as an antibacterial [346]. This diminution implied chiral recognition. This ligand was identified as the 1,2-diacyl-sn-glycerol phosphate (phosphatidylglycerol) of the bacterial membrane [346]. This identification is consistent with the lack of clinical efficacy of daptomycin in gram-positive pneumonia. Lung surfactants have a high proportion of phosphatidylglycerol, and these surfactants compete for daptomycin binding. Given the importance of lipid fluidity to the organization of the enzymes of cell envelope biosynthesis, altered fluidity by daptomycin may disrupt this organization [347]. Mechanistic studies with S. aureus showed daptomycin to localize to the septal site where cell envelope biosynthesis is active, coincident with disrupted integrity of the multiprotein divisome complex as evidenced by cessation of the synthesis of the cell wall peptidoglycan. The critical equilibrium affecting this cessation is suggested to involve the formation of a tripartite complex of calcium–daptomycin, phosphatidylglycerol, and undecaprenyl phosphate [348]. The structurally related calcium-dependent antibiotic, laspartomycin C, forms a stable complex with an undecaprenyl phosphate-type lipid [349]. Undecaprenyl phosphate segments are used as the saccharide carrier in peptidoglycan biosynthesis. Loss of lipid II as a result of its participation in a lipid–daptomycin tripartite complex is consistent with a bactericidal mechanism.

Resistance. Resistance to daptomycin appeared following its clinical use. Daptomycin resistance is occurred by the complex adjustment of bacterial metabolism and enzyme mutation. While the exact resistance combination is not generalizable—each bacterial strain appears to evolve a different resistance solution—the focus is this resistance mutation in the MprF (“multiple peptide resistance factors”) enzyme. MprF is a bifunctional catalyst of the synthesis of lysylphosphatidylglycerol and the translocation of this lipid to the outer leaflet of the membrane [350–352]. While MprF resistance mutation is understood to represent gain-of-function [353–355], the function gained is uncertain. MprF mutation can coincide with cross-resistance to vancomycin [356]. In combination with metabolic adjustments [357–360], MprF mutation reduces membrane affinity for daptomycin, slows bacterial growth, and increases cell wall thickness. Monoclonal antibodies validated MprF inhibition for the reversal of daptomycin resistance [352]. The resistance mechanism in S. aureus is not yet mobile.

Combination. A recurrent clinical dilemma is the appropriate chemotherapy following monotherapy failure. The possibility that daptomycin could replace vancomycin against S. aureus infections [361] has focused study on how bacteria resist its mechanism. In in vitro culture of MRSA, daptomycin demonstrates a “seesaw” effect with β-lactams: the resistance response to daptomycin renders the bacteria more susceptible to β-lactams [362,363]. Prolonged exposure of daptomycin-resistant S. aureus to β-lactams restores daptomycin sensitivity [359,362]. An important contributing factor to the seesaw phenomenon is the proportion of phosphatidylglycerol in the membrane [364]. Nonetheless, the seesaw phenomenon is multifactorial [365,366] and also includes as a variable the cardiolipin content of the membrane [367]. A contributing role for MprF is confirmed [368]. The promising clinical efficacy of combination therapy of daptomycin with ceftaroline (a β-lactam with enhanced MRSA activity) has clinical promise [280,369,370] and is consistent with the seesaw phenomenon, but is not proven [371]. The combination of daptomycin with fosfomycin (79) also is synergistic in vitro [372]. Fosfomycin is an inhibitor of peptidoglycan biosynthesis (see Section 6.7.2.4). Clinical evaluation of this combination was not decisive, however. The daptomycin–fosfomycin combination favorably prevented microbiological failure and complicated bacteremia, but with an increase in adverse events [373]. Daptomycin is first-line therapy against vancomycin-resistant enterococcal infections [374]. Mobile daptomycin resistance in the Enterococci has developed [375]. Daptomycin combination therapy with fosfomycin is effective against daptomycin-resistant Enterococci [376,377].

6.6.3.2 New lipopeptides

Synthetic efforts have identified loci within the daptomycin structure for favorable alteration [331,378] and identifying derivatives with a lower MIC, and a lower calcium ion dependency [378]. The combination of biosynthetic manipulation [327], synthesis, and the modeling of the daptomycin–undecaprenyl phosphate complex [379] will define the future medicinal chemistry effort. Moreover, the daptomycins are not the only structural class of calcium-dependent antibiotics [314]. The malacidins are a new and potent antibacterial class with a different calcium-binding motif, receiving synthetic and biosynthetic attention [380–382]. Bioinformatic analysis of a biosynthetic gene cluster of Paenibacillus mucilaginosus led to a structural prediction for its biosynthetic product, the lipodepsipeptide cilagicin [383]. The structure was verified by synthesis (“synthetic-bioinformatic natural product” discovery). Its mechanism as a gram-positive bactericidal antibiotic is complexation with undecaprenyl phosphate and undecaprenyl diphosphate, thus preventing their recycling as is required for provision of the key saccharide intermediates of cell envelope biosynthesis [384]. While this mechanism is similar to that of the calcium-binding antibiotic structures, the structure of cilagicin lacks the calcium-binding motif of daptomycin, thus indicating a unique lipid recognition motif. Optimization of its lipid tail (fatty acid–derived amide replaced by the biphenylcarboxylic acid–derived amide) gave structure cilagicin BP (Fig. 6.28). This exchange reduced the unfavorable serum binding and allowed demonstration of pharmacologic efficacy in a murine model of MRSA infection [383].

Figure 6.28. Structure of cilagicin BP.

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2.1 Daptomycin

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4 Daptomycin against Gram-positive bacteria

Daptomycin (Fig. 5) is a cyclic lipopeptide antibiotic produced by Streptomyces rososporus [455]. It has a narrow antibacterial spectrum and is mainly used for the treatment of infections caused by Gram-positive bacteria, including MRSA, VRE and St. pneumoniae [456,457]. It was first discovered in the 1980s but the development was halted after Phase I/II trials as high doses of daptomycin caused skeletal muscle toxicity [458]. Cubist Pharmaceuticals acquired daptomycin and developed it using a PK/PD approach. In 2003 the FDA approved daptomycin for the treatment of complicated skin and skin-structure infections (cSSSIs), albeit at a lower dose than used in the clinical trials [459].

Fig. 5. Structure of daptomycin.

Daptomycin consists of a 13-member amino acid cyclic lipopeptide (hydrophilic core) with a decanoyl side chain (lipophilic tail) [460–462]. It contains several non-proteinogenic amino acids including ornithine, L-3-methyl-glutamic acid, and L-kynurenine [460–462]. At neutral pH, daptomycin is negatively charged [463,464]. Its unique chemical structure confers a mechanism of action that is different from that of the glycopeptides, acting mainly on the cell membrane of Gram-positive bacteria. Initial binding of daptomycin to the bacterial membrane is not well understood, although it shows increased binding affinity to negatively charged membranes containing phosphatidylglycerols, an important lipid component of bacterial membranes [465]. Insertion of daptomycin into bacterial membrane occurs in a Ca2+-dependent manner, with Ca2+-daptomycin forming a tripartite complex with undecaprenyl-coupled cell envelope precursors and the anionic phospholipid phosphatidylglycerol in the membrane [466–470]. Daptomycin does not lyse bacterial cells and generally does not cause serious inflammatory reactions due to the release of inflammatory mediators (e.g. lipoteichoic acid) from bacteria [471].

Resistance to daptomycin in patients was first reported only two years after it was approved in 2003 [472]. Mutations, thickening of the bacterial cell wall, changes in cell surface charge, and altered lipid metabolism are all associated with daptomycin resistance in Gram-positive pathogens [473] including En. faecalis [474], S. aureus [475], St. mitis/oralis [476] and Bacillus subtilis [465]. Mutations in mprF (multiple peptide resistance factor), rpoB and rpoC, and membrane spanning sensor/histidine kinase yycG are involved in daptomycin resistance in S. aureus [467].

Daptomycin displays rapid, concentration-dependent bactericidal activity against Gram-positive bacteria including VRE, MRSA and streptococci [477]. In the neutropenic mouse thigh model, daptomycin (0.20–400 mg/kg/day in divided doses) displayed concentration-dependent killing and produced in vivo PAEs of ∼5–11 h against strains of S. aureus, St. pneumoniae and En. faecium [478]. Daptomycin is mainly excreted renally (78%), with ∼50% of the unchanged drug recovered in urine within 24 h [477]. Total clearance of daptomycin in patients undergoing continuous renal replacement therapy varied and was 0.22, 0.24, 0.94 and 0.53 L/h in patients undergoing haemodialysis, continuous ambulatory peritoneal dialysis (CAPD), continuous veno-venous haemodialysis (CVVHD) and continuous veno-venous haemodiafiltration (CVVHDF), respectively. For patients with creatinine clearance ≥30 mL/min, the clearance was 0.75 L/h [479]. Protein binding of daptomycin in human plasma is ∼92%, with most bound to albumin [480,481]. Following intravenous administration, daptomycin cannot penetrate the blood–brain or placental barriers [459], and hence remains mostly in plasma and interstitial fluid (volume of distribution, ∼0.1 L/kg) [477,482]. The elimination t1/2 of daptomycin is ∼8–9 h in patients [483,484]. The PK of daptomycin is different between adults and children (especially neonates and infants), with the drug being cleared more rapidly in the latter resulting in lower AUC and Cmax levels [485]. Consequently, higher doses of daptomycin are required in younger children to achieve adequate bacterial killing. Higher than recommended doses may also be required in patients with special clinical conditions (e.g., sepsis, obesity, chronic renal disease, renal replacement therapy, and hypoproteinemia) where pathological changes lead to variable drug exposure [482].

Cmax/MIC and AUC/MIC are the most predictive PK/PD indices for daptomycin efficacy in mice (Fig. 6) [478,486]. In the neutropenic mouse thigh infection model, PK/PD targets for bacteriostasis against S. aureus, St. pneumoniae and En. faecium were 59–94, 12–36 and 0.14–0.25 for Cmax/MIC and 388–537, 75–237 and 0.94–1.67 for AUC/MIC, respectively [478]. More recently, clinical studies have shown improved efficacy with an AUC/MIC > 666 [487–489] and a Cmax/MIC between 12 and 94 for bacteriostasis [488] and resistance suppression [490]; a Cmin <∼3 mg/L was associated with poor outcomes [484]. However, PK alternations in critically ill patients and other patient groups mean that achieving adequate daptomycin exposure can be difficult [491]. In a clinical study involving 35 patients with severe Gram-positive infections, 11 patients receiving 8 mg/kg/day of daptomycin had significantly higher Cmax and AUC0-24 values (and consequently Cmax/MIC and AUC/MIC ratios) than in the 24 patients receiving a dose of 6 mg/kg/day (Cmax/MIC of 138 ± 35 and 87 ± 31, and AUC/MIC of 903 ± 280 and 692 ± 210 with the 8 and 6 mg/kg/day regimens, respectively) [490]. This suggests that a dose of 8 mg/kg/day has a greater likelihood of achieving clinical success.

Fig. 6. Relationships between PK/PD parameters (a) %T>MIC, (b) Cmax/MIC, and (c) AUC0-24/MIC with bacterial load in the thighs of neutropenic mice after 24 h of treatment with multiple dosing regimens of daptomycin. The dotted lines represent the log10 CFU/thigh at the start of therapy [478]. Permission obtained from the American Society of Microbiology.

While the PK/PD targets outlined above have been proposed, there is high variability in plasma concentrations of daptomycin following intravenous administration which is only partially explained by the dose administered and underlying renal function. For example, Galar et al. reported a median Cmin and Cmax of 10.6 mg/L (range, 1.3–44.7 mg/L) and 44.0 mg/L (range, 3.0–93.7 mg/L) following a median daptomycin dose of 7 mg/kg (interquartile range, IQR, 5.0 – 9.0) [484]; whereas the equivalent values reported by Reiber et al. were 16.7 mg/L (range, 2–68 mg/L) and 66.2 mg/L (20–236 mg/L) following a median dose of 6 mg/kg/day (range, 2.7–13.8 mg/kg) [492]. Creatinine clearance, 48-h dose interval, albumin and ICU hospitalisation are all known to contribute to unpredictable plasma concentrations of daptomycin [492]. Given such high variability, TDM has been suggested to provide guidance on dose adjustment to maximise efficacy and reduce the likelihood of serious adverse events, especially in those patients who have substantially altered PK [483,484,490–492]. For example, a population PK/PD analysis showed that increasing the dose helped to increase the probability of target attainment (AUC/MIC of ≥ 666) in patients with a creatinine clearance ≥60 mL/min, in those with a creatinine clearance < 60 mL/min but receiving CRRT, or with MICs ≥ 1 mg/L [493]. Compared with emipirical treatment, targeted treatment has significently improved the clinical outcome with P = 0.033 [484]. Overall, TDM is critical for determining AUC/MIC and adjusting doses accordingly to maximise efficacy [483,484,490,492].

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Daptomycin

Daptomycin, a novel lipopeptide antibiotic, is bactericidal against a range of gram-positive isolates.10 Its exact mechanism of action is not completely understood. It is thought to disrupt plasma membrane function, leading to the release of intracellular ions, specifically potassium, resulting in cell death.13 It exhibits rapid, concentration-dependent bactericidal activity against susceptible isolates, including MRSA and vancomycin-resistant Enterococcus faecium (VREF).13 It is used primarily for skin and soft-tissue infections caused by gram-positive bacteria, but is also used for complicated urinary tract infections caused by gram-positive pathogens. It is inactivated by surfactant and is not useful for treating pneumonia.10 It is a relatively safe drug with very few reported adverse effects.10 Daptomycin is eliminated by the kidneys, and dosage adjustments may be necessary in patients with renal dysfunction. Hepatic metabolism is limited. Daptomycin is available only for parenteral administration.10

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Daptomycin

Daptomycin, a novel parenterally administered lipopeptide antibiotic, is bactericidal against a range of gram-positive isolates.8,14 Its exact mechanism of action is not completely understood. It is thought to disrupt plasma membrane function, which leads to the release of intracellular ions, specifically potassium, and results in cell death.14 It exhibits rapid, concentration-dependent bactericidal activity against susceptible isolates, including MRSA and vancomycin-resistant Enterococcus faecium (VREF).2,14 It is used primarily for skin and soft tissue infections caused by gram-positive bacteria but is also used for complicated urinary tract infections. It is inactivated by surfactant and is not useful for treating pneumonia. It is a relatively safe drug with very few reported adverse effects. Daptomycin has limited hepatic metabolism and is eliminated primarily by the kidneys; dosage adjustments may therefore be necessary in patients with renal dysfunction. There are no reports of its use in veterinary medicine.2

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Daptomycin and Linezolid

Daptomycin is a novel cyclic lipopeptide antibiotic derived from Streptomyces roseosporus as a fermentation product. The drug must be administered intravenously once a day and was approved by Food and Drug Administration (FDA) in 2003. Daptomycin has bactericidal activity against Gram-positive bacteria including methicillin-susceptible S. aureus, MRSA, VRSA, penicillin-resistant S. pneumoniae, and ampicillin as well as VRE. This drug is also effective in treating complicated skin and skin-structure infections. Daptomycin binds to the bacterial cell membrane via calcium-dependent insertion of its lipid tail, forming an ion-conduction structure which rapidly depolarizes the cell membrane via efflux of potassium and possibly other ions. As a result there is a disruption of DNA, RNA, and protein synthesis which eventually causes bacterial cell death. The standard dose is 4 mg/kg in a 24 hours period. Dose should be lower in renally compromised patients (creatinine clearance <30). The drug has a good safety profile and low potential for resistance [12]. The drug is not approved for use in treating pneumonia due to its interaction with pulmonary surfactant, which results in inhibition of the antibiotic.

Linezolid is the first member of a new class of antibiotic drugs, the oxazolidinones. It has a broad range of activities against various Gram-positive bacteria including MRSA, VRE, and penicillin-resistant S. pneumoniae, but is bacteriostatic against these organisms. Linezolid also has some activity against atypical bacteria including some Nocardia and rapidly growing mycobacteria. Linezolid can be administered orally 400 mg or 600 mg twice daily. Linezolid is well tolerated with good safety record. Thrombocytopenia was documented as a side effect in only 2% of patients [13].

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Results

Daptomycin

Daptomycin, a fermentation product of Streptomyces roseosporus, is a cyclic lipopeptide antibiotic with potent bactericidal activity against most gram-positive organisms. It is approved for the treatment of complicated skin and skin structure infections and S aureus bacteremia, including those with right-sided infective endocarditis, caused by methicillin-susceptible S aureus and MRSA.1 It has a unique structure among currently available antibiotics and a novel mechanism of action involving insertion of the lipophilic daptomycin tail into the bacterial cell membrane in a calcium-dependent manner, causing a potassium ion efflux and rapid membrane depolarization. This action is followed by arrest of DNA, RNA, and protein synthesis, resulting in bacterial cell death.2

In a simulated endocardial vegetation model, daptomycin remained bactericidal (99.9% kill within 24 hours) against stationary phase cultures of both methicillin-susceptible S aureus and MRSA present at high density (109 CFU).3 Daptomycin demonstrates concentration-dependent activity, a half-life of 8 hours, a prolonged postantibiotic effect (PAE) up to 6.8 hours, and linear pharmacokinetics with minimal drug accumulation.4 Daptomycin is primarily renally excreted, with the majority of the drug remaining intact in the urine. Because of daptomycin׳s unique mechanism of action and because it is not metabolized by cytochrome P-450 or other hepatic enzymes, it has minimal drug interactions.5,6

Based on its concentration-dependent activity, linear pharmacokinetics, and favorable safety profile, daptomycin has been used and studied at higher-than-indicated doses. Infectious Diseases Society of America guidelines from 2011 suggest using high-dose daptomycin (10 mg/kg/d), if the isolate is susceptible, in combination with another agent (eg, gentamicin 1 mg/kg IV every 8 hours, rifampin 600 mg PO/IV daily, or 300–450 mg PO/IV BID, linezolid 600 mg PO/IV BID, trimethoprim/sulfamethoxazole 5 mg/kg IV BID, or a β-lactam antibiotic) in the management of persistent MRSA bacteremia and vancomycin treatment failures in adult patients (B-III indication).7

Overall rates of resistance of daptomycin in staphylococci and enterococci remain rare. However, there are numerous reports of emergence of resistance during treatment with daptomycin in settings of at least one of the following factors: (1) high inoculum infections; (2) endovascular infections; (3) infections of biomedical devices with prolonged retention; (4) bone and joint infections; (5) hemodialysis patients; and (6) lower than recommended doses of daptomycin monotherapy.8 Mechanisms of daptomycin resistance are still being elucidated and remain diverse. Daptomycin-resistant S aureus is usually caused by modification of the cell membrane. Resistant isolates often exhibit progressive accumulation of single nucleotide polymorphisms in the multipeptide resistance factor gene (mprF) and the yycFG components of the yycFGHI operon. Both of these loci are involved in key cell membrane events. mprF is responsible for the synthesis and outer cell membrane translocation of positively charged lysyl-phosphatidylglycerol. The resultant phenotype readout is increased in the relative positive surface charge and is associated with decreased daptomycin binding. It has also been demonstrated that the VraSR 2-component regulatory system contributes to mprF-mediated decreased susceptibility to daptomycin.9 Other cell membrane mechanisms associated with daptomycin resistance in S aureus isolates are altered cell membrane order, increased cell membrane pigment production, resistance to depolarization and/or permeabilization, and reduced cell membrane peptidoglycan content. Modifications of the cell wall (including enhanced expression of dlt operon and progressive cell wall thickening) also contribute to daptomycin resistance.10

The mechanism of daptomycin resistance in enterococci may be associated with various gene mutations, increased septum formation, and alterations in membrane charge and phospholipid content. Whole-genome analysis suggests that mutations in several genes may play a role in the development of daptomycin resistance in enterococci. These include: (1) a 3-component regulatory system (designated liaFSR) that orchestrates the cell envelope response to antibiotics; (2) genes encoding proteins involved in phospholipid metabolism, including glycerophosphoryl diester phosphodiesterase (gdpD) and cardiolipin synthase (cls); and (3) a putative histidine kinase gene yycG, a member of the YycFG system that is involved in cell envelope homeostasis and daptomycin resistance in other gram-positive cocci. Nevertheless, none of the aforementioned gene mutations alone is sufficient to confer clinical levels of daptomycin resistance.11

Furthermore, analysis of an isolated cave microbiome, in low G+C gram-positive bacteria, revealed a novel mechanism of daptomycin resistance that involved inactivation by hydrolytic cleavage of the ester bond between the threonine and kynurenine residues, resulting in ring-opening inactivation.12

Rationale of Combination Antibiotics

Combinations of antibiotics are used to take advantage of the agents’ different mechanisms of action and toxicity profiles. Common indications for combination antibiotic therapy is broad-spectrum empiric treatment of life-threatening infections, treatment of polymicrobial infections, minimization of drug toxicity by using relatively low doses of ≥2 drugs with additive efficacies but independent toxicities, prevention of emergence of antibiotic resistance to a single agent, and exploitation of the possibility of synergistic inhibitory or bactericidal activities. Antibiotic synergy refers to a net increased antimicrobial effect resulting from the interaction of ≥2 drugs that is greater than the sum of their independent contributions.13,14

Various mechanisms of this synergistic activity have been proposed. A cell wall–active agent with aminoglycoside proves synergistic activity, with increased intracellular uptake of aminoglycosides leading to enhanced killing and bactericidal activity in certain gram-positive organisms.15 In addition, inactivating enzyme inhibitors (eg, a combination of a β-lactam agent plus β-lactamase inhibitors) are another possible mechanism of this synergistic activity. Other examples include combinations of drugs acting at proximate steps of a metabolic pathway (eg, trimethoprim/sulfamethoxazole rendering the combination drug bactericidal and less prone to resistance) and combinations of drugs acting at various levels of peptidoglycan synthesis (eg, β-lactams, fosfomycin, glycopeptides, and lipopeptides).16 Synergy in PAE is another possible mechanism. Synergistic PAEs have been observed classically in combinations of β-lactams with aminoglycosides and by addition of rifampin to other classes of drugs. Prolongation of PAE may provide higher protection against organism regrowth in situations when one or both antibiotics become subtherapeutic during the dosing interval.17 Disadvantages of combination therapy includes the possibility of antagonism, increased risk of adverse effects, risk of emergence of other resistant organisms, Clostridium difficile infection, and increased cost of therapy. Short-course, low-dose gentamicin combined with vancomycin for MRSA bacteremia and native valve endocarditis and in combination with other β-lactams may be associated with an increased risk of nephrotoxicity.18,19

Based on the National Healthcare Safety Network data, in 2009–2010, S aureus remained the most common cause of health care–associated infection, with MRSA accounting for >50% of the clinical S aureus isolates recovered in US hospitals.20 Infection with MRSA is associated with increased morbidity, requirement for a longer duration of antibiotic therapy, higher health care costs, prolonged hospitalization, and an increased risk of death.21 S aureus bacteremia is associated with a poor outcome and a high rate of secondary infections such as infective endocarditis, septic arthritis, and osteomyelitis.22 Vancomycin has been the cornerstone of treatment of patients with serious MRSA infections for 5 decades. Consequently, vancomycin use has been increasing since the mid-1980s, resulting in the emergence of MRSA with reduced susceptibility to vancomycin. S aureus strains with reduced susceptibility can be divided into 3 categories; vancomycin-resistant strains (MIC, ≥16 μg/mL); vancomycin-intermediate strains (VISA; MIC, ≥4 μg/mL); and heterogeneous VISA, which have MIC <4 μg/mL but subpopulations that grow at higher MICs.

Within the populations of S aureus that are considered to be susceptible, a changing pattern of vancomycin MICs has been observed in some centers, demonstrating an overall population drift in the clinical isolates of S aureus toward reduced vancomycin susceptibility. This phenomenon of “vancomycin MIC creep” varies considerably around the world and may not be uniformly applicable in all health care settings.23 Infections caused by MRSA with higher vancomycin MICs are seen in patients with recent exposure to vancomycin within 1 month of the current infection, recent hospitalization, surgery within the last 6 months, and those with bloodstream infections before admission in intensive care units. In the treatment of MRSA bloodstream infections with vancomycin, higher vancomycin MIC values (≥1.5 μg/mL), regardless of MIC testing method and infection source, are predictive of treatment failure and associated with higher mortality.24 These data highlighting such poor outcomes in patients with serious MRSA infections (including bacteremia) suggest that in many of these instances, the treatment strategy of vancomycin specifically, and monotherapy in general, seems to be failing. Evidence is mounting that serious MRSA infections such as bacteremia may require combination antibiotic therapy for optimal management, improving antibiotic durability and slowing the rate of emergence of resistance.25–29

Although new antimicrobial drugs (eg, linezolid, daptomycin, tigecycline, telavancin, ceftaroline) have been developed, none has been shown to be consistently superior to vancomycin for the treatment of MRSA infections.30–32 This finding is likely due to the fact that most of the randomized clinical trials comparing the newer antibiotics with vancomycin are restricted to relatively “low-risk” clinical situations because of the use stringent exclusionary criteria.

The optimal treatment of complicated MRSA infections thus remains a challenge. Physicians and pharmacists are meeting these challenges in a variety of ways, including: (1) the adoption of rapid molecular tests to quickly differentiate MRSA from β-lactam– susceptible strains and, therefore, convert patients with the latter more rapidly to superior β-lactam therapy; (2) optimization of antibiotic doses targeting higher trough levels for vancomycin and higher daptomycin levels for breakthrough MRSA infections and serious vancomycin-resistant enterococci infections; (3) switching early-on to alternative agents for MRSA infections when vancomycin MIC is 2 mg/L; and (4) using combination antibiotic therapy.

The combination of high-dose daptomycin with a second antibiotic has been used to treat refractory S aureus bacteremia because: (1) vancomycin first-line therapy has been shown to elicit changes that confer cross-resistance to daptomycin33; (2) in vivo persistence under selection pressure from innate cationic host defense peptides also independently select for reduced susceptibility to daptomycin34; and (3) organisms that establish endovascular infections such as endocarditis that frequently are the cause of persistent bacteremia demonstrate a fitness advantage of intrinsic resistance to cationic host defense peptides, with resulting increased heteroresistance to daptomycin.25,35–38

Combination of Antibiotics With Daptomycin: Clinical Data

In vitro data of interactions between daptomycin and other antibiotics have been reviewed extensively in other publications.25,39,40 There are limited clinical data on the use of daptomycin in combination with other antibiotics. Most of this use has occurred in the setting of failing therapy and/or relapsing infection and “difficult to treat” infections. Characteristics of the antibiotics that were used in these studies, their mechanism of action, mechanism of resistance, and possible mechanisms of interactions with daptomycin are summarized in Table I.41–56

Table I. Characteristics of antibiotics used as combination therapy with daptomycin (DAP).

Drug	Mechanism of Action	Mechanism of Resistance	Interaction With DAP
β-lactams	β-lactams act as substrate analogs for the PBPs. They bind irreversibly to the PBPs’ active site, leading to termination of peptidoglycan cross-linking causing disruption of cell wall leading to cell lysis and death41 Antistaphylococal β-lactams also sensitize MRSA for augmented clearance by innate immune effectors as phagocytes and cationic host defense peptides from keratinocytes, neutrophils, and platelets23,42 β-lactams may inhibit surface expression of fibronectin binding protein gene, thereby diminishing endovascular and osteoarticular virulence43	Staphylococci: Mutations in PBPs: PBP2a, PBP2׳, resulting in decreased affinity to all β-lactams41 Expression of blaZ gene: degradation of penicillins44 Enterococci: High levels of resistance involves expression of PBP5-R, alterations in the PBP5 protein around the active site, increased expression of PBP5, and utilization of a β-lactam–insensitive transpeptidase for cell wall synthesis45	See-saw effect: Increased susceptibility of antistaphylococcal β-lactam antibiotics with reduced susceptibility to glycopeptides and lipopeptides46. This is possibly mediated by reduction of PBP4 and PBP2a with a relative increase in PBP247 Synergy: β-lactam exposure increases the net surface negative charge on the bacterial cell wall leading to increased binding of the positively charged DAP Ca2+ complex, which results in synergy and enhanced killing. β-lactam exposure leads to host defense peptide–mediated innate immune response against MRSA, resulting in additional synergy between them and DAP or vancomycin23,42 Combination of DAP and a β-lactam delays or prevents the selection of DAP-resistant variants in vitro48,49
Rifampin	Rifampin acts by interacting specifically with bacterial RNA polymerase encoded by the gene rpoB50	Mutations in rpoB, the gene that encodes the β subunit of RNA polymerase, are responsible for rifampin resistance.51 Because of the rapid development of resistance, it should not be used as monotherapy but may be used in combination with another active antibiotic in selected scenarios	In vitro synergy has been show with various antibiotics, including DAP. In the presence of DAP, a striking reduction in the rifampicin MIC was seen in 11 of 15 (73.3%) VRE that were resistant to rifampicin52
TMP/SMT	The 2 components, TMP and SMT, work sequentially to inhibit enzyme systems involved in the bacterial synthesis of tetrahydrofolic acid. Reduced availability of tetrahydrofolic acid inhibits thymidine synthesis and, subsequently, DNA synthesis. The combination (TMP/SMT) has a broader spectrum of antimicrobial activity, is more rapidly bactericidal, and is less susceptible to the development of resistance than either of the component drugs53	Overproduction of para-aminobenzoic acid causes resistance to sulfonamides. Amino acid substitutions in both enzymes (dihydropteroate synthase and tetrahydrofolate reductase). Exogenous thymidine as produced by some staphylococci also renders TMP/SMT inactive because it bypasses the double biosynthetic blockade54	In vitro synergy has been show with various antibiotics, including DAP
Fosfomycin	Targets the bacterial mucopeptide synthesis by inhibiting phosphoenolpyruvate transferase, which is involved in peptidoglycan synthesis. This results in a broad-spectrum bactericidal effect55	In gram-positive organisms, resistance may be mediated by fosfomycin resistance proteins (FosA, FosB, or FoX) that chemically modify and inactivate the drug55	In vitro synergy has been show with various antibiotics, including DAP.56 Similar to other cell wall active agents such as β-lactams, fosfomycin may also lead to increased DAP binding by altering the charge of the outer membrane.

PBP = penicillin-binding proteins; MRSA = methicillin-resistant Staphylococcus aureus; VRE = vancomycin-resistant enterococci; TMP/SMT = trimethoprim/sulfamethoxazole.

Table II23,57–75 summarizes the clinical data regarding the use of daptomycin in combination with other antibiotics for the treatment of complicated bacteremia and other associated invasive infections caused by resistant gram-positive organisms. In these studies, daptomycin was used in combination with β-lactams, rifampin, trimethoprim-sulfamethoxazole, fosfomycin, tigecycline, and linezolid. Because most of the available clinical and in vitro data are for the combination therapy of daptomycin with various β-lactam agents, further discussion will focus primarily on this combination.

Table II. Summary of clinical studies with daptomycin (DAP) combination therapy for disseminated infections.

Study	Antibiotic	Infection	Outcome	Comments
Antibiotic combination of DAP + β-lactam agent
Arias et al,57 2007	DAP 8 mg/kg/d	Enterococcus faecium (VRE)	Cure at 6-month follow-up	DAP heteroresistance noted
	Ampicillin 16 gm/d	MV endocarditis		DAP MIC, 2–4; ampicillin MIC, 16–34
	Gentamicin 1 mg/kg q 12 × 6 weeks	Relapsing bacteremia
Dhand and Sakoulas,23 2011	Daptomycin (high dose) + nafcillin/oxacillin	Series of 7 patients with noncatheter-associated persistent MRSA bacteremia	Rapid clearance of bacteremia after addition of β-lactam	Initial cure in 7 of 7 patients, with a delayed relapse in 2 of the 7 patients. One isolate developed DAP nonsusceptibility. In vitro studies showed enhanced DAP bactericidal activity, increased membrane DAP binding, and decreases in positive surface charge induced by ASBLs against DAP nonsusceptible MRSA
Sakoulas et al,58 2011	DAP 12 mg/kg/dose Ampicillin 1 g q 6	E faecium (VRE) DAP MIC 1 Ampicillin MIC, >128	Rapid clearance of persistent bacteremia	Addition of ampicillin to DAP in vitro enhanced DAP activity and binding, changed the antibiotic profile from static to bactericidal, showed slow reduction in net positive surface charge, and made VRE more susceptible to killing by innate immune response mediated by cationic host defense peptides
Rose et al,59 2012	DAP 10 mg/kg/dose Ceftaroline 200 mg q 12	S aureus (MRSA, DNSA, VISA) HD catheter–related bacteremia, right-sided endocarditis, septic arthritis	Clearance of bacteremia	Ceftaroline restored DAP sensitivity in vivo. Improved DAP susceptibility in vitro in presence of oxacillin and ceftaroline. Rapid and sustained bactericidal activity
				Combination prevented emergence of DAP resistance in vitro. In DNSA, higher dose of DAP is required to optimize cell membrane damage
Sierra-Hoffman et al,60 2012	DAP 6 mg/kg q 48 Ampicillin 1 g q 6 × 6 weeks	E faecalis MV endocarditis	Cure at 12-month follow-up	DAP MIC, <4; ampicillin sensitive Overall efficacy of DAP was slightly enhanced (not statistically significant) with the addition of β-lactams. This benefit was most pronounced in bacteremia associated with endocarditis, osteoarticular infection, and bacteremia of unknown source. Combination therapy was well tolerated.
Moise et al,61 2013	Daptomycin with and without β-lactam	CORE data 2005–2009 106 patients with S aureus bacteremia		Addition of rifampin or gentamicin or vancomycin to DAP did not result in any significant change in outcome
Sakoulas et al,62 2013	DAP 8 mg/kg/dose Ceftaroline 600 mg q 8	E faecalis Aortic valve endocarditis High-level gentamicin resistance	Clearance of bacteremia Cure after 4 week of therapy and AVR	In vitro: 4-fold decrease in DAP MIC with addition of ampicillin or ceftaroline and synergy between DAP and ceftaroline. Enhancement of cathelicidin peptide activity and DAP binding in presence of ceftaroline
Antibiotic combination of DAP + rifampin
Stevens and Edmond,63 2005	DAP 8 mg/kg/dose Rifampin 300 mg q 8 h Gentamicin after HD 11 weeks	E faecium (VRE) Prosthetic MV endocarditis DAP MIC, 4	No microbiologic reoccurrence after 4 weeks of completion	In vitro synergy noted between DAP/rifampin/gentamicin
Ahmad and Rojtman,64 2010	DAP 6 mg/kg/dose Rifampin 300 mg q12 h 6 weeks	Persistent MRSA bacteremia DAP MIC increased to 2 while on DAP therapy	Rapid clearance of bacteremia after adding rifampin. Cure at 4-month follow-up	No in vitro synergy was noted

Lee et al,65 2008	DAP 6 mg/kg/dose Rifampin 6 weeks	MRSA Bacteremia, Likely AV graft infection, Septic brain emboli, meningitis	Cure	MRSA DAP MIC, 1 Leukocytoclastic vasculitis with vancomycin. Rifampin added for CNS disease
Jugun et al,66 2013	DAP 8 mg/kg/dose Rifampin 600 mg q 24 h	Gram-positive osteoarticular infections, N = 16 (staphylococcal, n = 15, streptococcal, n = 1)	Successful outcomes at >1-year follow-up	Median duration of treatment was 21 days (range, 10–122 days). Combination therapy well tolerated. Prosthetic device removal in 5 of 16, device exchange in 4 of 16, and device retention in 4 of 16
Rose et al,67 2013	DAP 4–8 mg/kg/dose Rifampin 300–600 mg/d	MRSA (n = 12) Osteoarticular (N = 9) HD catheter infection (1) Prosthetic valve endocarditis (1)	Cure in 9 of 12 patients	Checkerboard synergy was seen in 9 of 12 patients and was predictive of therapeutic success. Failure seen in prosthetic joint infection and deep abscess
Antibiotic combination of DAP + TMP/SMT
Avery et al,68 2012	DAP 10 mg/kg/dose TMP/SMT IV to oral	DNSA, VISA 1. Bacteremia with vertebral osteomyelitis 2. Bacteremia, TV endocarditis, osteomyelitis	1. Cure 2. Clearance of persistent bacteremia	Suppression with oral TMP/SMT; course complicated by reversible myopathy and renal failure. In vitro combination showed sustained bactericidal activity at 36 to 48 hours
DiCarlo et al,69 2013	DAP 8 mg/kg/dose TMP/SMT 15 mg/kg/d	MRSA bacteremia MV endocarditis Intracranial hemorrhage	Cure	6 weeks of oral TMP/SMT after 6 weeks of combination IV therapy VAN MIC, 2
Antibiotic combination of DAP + fosfomycin
Miro et al,70 2012	DAP 10 mg/kg/d	3 cases of left-sided endocarditis	Alive at >6-month follow-up	In vitro activity of combination against (7 MSSA, 5 MRSA, 2 GISA) isolates showed synergy in 79% of isolates and bactericidal activity in 57% of isolates. Combination therapy was well tolerated
	FOS 2 g q 6 h	(MRSA, n = 2; MSSA, n = 1)
Chen et al,71 2011	DAP 12 mg/kg/d FOS 6 g q 6 h	MRSA/DNSA bacteremia, AICD infection, endocarditis, osteomyelitis	Cure	Delayed surgical removal of pacing wire. Eight weeks of intravenous therapy. Combination well tolerated. In vitro additive effect.
Teng et al,72 2012	DAP 12 mg/kg/d	MSSA, VT-MRSA	Cure	Combination well tolerated
	FOS 6 g q 6 h	Bacteremia,
		MV endocarditis, osteomyelitis
Antibiotic combination of DAP + tigecycline
Jenkins,73 2007	DAP 6 mg/kg/dose	E faecium (VRE)	Cure at 16-week follow-up
	Tigecycline 50 mg q 12 h	MV endocarditis
	× 70 d	DAP MIC, 4
Schutt and Bohm,74 2009	DAP 8 mg/kg/dose Tigecycline 50 mg q 12 h	E faecium (VRE) Bacteremia Possible TV endocarditis with pulmonary septic emboli	Rapid clearance of refractory bacteremia	Resistant to vancomycin, linezolid. DAP MIC, 3–4
Antibiotic combination of DAP + linezolid + rifampin
Kelesidis et al,75 2011	DAP × 6 weeks Linezolid 600 mg q 12 h Rifampin 300 mg q 12 h	MRSA prosthetic device infection, bacteremia, meningitis, osteomyelitis	Cure after removal of shunt and combination antibiotics	In vitro analysis found that combination of linezolid with DAP produced indifference in checkerboard analysis and antagonism in time-kill assays. The addition of rifampin to the combination linezolid + DAP resulted in synergy in the time-kill assays when tested at 0.5 times the MICs for each drug and achieved 99.9% killing significantly quicker than the other combinations

VRE = vancomycin-resistant enterococci; MV = mitral valve; MRSA = methicillin- resistant Staphylococcus aureus; ASBL = antistaphylococal β-lactam; DNSA = DAP nonsusceptible S aureus; VISA = vancomycin-intermediate S aureus; HD = hemodialysis; CORE = Cubicin Outcomes Registry and Experience; AVR = aortic valve replacement; AV = arteriovenous; CNS = central nervous system; TMP/SXT = trimethoprim/sulfamethoxazole; FOS = fosfomycin; TV = tricuspid valve; MSSA = methicillin-susceptible Staphylococcus aureus; GISA = glycopeptide-intermediate Staphylococcus aureus; AICD = automated implantable cardioverter-defibrillator; VT = vancomycin tolerant.

Daptomycin and β-Lactam Combination Therapy

Daptomycin and β-lactam combinations have been used successfully and increasingly as salvage treatment for refractory or relapsing infections caused by resistant gram-positive organisms (Table II). In addition to the “see-saw” effect,76 the improved outcomes are based on:

•

Synergy: β-lactam exposure increases the net surface negative charge on the bacterial cell wall leading to increased binding of the positively charged daptomycin Ca2+ complex, resulting in synergy and enhanced killing of resistant gram-positive organisms.23,42,58

•

β-lactam–mediated increased killing by various cationic host defense peptides (HDPs): Increased resistance to vancomycin and daptomycin is associated with concomitant resistant to various HDPs that are produced by platelets, leukocytes, and keratinocytes.35 Antistaphylococal β-lactams sensitize MRSA for augmented clearance by innate immune effectors such as HDP and phagocytes and therefore augment the synergistic activity between these antistaphylococal β-lactams and daptomycin.23,42,77

•

Prevention of emergence of resistance: β-lactams when used along with daptomycin prevent the emergence of resistance to daptomycin in clinical MRSA isolates and in enterococci.48,49,59,78

Unique Role of Ceftaroline

Unlike other β-lactams, ceftaroline has activity against MRSA, heterogeneous VISA, VISA, vancomycin-resistant strains, and daptomycin-nonsusceptible S aureus, which is mediated by binding to PBP2a with 128 times greater affinity than any other clinically available β-lactam.79 Because PBP2a on the cell surface decreases with reduced glycopeptide and lipopeptide susceptibility, the enhanced activity of daptomycin mediated by ceftaroline is likely a result of synergistic activity as well. Ceftaroline has been used in combination with daptomycin to eradicate resistant S aureus and enterococcal infections and offers an attractive and potent therapeutic option for the treatment of resistant gram-positive infections.59,62,77,80

Is the Synergistic Activity of All β-Lactams With Daptomycin the Same?

While nafcilln and oxacillin enhance daptomycin and killing of MRSA, b-lactam antibiotics with penicillin-binding protein-1 (PBP1) binding demonstrate enhance the activity of daptomycin compared to those with relatively less PBP1 binding (cefoxitin, and cefaclor).81 The mechanism for this specificity is unknown. However, given that PBP1 is a critical component of cell divisome formation that may be a compensatory response to daptomycin membrane insertion for initiation of surface repair, PBP1 inhibition or interference by β-lactam antibiotics that bind it may result in cell death with fewer daptomycin molecules inserted per cell (G.S., unpublished observations).82

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9 Lipopeptides

The structure of this class of antimicrobials includes a cyclic peptide with a hydrophobic tail. Of significant clinical relevance is colistin (also known as polymyxin E), a polypeptide antibiotic produced by certain strains of Paenibacillus polymyxa (formerly Bacillus polymyxa var. colistinus). It was discovered in Japan in 1947 and entered the clinical practice in 1949 [215]. It fell out of favour, however, because of a variety of adverse effects, such as nephrotoxicity, ototoxicity, and neuromuscular blockade, and when other, less toxic, antimicrobials became available [249]. With the emergence and dissemination of Gram-negative bacterial pathogens that are resistant to the mainstream treatment with the aminoglycosides, β-lactams, and quinolones, there is a renewed interest in the use of colistin. It can be used as a last resort antibiotic against serious and difficult-to-treat infections such as those caused by multidrug-resistant P. aeruginosa, K. pneumoniae, and A. baumannii [79]. Multidrug-resistant isolates of the Enterobacteriaceae expressing the novel NDM-1 metallo-β-lactamase still remain susceptible to colistin [130].

Colistin targets the bacterial cell membrane of Gram-negative bacteria. It initially associates with the anionic lipopolysaccharide (LPS) molecules in the outer membrane of Gram-negative bacteria and displaces magnesium and calcium, which stabilize the negatively charged LPS molecules [78]. This results in a local disturbance of the outer membrane, with increased permeability, leakage of the cell content, and, eventually, cell death. Although presently rare, resistance to colistin is emerging. It is encoded on a plasmid with a very high conjugative transfer frequency and a potential for rapid dissemination to key pathogenic species of the Enterobacteriaceae [140]. The authors suggest that one of the main causes of the emerging resistance could be its large-scale use in agriculture. Another worrying finding is that colistin therapy may increase pathogen resistance to host cationic antimicrobials [161]. Colistin selection for pathogen resistance against the first line of host’s innate immunity defence may potentially facilitate the infection process and thus increase the infection rates.

Another cyclic lipopeptide antibiotic, daptomycin, is produced by Streptomyces roseosporus [218]. It was discovered by researchers at Eli Lilly and Company in early 1980s but did not enter the clinical practice until 2003 [212]. It is active only against Gram-positive bacteria, including vancomycin-resistant enterococci (VRE) and methicillin-resistant S. aureus (MRSA). The mechanism of action includes primarily targeting bacterial cell membranes leading to the mislocalization of essential cell division proteins and causing severe cell wall and membrane defects, with an eventual breach in the cell membrane integrity and cell death [176]. The antibiotic is well tolerated, with the frequency and distribution of adverse effects similar to comparator drugs [194]. Resistance to daptomycin remains rare. In S. aureus, it is the result of incremental accumulation of point mutations in genes encoding a lysylphosphatidylglycerol synthetase, a histidine kinase, and RpoB and RpoC subunits of RNA polymerase [89]. There is a good potential for the development of various daptomycin derivatives using a biosynthetic engineering approach [23].

A group of lipopeptides called echinocandins display potent antifungal activities [65]. They noncompetitively inhibit β-(1,3)-d-glucan synthase, an essential enzyme complex for the synthesis of glucan in the fungal cell wall [156]. They were discovered in 1970s during extensive screening programmes for antifungals with a broad-spectrum activity against the species of Candida. Although the natural products appeared to be toxic, the synthetic modifications allowed lowering the toxicity, and the approved drugs among the semi-synthetic echinocandins include caspofungin, micafungin, and anidulafungin [156]. In a recent report by the Centers for Disease Control and Prevention regarding the microorganisms with a serious threat level, the only fungal pathogen among the 12 most serious threats is a fluconazole-resistant Candida [51]. Thus the echinocandins serve as a valuable first-line treatment option against these serious fungal infections. Resistance to the echinocandins is rare, essentially limited to the case studies with the resistance emerging during the treatment [77].

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Chapters and Articles

8.1.56 2003

2 Natural antibacterial drugs approved by FDA

2.1 Daptomycin

2.2 Fidaxomicin

2.3 Ertapenem sodium

2.4 Tigecycline

2.5 Retapamulin

2.6 Telavancin hydrochloride

2.7 Ceftaroline fosamil

2.8 Dalbavancin

2.9 Oritavancin

2.10 Cetolozane/tazobactam

2.11 Telithromycin

2.12 Doripenem

6.6.3 Chemistry of the lipopeptides

6.6.3.1 Daptomycin

6.6.3.2 New lipopeptides

2.1 Daptomycin

4 Daptomycin against Gram-positive bacteria

Daptomycin

Daptomycin

Daptomycin and Linezolid

Results

Daptomycin

Rationale of Combination Antibiotics

Combination of Antibiotics With Daptomycin: Clinical Data

Daptomycin and β-Lactam Combination Therapy

9 Lipopeptides

Peptide Therapy Guide Editorial Team

Lipopeptide antibiotics | Health and Medicine

Lipopeptide

What Are Lipopeptides?

Lipopeptides: Drug Class, Uses, Side Effects, Drug Names