Future directions in antimicrobial chemotherapy.

Future directions in antimicrobial chemotherapy R. Janknegt Introduction Except for the introduction of the fluorinated quinolones t h e r e h a v e been few major advances in antimicrobial c h e m o t h e r a p y during the last few years. This article discusses anticipated developments in antimicrobial p h a r m a c o t h e r a p y in the coming years. C u r r e n t antimicrobial research focuses on fluoroquinolones with an extended spectrum of activity against anaerobes and Gram-positive organisms, macrolides with improved pharmacokinetics and an extended spectrum, oral broad-spectrum cephalosporins, and the so-called fourth-generation cephalosporins which are more active against Grampositive bacteria. Oral c e p h a l o s p o r i n s A relatively large n u m b e r of oral broadspectrum cephalosporins are u n d e r development. The bacteriological and pharmacokinetic properties of these drugs are listed in Tables 1 and 2 [1-15].

Cefpodoxime proxetil Bacteriology. The in vitro activity of cefpodixime is comparable to t h a t of cefixime, the only oral third-generation cephalosporin currently available. It is 1 to 2 times less active t h a n cefixime against G r a m - n e g a t i v e bacteria but m u c h more active t h a n cefixime against Gram-positive bacteria, such as streptococci and staphylococci. Its activity against staphylococci is only moderate, however. Like other cephalosporins, cefpodoxime is not active against enterococci, most anaerobes, and intracellular organisms such as Chlamydia and Mycoplasma. Pharmacokinetics. After oral a d m i n i s t r a t i o n cefpodoxime is incompletely absorbed. The drug's bioavailability tends to be higher w h e n it is t a k e n together with food. H u g h e s et al. [17] found t h a t bioavailability increased from 41 to 64% w h e n the drug was t a k e n with food. This increase m a y be due to decreased esterification prior to absorption [6]. The m a x i m u m s e r u m concentration, w h e n corrected for dose, is similar to

Keywords Azithromycin Cefepime Cefodizime Cefpirome Daptomycin Meropenem Sparfloxacin Temafloxacin

Cefetamet pivoxil Bacteriology. C e f e t a m e t is highly active (MIC90 < 1) against Proteus spp., Shigella, Providencia spp. and Salmonella. Serratia marcescens and Yersinia spp. are less sensitive, with an MIC90 of 4 to 8 mg/1 [27 28]. Cefetamet is as active as cefaclor against streptococci, but inactive against staphylococci. Pharmacokinetics. C e f e t a m e t pivoxil is absorbed slowly and incompletely after oral ad-

Janknegt R. Future directions in antimicrobial chemotherapy. Pharm Weekbl [Sci] 1992;14(4A):229-44.

R. Janknegt: Department of Clinical Pharmacy and Toxicology, Maasland Hospital, P.O. Box 5500, 6130 MB Sittard, the Netherlands.

14(4A) 1992

t h a t of the other cephalosporins. The drug's volu m e of distribution (V) after intravenous adm i n i s t r a t i o n of the sodium salt is relatively high for a cephalosporin, 32.3 1 [7]. The tissue penetration of cefpodoxime appears to be similar to t h a t of cefaclor and cefixime [18 19]. Clinical studies. Cefpodoxime proxetil (mean dose 200 m g q12 h) has been compared with standard antimicrobial agents such as amoxicillin (3 x 500 mg), amoxicillin/clavulanic acid (3 x 625 mg), cefaclor (3 x 500 mg) and cefuroximeaxetil (2 x 250 mg) in a v a r i e t y of respiratory tract infections, such as acute bronchitis, exacerbations of chronic bronchitis, pneumonia, and sinusitis. Both the clinical efficacy and bacteriological efficacy of cefpodoxime were similar to those of the comparative drugs [20-23]. Cefpodoxime was also similar in efficacy to intravenous ceftriaxone (1,000 m g qd) in vulnerable patients with bronchopneumonia [24]. Side-effects were observed in 13% of all 1,468 patients studied. These were usually mild and transient. Gastrointestinal side-effects were most common, with diarrhoea observed in 4.6% of patients and n a u s e a or abdominal pain in 1.2%. Skin reactions were noted in 1.5% and headache in 0.9% of all patients. Tolerance was similar to t h a t of the comparative drugs [23]. Interactions. The absorption of cefpodoxime proxetil is diminished w h e n the drug is administered in combination with H2-receptor antagonists (ranitidine or famotidine) or antacids. Co-administration reduces the a r e a under curve (AUC) by 40 to 50% [25 26].

Abstract New developments in the treatment of bacterial infections are discussed. The most important developments include oral broad-spectrum cephalosporin derivatives and extended-spectrum injectable cephalosporins with improved activity against Gram-positive bacteria. Meropenem is a new carbapenem agent with markedly improved activity against Gram-negative bacteria. Many fluoroquinolones are in various phases of development. The most interesting new compound is sparfloxacin. Azithromycin is a new macrolide which, because of its very long half-life, attains very high levels in most tissues. Potential uses of the newer agents are discussed. Accepted June 1992.

P h a r m a c e u t i s c h Weekblad Scientific edition

229

Table 1

In vitro activity of oral cephalosporins (MIC50)* Cefaclor

Citrobacter spp. Enterobacter spp. E. coli KlebsieUa M. morganii P. mirabilis P. vulgaris Providencia spp. Salmonella typhi Serratia Shigella Yersinia spp. H. influenzae M. catarrhalis N. gonorrhoeae Staph. aureus Staph. epidermidis Streptococcus gr. A Streptococcus gr. B Streptococcus gr. C S. pneumoniae

Cefuroxime

32 64

4 8

2

2

0.5 64

2 64

4 64 8 0.25 64

4 64 2 2 64

1

2

16

4

8

1

4 8

0.5 0.06

2

1

1 0.06 2 0.03 2

0.5 0.03 0.06 0.03 0.03

Cefixime

Cefpodoxime

Cefetamet

Ceftibuten

1-2 1 0.25 0.03 2 0.015 0.03 0.06 0.12 1 2 0.5 0.06 0.12 0.015 16 8 0.5 0.25 0.12 0.5

1-2 1 0.25 0.12 0.5 0.06 0.03 0.12 0.25 2 0.25 1 0.06 0.25 0.015 2 1 0.015 0.06 0.015 0.03

1-2 0.5 0.5 0.5 1 0.12 0.25 0.25 0.5 2 0.12 0.5 0.25 0.25 0.015 > 32 32 0.12 0.5

0.5 0.5 0.12 0.06 0.25 0.03 0.03 0.03 0.03 0.25 0.12 0.12 0.06 1 0.015 > 64 32 1 1 1 4

0.25

* F r o m references 1-4.

Table 2

Pharmacokinetics of oral cephalosporins* Parameter

Cefuroxime axetil (250 rag)

Cefixime (200 mg)

Cefpodoxime proxetil (200 rag)

Cefetamet pivoxil (1,000 rag)

Ceftibuten (400 mg)

Loracarbef (200 mg)

Cmax (mg/1) tm~ (h) F (%)~ Protein binding (%) AUC (mg. h/l) tl/2 (h) % Excreted in urine

5-7 2-3 30-50 30 11-16 1.5 30-50

2-3 3-4 50 60-70 15-23 3-4 18-20

2-2.5 2-3 45-50 40 15 2-2.5 40

7-8 3-4 40-50 22 45 2-2.5 40

15-20 2-2.5 90

7-8 1-1.5 >90

80 2-2.5 70-75

10-15 1-1.5 85-90

* F r o m references 5-15. ~F: bioavailability.

ministration. It is released rapidly in the body and no intact ester can be d e m o n s t r a t e d in the blood. P e a k levels of about 7.4 mg/1 are achieved 3 to 4 h after a single 1,000 mg dose of cefetamet pivoxil (containing 693 mg cefetamet) [11 12]. At high dosages, p e a k levels are reached later and bioavailability is about 10% lower at a dose of 2,000 m g t h a n at a 500 m g dose [13]. Food increases the bioavailability of cefetamet from 41 to 51% in young subjects and to 47% in elderly volunteers [11]. The volume of distribution of intravenous cefet a m e t is 0.29 1/kg. Almost all of the absorbed drug is eliminated by renal excretion; the renal clearance of cefetamet is similar to the creatinine clearance. The elimination half-life increases from 2 h to approximately 24 h in patients with severely impaired renal function. The dosage can be corrected using the m e a s u r e d 230

or estimated creatinine clearance [29]. Hepatic cirrhosis does not significantly influence the pharmacokinetics of cefetamet pivoxil [30]. Clinical studies. Over 3,800 patients have participated in clinical trials of cefetamet. The m e a n dose in adults is 500 to 1,000 mg ql2h. C e f e t a m e t (1,000 mg ql2h) has been shown to be at least as effective as cefaclor (250 to 500 m g q8h) or amoxicillin (750 m g q8h) in acute exacerbations of chronic bronchitis. Cure r a t e s were close to 100% in sinusitis and pharyngitis. In lower and uncomplicated u r i n a r y tract infections cefetamet was more effective t h a n cefadroxil (1,000 m g ql2h). Overall bacteriologic eradication r a t e s were 91% for Enterobacteriaceae, 85% for Haemophilus influenzae and 67% for Pseudomonas infections. A total of 13.2% of 2,517 patients developed one or more side-effects. There reactions were mainly gastrointestinal (9.9%) and dermatologic (1.1%).


14(4A) 1992

Two cases of pseudomembraneous colitis were reported, but both patients recovered without t r e a t m e n t [data on file, Roche].

Ceflibuten Bacteriology. The in vitro activity of ceftibuten against Gram-negative bacteria is comparable to t h a t of cefixime. However, the drug is more acrive t h a n cefixime against Morganella morganii, Shigella and Yersinia. It is not active against staphylococci and most streptococci. Its activity against S. pneumoniae is only moderate, with an MIC of 2 to 8 mg/1 [1-3]. Pharmacokinetics. Ceftibuten is well-absorbed after oral administration in young as well as old patients. The AUC is reduced by about 20% when the drug is t a k e n with food. The apparent volume of distribution after oral dosing is about 0.2 1/kg and the drug penetrates well into blister fluid. Renal excretion is the most important route of elimination, accounting for about 70% of an oral dose. Approximately 20% of the dose is excreted in the urine in the form of the trans isomer, which is 8 times less active t h a n the parent compound. In patients with poor renal function (creatinine clearance 90 AUC0_~ (mg. h/l) 110-190 (1,000 rag) CLtot (ml/min) 115-145 CL R (ml/min) 100-130 tl/2(h) 1.8-2.2 % in blister fluid 89

0.3 10

0.2 73-89

0.2

31 60 (1,000 rag) (1,000 mg) 90 88 156 400 (1,000 rag) (1,000 rag) 110 150-180 82 90-110 2.3 3.5 123

30 (1,000 mg) > 95 140-200 (1,000 rag) 90-120 90-110 1.8 80

I m i p e n e m Meropenem Piperacillin T a z o b a c t a m 0.22-0.28 10-20

37-46 (500 rag) 175-215 1.1 73

0.3

67 (1,000 rag) 250-275 180-200 1.1 110

0.3

0.25

38 (2,000 mg) 71 122 (2,000 rag) 275 155 1.0

16 (250 mg) 83 18 (250 rag) 230 146 0.9

* From references 44-53. 232


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creases from 773 mg. h/1 in healthy subjects to 2,635 mg.h/] in patients with end-stage renal disease, and t h a t the half-life increases to about 10 h [47]. After intravenous administration of the drug to 4 patients undergoing continuous ambulatory peritoneal dialysis (CAPD), the ob~ served half-life was 4.1 to 6.8 h and peritoneal clearance (0.3 to 0.9 ml/min) contributed insignificantly to the total clearance of 16 to 32 ml/min. Nevertheless, the peritoneal levels achieved were sufficiently high, ranging from 3.8 to 12.7 mg/1 [55]. Cirrhosis has no significant influence on the pharmacokinetics of cefodizime [47]. The pharmacokinetics of cefodizime are not markedly different in healthy elderly subjects. In elderly patients with renal dysfunction, the half-life has been shown to correlate with the degree of renal impairment [56]. Immunomodulation. The most interesting aspect of cefodizime is its activity as a biological response modifier. The in vivo activity of the drug in experimental infections is considerably better t h a n would be expected on the basis of its in vitro activity [57]. The drug enhances phagocytosis, B-lymphocyte responsiveness, and delayed hypersensitivity, and it restores natural killer activity and interleukin-1 and interferon production in immunocompromized animals [58]. The thio-thiazolyl side-chain of cefodizime plays an important role in its immunomodulating activity. The clinical relevance of these data in treating infections in patients with diminished immune function has yet to be determined. Clinical studies. Intravenous cefodizime, 2,000 mg bid, has been shown to be as active as cefotaxime, 2,000 mg bid, or cefuroxime, 1,500 mg bid or qid, in 3 studies involving about 300 patients with lower respiratory infections. Bacteriologic eradication was observed in 95 to 100% of all cases. Cefodizime, 2,000 mg q24h, has been found to be as active as cefuroxime, 1,500 mg q8h, or ceftizoxime, 2,000 mg q24h, in complicated urinary tract infections. Cefodizime is well-tolerated. Side-effects (mainly gastrointestinal and skin reactions) have been observed in only 3.8% of all 5,801 patients participating in clinical trials. Treatment had to be discontinued because of adverse reactions in 1.1% of patients. Local reactions were observed in only 2.4% of all patients after intravenous injection, but 27.3% of patients complained of pain at the injection site after intramuscular injection [59].

Cefpirome Bacteriology. Cefpirome is a broad-spectrum aminothiazolyl cephalosporin. Its in vitro activity against Enterobacteriaceae is usually 2 to 4 times as great as t h a t of ceftazidime. It is 4 to 8 times as active as ceftazidime against Grampositive bacteria and it is not active against anaerobes such as B. fragilis. In vitro studies, however, have shown t h a t cefpirome has only modest activity against methicillin-resistant Staph. aureus (MRSA) [60]. Clinical studies are 14(4A) 1992

Pharmaceutisch Weekblad Scientific edition

needed to determine the role of cefpirome in treating MRSA infections. Its activity against Ps. aeruginosa is two times less t h a n t h a t of ceftazidime and it has no useful activity against Xanthomonas maltophilia. Cefpirome is active against other Pseudomonas species, but usually less so t h a n ceftazidime [40]. It has a high betalactamase stability, but shows a high degree of cross-resistance with ceftazidime and cefotaxime. Pharmacokinetics. Cefpirome has a relatively high volume of distribution and penetrates well into blister fluid [50]. 2 To 12 h after administration of a single intravenous dose of 2,000 mg to patients with inflamed meninges, cerebrospinal fluid drug levels have been shown to range between 2.2 and 4.1 mg/1 [61]. The AUC of cefpirome is about two times as high as t h a t of meropenem but lower t h a n t h a t of cefodizime. Clinical studies. Only a few published clinical studies are available. Cefpirome, 1,000 mg ql2h, was shown to be as effective as ceftazidime, 1,000 g q12h, in 469 patients with upper and complicated urinary tract infections. Cure or improvement was observed in 97% of patients in both groups [62]. In a dose of 2,000 mg q12h, the drug was found to be as effective as ceftazidime, 2,000 mg q8h, in patients with nosocomial pneumonia. In this study, the clinical cure rate was 83% and the bacteriological cure rate was 84% [63]. Cefpirome was reported to be as effective as ceftazidime in an open multicentre study of 598 patients with severe lower respiratory tract infections. Tolerance of both drugs was also similar. Side-effects were observed in 19% of the cefpirome-treated patients and in 16% of ceftazidime-treated patients [64]. Cefpirome caused a disturbance of serum creatinine determinations when the Jaffe method was used [65]. No large-scale data on cefpirome tolerance are available. Skin reactions and gastrointestinal side-effects appear to be the most frequently observed adverse reactions. Several authors have described a disturbed taste sensation, a sideeffect t h a t is rarely reported with other cephalosporins [50].

Cefepime Bacteriology. Cefepime has shown excellent in vitro activity against both Gram-positive and Gram-negative bacteria. It is about 4 times as active as ceftazidime against Gram-negative bacteria. The frequency of in vitro development of resistant m u t a n t s of Ps. aeruginosa was much (10 3 to 10 4) lower with cefepime t h a n with ceftazidime. Mutants that were resistant to ceftazidime were usually still susceptible to cefepime [67]. Cefepime has shown good in vitro activity against derepressed class I beta-lactamaseproducing bacteria, such as E. cloacae, C. freundii, M. morganii and Ps. aeruginosa. All of these organisms were resistant to ceftazidime and ceftizoxime [68]. Cefepime has shown a limited degree of synergy with aztreonam, ciprofloxacin and tobramycin against Ps. aeruginosa and Ps. cepacia [69]. Pharmacokinetics. The volume of distribution 233

of cefepime is lower t h a n that of cefpirome teria, such as B. fragilis, peptostreptococci and (21.3 1). Penetration into b l i s t e r fluid is also Clostridium spp. Meropenem still has considerable activity lower t h a n t h a t of cefpirome. The elimination half-life and the AUC of both compounds are against beta-lactamase (e.g., TEM.3, TX-1, CAZcomparable. The pharmacokinetics are linear in 2) producing bacteria such as K. pneumoniae or the dose range 62.5 mg to 2,000 mg and have E. coli, which are resistant to cefotaxime and cefbeen shown to be similar with a single dose or tazidime [76 77]. It induces class 1 chromosomal beta-lactamases below the MIC, but is very with multiple dosing [51]. Renal excretion is the most important elimin- stable against these enzymes. Cephalosporins ation route for cefepime, accounting for over 80% are weaker inducers of these enzymes but are of its total clearance. The renal clearance of cefe- vulnerable to their action. Meropenem (and imipime is very similar to the creatinine clearance, penem) are active against 'stable derepressed' suggesting only negligible tubular secretion [51]. strains, which continuously produce class 1 The half-life in haemodialysis patients is 13.5 h beta-lactamases [78]. Meropenem has some activity (MIC90, 2 mg/1) during the off-dialysis period and 2.3 h during dialysis [70]. The residual clearance in CAPD against MRSA, but this is 8 to 16 times less t h a n patients was 14.7 ml/min while CAPD clearance its activity against methicillin-sensitive strains averaged 4.1 ml/min. A relatively high propor- [42 43]. Imipenem is usually more active t h a n tion, 26.2%, of an intravenous dose is excreted in meropenem against MRSA. Meropenem and imithe dialysate. Peak diatysate levels were 50 mg/1 penem both have an in vitro postantibiotic effect and were still 13 mg/148 h after a 2,000 mg intra- ranging from 0.8 to 2 h against Ps. aeruginosa venous dose. Half-life was 18.2 h. Because of and Staph. aureus [79]. Pharmacokinetics. After 30 min intravenous these high levels and the drug's broad spectrum, cefepime appears to be an attractive option for infusions of 250, 500 and 1,000 mg meropenem, the t r e a t m e n t of peritonitis in patients on CAPD. peak serum levels of 12.1, 25.6, and Clinical studies. Cefepime, 1,000 to 2,000 mg 55.4 mg/1, respectively, were reached [48]. The ql2h, has been compared with ceftazidime, 1,000 drug's volume of distribution of about 20 1 is to 2,000 mg q8h, in a n u m b e r of nonblinded ran- higher t h a n that of imipenem (17 1). The pendomized studies in patients with skin and soft etration of meropenem (111%) into an inflammatissue infections, respiratory tract infections and tory exudate has been shown to be better t h a n urinary tract infections. Cefepime and ceftazi- t h a t of imipenem (73%) [52]. Renal excretion is the most important route of dime both yielded similar clinical results [71]. Failures were observed in infections caused by elimination for meropenem. Approximately 70% Staphylococcus aureus and enterococci. In an of an intravenous dose is excreted unchanged in open study of intensive care patients with respir- the urine. Active tubular secretion contributes to atory tract infections, cefepime, 2,000 mg q12h, renal excretion and the AUC of 1,000 mg meroperformed better t h a n ceftazidime, 2,000 mg penem increased from 62 to 95 mg.h/1 after coq8h, with cure rates of 75% and 56%, respect- administration of probenecid. About 20% of the dose is excreted as the open beta-lactam metabively [72]. Cefepime is usually well-tolerated. An intra- olite [48]. In contrast to imipenem, no significant renal muscular injection of 500 mg cefepime has been reported to be less painful t h a n a 500 mg dose of metabolism by dehydropeptidase-1 occurs, alceftriaxone [73]. In a Japanese study involving though some renal metabolism has been found in 308 patients, the incidence of side-effects was subjects with known renal metabolism of imipenem [80]. 2.8% [74]. The elimination half-life of meropenem is relatively short, about 1.1 h, in healthy volunteers. Meropenem Clinical studies. In experimental animal Bacteriology. Meropenem (SM 7338, ICI 194660) is a new parenteral carbapenem anti- studies, meropenem has been found to have a low biotic with a very wide spectrum of antibacterial tendency to induce convulsions, as compared activity. Its in vitro activity against Gram- with imipenem. The nephrotoxic potential of menegative bacteria is 4 to 32 times better t h a n ropenem in rabbits is lower t h a n t h a t of imipet h a t of imipenem and it is at least as active as nero, but higher t h a n t h a t of cefotaxime or ceftasuch new cephalosporin derivatives as cefpirome zidime. Clinical experience with meropenem is still very limited. and cefepime. Meropenem is 4 times as active as imipenem and ceftazidime against Ps. aeruginosa and other Piperacillin-tazobactam Bacteriology. The in vitro activity of an 8:1 comPseudomonas species, such as Ps. putida, Ps. cepacia and Ps. stutzeri [42 75]. Its activity against bination of piperacillin with the beta-lactamase most Gram-negative bacteria is similar to that of inhibitor tazobactam against Gram-negative ciprofloxacin but is much more active against bacteria is 4 to 16 times better t h a n t h a t of Gram-positive bacteria. The activity of merope- piperacillin alone and also 2 to 4 times better nem against Gram-positive bacteria is usually si- t h a n that of ticarcillin-clavulanic acid [81]. In milar to that of imipenem and it is much more contrast to clavulanic acid, the beta-lactamase active t h a n third-generation cephalosporins inhibitor tazobactam is a poor inducer of these enzymes [82]. The development of in vitro against staphylococci and enterococci. Unlike fluoroquinolones and cephalosporins, resistance by mutation is significantly reduced meropenem is very active against anaerobic bac- by the addition of tazobactam. Tazobactam itself 234


14(4A) 1992

has little or no antibacterial activity. Pharmacokinetics. The pharmacokinetic para m e t e r s of the combination of piperacillin and t a z o b a c t a m are shown in Table 4. The addition of piperacillin increases the AUC of t a z o b a c t a m (250 rag) from 10.2 to 15.3 mg.h/1, and reduces the renal clearance 279 to 164 ml/min. The pharmacokinetics of piperacillin are not m a r k e d l y affected by the addition of tazobactam. No significant increase in AUC or decrease in clearance has been found [84].

Place of new injectable beta-lactams in clinical practice The antibacterial spectrum of cefodizime offers no a d v a n t a g e over currently available cephalosporins. Its i m m u n o m o d u l a t i n g effects are very interesting, but no clinical d a t a are available as yet to prove t h a t these properties result in higher cure rates, especially in i m m u n o c o m p r o m i s e d patient. Cefpirome and cefepime h a v e improved activity against staphylococci, in comparison with ceftazidime. F u t u r e comparative trials will be necessary to determine w h e t h e r these drugs offer clinical a d v a n t a g e s over ceftazidime. The better stability of these drugs against stable derepressed class I b e t a 4 a c t a m a s e s is advantageous. M e r o p e n e m is more active t h a n ceftazidime and 8 to 16 times as active as i m i p e n e m against Gram-negative bacteria. It is very stable against class I beta-lactamases. The addition of a dehydropeptidase inhibitor such as cilastatin is not necessary, which is especially useful in patients with meningitis or renal failure. F u t u r e clinical

trials will be necessary to establish w h e t h e r meropenem offers clinical a d v a n t a g e s over imipen e m or ceftazidime. Piperacillin in combination with the betal a c t a m a s e inhibitor t a z o b a c t a m shows better in vitro activity t h a n ticarcillin/clavulanic acid. Its position in the t r e a t m e n t of serious infections rem a i n s to be defined.

Fluorinated quinolones A large n u m b e r of fluoroquinolones are now in various stages of development. Only those quinolones whose introduction seems likely within the next 5 y e a r s will be discussed here. It is not cert a i n t h a t all of these drugs will enter the Dutch pharmaceutical market. The most i m p o r t a n t bacteriological and pharmacokinetic properties of the fluoroquinolones are shown in Tables 5 and 6 [85-103]. Fleroxacin Bacteriology. Fleroxacin is usually 4 to 8 times less active t h a n ciprofloxacin against Gramnegative bacteria and Gram-positive bacteria. It is about as active as ciprofloxacin against Acinetobacter and more active against Mycoplasma spp. Its activity is reduced to a similar extent as t h a t of ciprofloxacin by a lowering of urine pH and by m e t a l ions, such as m a g n e s i u m [104]. Pharmacokinetics. Fleroxacin is completely absorbed after oral administration. The pharmacokinetics of the drug are linear in the dose r a n g e 400 to 1,200 m g and food does not affect its bioavailability. Fleroxacin p e n e t r a t e s well into skin blister fluid, prostate, and lung tissue, reaching

Table 5 Antibacterial activity of fluoroquinolones relative to ciprofloxacin *

E. coli Klebsiella spp. Citrobacter spp. Enterobacter Proteus spp. Providencia spp. Acinetobacter Ps. aeruginosa H. influenzae B. catarrhalis N. gonorrhoeae Salmonella spp. Serratia Shigella Yersinia spp. Staph. aureus meth-resistant meth-sensitive Staph. epidermidis S. pneumoniae S. agalactiae S. pyogenes S. faecalis

Fleroxacin

Lomefloxacin

Temafloxacin

Tosufloxacin

Sparfloxacin

DR 3355

0.25 0.25 0.25 0.25 0.25 1 0.5-1 0.12 0.25 0.25 0.5 0.25-0.5 0.25-0.5 0.12-0.25 0.12

0.25 0.25 0.12 0.25 0.25 1 0.5 0.06 0.5 0.25 1 0.25 0.25 0.25 0.25-0.5

0.5 0.25 0.25 0.25-0.5 0.12 0.25 2-4 0.25 0.5 1 0.5-1 0.12-0.25 0.12 0.5 0.25

0.5-1 0.25-1 0.25 0.5 1 0.5-1 4-8 0.5 1 2 1 0.5-1 1 1-2 0.5-1

1 1 0.5 1 0.25 0.5 4-16 0.25 1 1-2 1-2 0.5-1 0.25 1 1

0.5 0.5 0.5 1 0.5 1 2 0.25 1 0.5 0.5 0.25 1 0.25 1

1 0.5 0.25-0.5 0.12-0.25 0.12 0.12 0.25-0.5

0.5 0.5-1 0.5 0.12-0.25 0.12 0.12-0.25 0.12-0.25

4 4-8 14 2-4 1 1 0.5-1

8 8 4-8 4 4 4 2

8-16 4-8 2-8 2-8 1-4 1-2 2

8 4 2 0.5 1 1 1


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235

Table 6 Pharmacokinetic properties of new fluoroquinolones* Parameter

Ciprofloxacin Ofloxacin Fleroxacin Lomefloxacin Temafloxacin Tosufioxacin Sparfioxacin (500 mg) (200 mg) (400 mg) (400 mg) (400 mg) (150 mg) (200 mg)

Cmax(mg/1) tmax(h) F (%) AUC (mg. h/l) Vss(]/kg) CLtot(ml/min) CLn(ml/min) tl/2(h) Protein binding (%)

2-4 1-2 65-80 10 2-3 400-600 200-300 3-5 20-40

2-2.5 1-2 90 15-20 1.3-2 200-250 160-200 5-9 20

4-6 1-1.5 98 50-60 1.3 130 75 8-11 23

3-3.5 1-1.5 98 25-35 1.6-2.5 200-260 140-160 5.5-7.5 10

3.5-5.5 1.5-2.5 93 28-45 2 200-260 140-160 7-9 26

0.3-0.7 2-3

0.8-1.2 5-6

2-3

17-20

3.5-4.5 40

180-250/F 18-25/F 15-20 40


concentrations 1 to 3 times as g r e a t as the corresponding p l a s m a level. Less t h a n 3% of a dose is recovered in bile. Levels in urine after a 400 mg single dose are about 230 mg/1 and are still 5-10 mg/1 after 48-72 h [105]. Fleroxacin is partly metabolized to N-oxide, N-demethyl and glucuronide metabolites. The elimination half-life of fleroxacin is increased to about 40 h in patients with severe renal disease. The half-life is not m a r k e d l y infiuenced by liver cirrhosis. Drug interactions. Fleroxacin does not interact with theophylline and caffeine. Its absorption is only moderately reduced by antacids [106]. Clinical studies. Several studies h a v e been conducted comparing fleroxacin with other antimicrobial agents. Fleroxacin, 200 mg q24h for 7 days, and ciprofloxacin, 250 mg q12h for 7 days, were both d e m o n s t r a t e d to produce clinical and bacteriological cure in more t h a n 95% of 242 patients with uncomplicated u r i n a r y tract infections. The 7-day r e g i m e n was found to be more active t h a n a single dose of 400 mg. In complicated u r i n a r y t r a c t infections, cure rates after t r e a t m e n t with fleroxacin, 400 m g q24h for 7 days, were similar to those achieved with ofloxacin, 200 mg bid, norfloxacin, 400 m g bid, and ceftazidime, 500 to 2,000 m g qd. Eradication r a t e s were more t h a n 95% for all pathogens, except for Ps. aeruginosa (76%) and S. marcescens (85%). A single 400 mg dose was as effective as ceftriaxone, 250 mg, in the t r e a t m e n t of gonorrhoea, with both regimens achieving 90% cure rates. Fleroxacin, 600 m g q24h for 7 days, was as effective as doxycycline, 100 m g q12h, in chlamydial urethritis or cervicitis. In a dosage of 400 mg q24h, the drug was at least as effective (cure rate, 93%) as ceftazidime, 500 to 2,000 m g q8h (cure rate, 80%) in an open study in patients with lower respiratory t r a c t infections [data on file, Roche]. Overall cure r a t e s were similar with the intravenous and oral formulations. The incidence of side-effects with fleroxacin is dose-dependent; 21.6% of all patients treated with 400 mg, 43.8% of those t r e a t e d with 600 mg, and 69.2% of those receiving 800 m g experienced at least one side-effect. The incidence of sideeffects with fleroxacin is relatively high, and was 236

greater t h a n t h a t reported with norfloxacin in two comparative studies [data on file, Roche]. As with other quinolones, the most i m p o r t a n t adverse events are gastrointestinal (11.8%) and central nervous system side-effects (9.2%), followed by skin reactions (2.8%).

Lomefloxacin Bacteriology. Lomefloxacin has an antimicrobial activity t h a t is similar to t h a t of fleroxacin. It is less active t h a n ciprofloxacin against both Gram-positive and G r a m - n e g a t i v e bacteria. Pharmacokinetics. Lomefloxacin is rapidly and almost completely absorbed after oral administration. P e a k levels are reached after about 1.5 h when the drug is t a k e n in the fasting state and after about 2 h when the drug is t a k e n with food [107]. The bioavailability is reduced when the drug is administered with an antacid or sucralfate, but to a lesser extent t h a n is seen with ciprofloxacin. Like all other quinolones lomefloxacin is widely distributed and high tissue levels are reached in such organs as the lung and prostate [108 109]. Renal excretion is the most i m p o r t a n t route of elimination for lomefloxacin. The half-life of the drug increases to about 30 to 40 h in patients with renal failure. The AUC after a single 400 m g dose is 200 to 240 mg.h/1 in these patients. The residual clearance in anuric patients is about 30 ml/min, while nonrenal clearance in patients with intact renal function is much higher, about 60 ml/min [110 111]. Drug interactions. Lomefloxacin has not been shown to interact with theophylline. Clinical studies. Lomefloxacin has been compared with norfloxacin and ciprofloxacin in 7 comparative trials involving about 2,000 patients with complicated or uncomplicated urin a r y tract infections. In a dose of 400 m g q24h, lomefloxacine was as effective or more effective t h a n norfloxacin, 400 m g ql2h, and as effective as ciprofloxacin, 250 to 500 m g q12h [data on file, Searle]. In acute exacerbations of chronic bronchitis lomefloxacin, 400 m g qd, was at least as effective as amoxicillin, 500 mg q8h or cefaclor, 500 mg q8h. Lomefloxacin is usually well-tolerated. Among 3,200 patients participating in clinical trials, the


14(4A) 1992

most frequently observed side-effects were nausea (1.4%), photosensitivity (1.3%) and dizziness (1.3%) [data on file, Searle].

Temafloxacin Bacteriology. Temafloxacin is about 4 times less active t h a n ciprofloxacin against Gramnegative bacteria, but 4 times more active against Acinetobacter and staphylococci and Mycoplasma pneumoniae [89]. The pH dependency and inoculum effect of temafloxacin are similar to those of ciprofloxacin and ofloxacin. The frequency of spontaneous r e s i s t a n t Staph. aureus m u t a n t s is 10 to 100 times as low as t h a t seen with ciprofloxacin [112]. Pharmacokinetics. The pharmacokinetics of temafloxacin are independent of dose in the dose r a n g e 100 to 800 mg. The p e a k s e r u m level lies around 1 mg/1 with 100 mg bid dosing, and trough levels are around 0.5 mg/], with both levels increasing linearly at higher dosages [113]. Temafloxacin is metabolized in the liver to form desmethylene and desethylene products as well as several conjugates. Only small a m o u n t s of all metabolites are recovered in the urine and about two-thirds of a dose is excreted unchanged in the urine [114]. The elimination half- life oftemafloxacin is about 8 h in h e a l t h y volunteers. Clinical studies. Temafloxacin, 400 m g q24h for 3 days, was as effective and well-tolerated as ciprofloxacin, 250 m g q 12 h for 7 days, in uncomplicated u r i n a r y t r a c t infections [115]. In a dosage of 400 m g q12h for 10 to 14 days, it was as effective and well-tolerated as norfloxacin in the same dosage in complicated u r i n a r y t r a c t infections [116 117]. A single oral dose of 200 or 400 m g of temafloxacin was also as effective as a 250 m g i n t r a m u s c u l a r dose of ceftriaxone in patients with uncomplicated gonococcal urethritis or cervicitis [118]. In a dose of 400 m g bid for 7 days, temafloxacin was effective in nongonococcal urethritis or cervicitis [119]. Temafioxacin, 600 m g q12h, was as effective as ciprofloxacin or amoxicillin in community-acquired respiratory t r a c t infections [120 121]. In the s a m e dose the drug was also as effective as ciprofioxacin or cefadroxil, 500 m g q12h, in skin or skin structure infections [122-124]. In over 4,800 clinical trials participants, the most frequently r e p o r t e d adverse events following temafloxacin were n a u s e a (3.7%), diarrhoea (2.8%), dyspepsia (1.7%), dizziness (2.8%), headache (2.9%) and somnolence (1.8%). Only gastrointestinal side-effects were seen more frequently with temafloxacin t h a n with placebo. Gastrointestinal side-effects were seen more frequently at higher dosages (600 m g q12h) t h a n at low dosages (400 m g qd) [125]. Recently, however, temafloxacin was withd r a w n from the m a r k e t , because of the occurrence of serious side-effects, such as haemolytic anaemia.

Tosufloxacin Bacteriology. Tosufloxacin (A60969, A61827, T3262) is a trifluoronaphthyridine quinolone analogue with a wide spectrum of activity. It is as active or slightly less active t h a n ciprofloxacin

14(4A) 1992


against G r a m - n e g a t i v e bacteria, but 4 to 8 times more active against Acinetobacter spp. and Pseudomonas spp. other t h a n Ps. aeruginosa. The MIC90 for Ps. cepacia and X. maltophilia is about i rag/1 [126]. It is also 4 to 8 times more active t h a n ciprofloxacin against Gram-positive bacteria, anaerobes, Legionella spp. and C. trachomatis [94]. The MIC of tosufloxacin is affected to the same extent as other fluorquinolones by urine pH and m a g n e s i u m ions. Pharmacokinetics. Only J a p a n e s e studies with short English abstracts h a v e been published on the pharmacokinetics of tosufloxacin. After a single 150 m g dose p e a k s e r u m levels r a n g e between 0.3 and 0.7 mg/1, w h e n the drug is t a k e n in the fasting state. When tosufloxacin is t a k e n with food, p e a k s e r u m levels are about 50% higher. The AUC is also about 50% higher w h e n the drug t a k e n with food, as is the u r i n a r y recovery of u n c h a n g e d tosufloxacin. The half-life of tosufloxacin has been reported to be about 4 h, but in a crossover study, its half-life was as long as t h a t of ofloxacin and lomefloxacin [103]. Clinical studies. Again, only J a p a n e s e studies have been published. The available d a t a indicate t h a t tosufloxacin is well-tolerated, with a 4 to 8% incidence of side-effects, which is similar to t h a t of ofloxacin or norfloxacin [127 128]. Tosufloxacin, 150 mg q8h, was as effective as ofloxacin (dose not stated) in respiratory t r a c t infections and more effective t h a n norfloxacin (5 days of t r e a t m e n t ) in complicated u r i n a r y t r a c t infections. The drug was also as effective as ofloxacin in skin infections [129]. The development of tosufloxacin has been stopped because of its low solubility in urine.

Sparfloxacin Bacteriology. Sparfloxacin (AT 4140) has excellent in vitro activity against a wide r a n g e of bacteria. Its activity against Enterobacteriaceae is between 0.5 and I times t h a t of ciprofloxacin, but it is about 8 times more active against Acinetobacter and staphylococci and about 4 times more active against streptococci. It has interesting activity against Mycoplasma, Chlamydia and Mycobacteria, against which it is 8 to 16 times more active t h a n ciprofloxacin [85 86]. The MIC of sparfloxacin is higher at pH < 6 t h a n at n e u t r a l pH, as is the MIC of ciprofloxacin. Sparfloxacin shows a m a r k e d postantibiotic effect in vitro against E. coli and S. pneumoniae and a good postantibiotic effect against Staph. aureus [130]. In legionnaires' disease in animals, the activity of sparfloxacin has been shown to be superior to t h a t of e r y t h r o m y c i n [131]. Pharmacokinetics. Sparfioxacin is slowly absorbed after oral administration. P e a k s e r u m levels are 0.7 to 1.0 mg/1 after 200 mg and 2.0 to 2.5 mg/1 after 800 m g [132]. Food does not affect the r a t e or extent of oral absorption of sparfloxacin. However, co-administration of the drug with an antacid reduces bioavailability by about 50% [133]. Only about 10% of the drug is excreted unchanged in the urine, and about 20% is excreted in the urine as conjugated sparfloxacin [132]. The 15-h to 20-h half-life of sparfloxacin is 237

longer t h a n t h a t of pefloxacin and fleroxacin against B. catarrhalis and N. gonorrhoeae [141]. The MIC of azithromycin decreases significantly [132]. Sparfloxacin penetrates well into lung tissue; in the presence of h u m a n serum. Azithromycin is the concentration in bronchial mucosa is 2 to a very interesting macrolide in t h a t it is the first 3 times higher t h a n in serum and concentrations to show significant activity (MIC about 4 mg/1) 10 to 15 times the serum level are attained in against E. coli, Salmonella and Shigella [142 epithelial lining fluid. Very high levels, up to 143]. It is 4 times more active t h a n erythromycin 70 mg/1, are reached in the alveolar macrophages against Borretia burgdorferi, but its in vivo activity in experimental Lyme disease is 70 times [134]. Drug interactions. Sparfioxacin has shown no greater [144]. It is as active as erythromycin and more active t h a n clarithromycin against Mycosignificant interaction with theophylline [138]. Clinical studies. Only a very limited n u m b e r of plasma pneumoniae. Experimental infections. A l t h o u g h ciprofloxclinical studies have been presented thus far. Sparfloxacin, in a single 100 mg or 200 mg dose, acin was 100 times more active in vitro against was effective in 33 of 37 patients (89%) and 28 of Salmonella, azithromycin, 5 mg/kg, produced a 29 (96%) of patients treated for uncomplicated greater reduction in colony forming units t h a n ciprofloxacin, 100 mg/kg, in experimental infeccystitis [135]. The efficacy of sparfloxacin, 300 mg qd, in com- tions. Azithromycin was also much more active plicated u r i n a r y tract infections was similar to t h a n amoxicillin or chloramphenicol [145]. The t h a t of enoxacin, 200 mg q8h, with cure rates drug was also highly active in experimental achieved in 80% of 123 patients receiving spar- syphilis in rabbits and at least as effective (at one floxacin and in 76% of 123 patients receiving sixteenth the dose) as erythromycin in experenoxacin. The 4.8% incidence of adverse reaction imental legionnaires' disease [146]. Pharmacokinetics. The pharmacokinetics of was similar in both groups [136]. Sparfloxacin, 150 mg qd, was effective in all 18 azithromycin are complex. After a single 500 mg patients treated for gonococcal urethritis treated dose low serum levels of about 0.4 rag/1 are atfor 3 days and in all 18 patients with nongonococ- tained and these increase only to a limited extent with multiple dosing. Bioavailability is about cal urethritis treated for 7 days [137]. 37%. The serum protein binding of azithromycin is 50% at 0.02 mg/1 and is reduced to 7% at I mg/1 DR 3355 DR 3355 is the S-(-)-isomer of ofloxacin, which [147]. The estimated elimination half-life is deis the active component of the racemic mixture. pendent on the period of sample collection and is It is usually about twice as active as ofloxacin about 9.6 h. In blister fluid a much longer halfagainst Gram-positive and Gram-negative bacte- life is observed and levels remained constant duria and its pharmacokinetics are similar to those ring a 24-h study period. The tissue levels are very high relative to the serum concentrations. of ofloxacin [139 140]. F u t u r e clinical trials will be necessary to de- After two 250 mg doses 12 hours apart, the peak monstrate whether the incidence of side-effects of levels of azithromycin in tonsillar, gynaecological, and lung tissue ranged between 3 and DR 3355 is lower t h a n that of ofloxacin. 8 mg/kg with extremely long half-lives of Place of new fluoroquinolones in clinical practice 2.3 days in prostate tissue and 3.2 days in tonsilFleroxacin and lomefloxacin, like ofloxacin, of- lar tissue [147]. Azithromycin is concentrated to a much higher fer the advantage of once-daily administration and absence of an interaction with theophylline. degree t h a n erythromycin in h u m a n fibroblasts More comparative studies are needed to assess or polymorphonuclear leukocytes and is very the relative incidence of side-effects with these slowly released from these cells [148]. The volume of distribution of azithromycin is very high, drugs. Both tosufloxacin and temafloxacin have been about 2.3 1/kg. Only 6.1% of on oral dose is excrewithdrawn due to side-effects. Sparfloxacin is ted unchanged in the urine between 0 and 14 still in an early phase of development. The agent days after a single dose [149]. In experimental possesses good activity against m a n y Gram- studies no effects of azithromycin could be depositive and Gram-negative bacteria. The monstrated on hepatic cytochrome PU 50 in the rat [150]. Antacids and cimetidine did not influclinical results are awaited with interest. ence the AUC of azithromycin in healthy volunteers [151]. Azalide macrolides Clinical studies. Azithromycin, 500 mg on day 1 followed by 250 rag/day on days 2 to 5, was as Azithromycin Azithromycin lacks the C9 ketone group of effective as erythromycin stearate, 2,000 mg/ erythromycin and represents the first member of day, in skin and soft tissue infections, but significantly better tolerated [152]. Cure rates were a new class of azalide macrolides. Bacteriology. The spectrum of activity is dif- also similar to those achieved with longer ferent from t h a t of the other macrolides, such as courses of doxycycline (200 rag/day for 14 days) erythromycin, clarithromycin and roxithromy- and cephalexine (500 mg q l 2 h for 10 days) [153]. A single 1,000 mg dose of azithromycin was sigcin. It is 2 to 4 times less active t h a n erythromycin against staphylococci and streptococci, but nificantly more effective (95% cure rate) t h a n cimore active against Gram-negative bacteria. It is profloxacin, 500 mg q l 2 h for 7 days (61% cure 16 times more active t h a n erythromycin against rate), in chlamydial urethritis or cervicitis [154] H. influenzae and 4 to 8 times more active and was at least as effective as doxycycline, 238


14(4A) 1992

200 mg/day for 7 days [155]. Azithromycin also performed well in respiratory tract infections in both children and adults. In a dose of 10 mg/kg on the first day, followed by 5 mg/kg on days 2 to 5, it was more effective t h a n amoxicillin/clavulanic acid in children with otitis media and at least as effective as amoxicillin in lower respiratory t r a c t infections [156]. Azithromycin, 500 m g on day 1 followed by 250 m g on days 2 to 5, was as effective as erythromycin, 500 m g q6h for 10 days, but m u c h better tolerated. Side-effects were observed in 1.6% of patients receiving azithromycin but in 13.6% of erythromycint r e a t e d patients.

Lipopeptide antibiotics Daptomycin (LY 146032) Bacteriology. Daptomycin is a new lipopeptide antibiotic, which has useful activity against both aerobic and anaerobic Gram-positive bacteria. It is 2 to 4 times more active t h a n vancomycin against staphylococci, and has similar activity against methicillin-resistant or methicillinsensitive Staph. aureus or Staph. epidermidis. The MIC90 against staphylococci is 0.5 to I mg/1. Daptomycin is 2 to 4 times less active t h a n vancomycin against streptococci, with an MIC90 of I to 4 mg/1. Its activity against Listeria monocytogenes and Corynebacterium group is similar to t h a t of vancomycin [157 158]. The m e c h a n i s m of bactericidal action of daptomycin is not yet fully understood. It interferes with the bacterial synthesis of lipids, inhibiting the synthesis of lipoteichoic acid by more t h a n 90%. Daptomycin does not enter the cytoplasm, but it is capable of binding to cell walls and memb r a n e s [159]. In e x p e r i m e n t a l studies daptomycin was more effective t h a n vancomycin in staphylococcal infections [160]. It showed superior bactericidal activity against enterococci in comparison with vancomycin [161]. Daptomycin, unlike vancomycin, reduced tobramycin-induced nephrotoxicity in an e x p e r i m e n t a l study in r a t s [162]. Pharmacokinetics. Only very limited published d a t a on the p h a r m a c o k i n e t i c s of daptomycin are available. In a patient with positive H I V serology, the following p h a r m a c o k i n e t i c p a r a m e t e r s were found after 30-min intravenous infusion of 150 m g q24h for 5 days. The AUC from zero to infinity was 198 mg-h/1 after the first dose and 206 m g . h/1 after the final dose. The p e a k level after the first dose was 22.7 mg/1 and the trough level 24 h after the last dose was 1.5 mg/1. Total clearance was 14.2 ml/min and renal clearance was 11.1 ml/min. The elimination half-life was 9.1 h after the first dose and 7.2 after the final dose. The protein binding of daptomycin was 80 to 95% [163]. Garisson et al. [164] h a v e shown t h a t the protein binding of daptomycin results in a low r a t e of killing of staphylococci. This phenom e n o n m a y be responsible for the failures of daptomycin, 2 m g . k g 1.d-1, in initial clinical studies. H i g h e r dosages are probably needed in severe staphyloccal infections. The development of daptomycin has (temporarily?) been stopped. 14(4A) 1992


Pristinamycin derivatives RP 59500 RP 59500 consists of a 30:70 m i x t u r e of a quinuclidinyl/thiomethylpristinamycin I A derivative and a diethylaminoethylsulfonyl-pristinamycin II A derivative. The chemical modification of the two original p r i s t i n a m y c i n constituents has m a r k e d l y improved the w a t e r solubility of the complex without affecting their antimicrobial activity [165]. Both compounds are m a r k e d l y synergistic against Gram-positive bacteria [166]. The two compounds both act in a different way on bacterial protein synthesis. They contract the channel t h r o u g h which proteins in formation are extruded [167]. The combination is bactericidal. The spectrum of activity of RP 59500 consists of Gram-positive bacteria such as staphylococci and streptococci, as well as Neisseria spp., B. catarrhalis, H. influenzae and Legionella spp. [168]. The drug is equally active against methicillin-resistant and methici]lin-sensitive Staph. aureus and equally active against erythromycin-resistant and erythromycin-sensitive strains [168]. It is as active as vancomycin and e r y t h r o m y c i n against streptococci and staphylococci, but shows little or no activity against vancomycin-resistant strains of staphylococci. In contrast to erythromycin, RP 59500 is about as active against Neisseria spp., B. catarrhalis, H. influenzae and enterococci. If the good in vitro activity of RP 59500 is confirmed in future clinical trials and if the drug's tolerance is acceptable, it m a y become an alternative to glycopeptides in the t r e a t m e n t of infections caused by methicillin-resistant staphylococci.

Conclusion A n u m b e r of new antimicrobial agents are now under development. Most belong to existing groups of antimicrobial agents, but offer the adv a n t a g e s of improved activity or pharmacokinetics. However, it has not yet been proven t h a t any of these new agents have major clinical adv a n t a g e s over existing drugs.

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P h a r m a c e u t i s c h W e e k b l a d Scientific e d i t i o n

14(4A) 1992

Antimicrobial Stewardship with Intravenous to Oral Conversion and Future Directions of Antimicrobial Stewardship.

Future directions in urological oncology.

Future directions in cancer rehabilitation.

Future directions in nutrition research.

Future directions in lung transplant.

Future directions in facial rejuvenation.

Summary and Future Directions.

Conclusions and future directions.

Future directions for NICE.

Future directions for face transplantation.

Future directions for flow cytometry.

Future directions and research needs.

Future directions for bronchoalveolar lavage.

Cytokines as mediators of chemotherapy-associated cognitive changes: current evidence, limitations and directions for future research.

High-dose chemotherapy for resistant germ cell tumors: recent advances and future directions.

Future Directions in Minimally Invasive Intervention.

Future directions in EUS-guided tissue acquisition.

Future research directions in cancer ecogenetics.

Future directions in the treatment of gastroparesis.

Future directions in cutaneous laser surgery.

Future directions in the treatment of osteosarcoma.

Biomarkers in Pediatric ARDS: Future Directions.

Future directions in esophageal cancer therapy.

Future directions in inflammatory bowel disease management.