Roxithromycin: review of its antimicrobial activity

Journal of Antimicrobial Chemotherapy (1998) 41, Suppl. B, 1–21

Introduction

Roxithromycin is a semi-synthetic 14-membered ringmacrolide antibiotic in which the erythronolide A lactonering has been modified to prevent inactivation by gastricacid.1 Roxithromycin differs from erythromycin A by thereplacement of the 9-keto group by an etheroxime sidechain (Figure).2

Factors influencing in-vitro activity

It is common practice to determine the influence of anumber of factors, such as culture medium, bacterialinoculum size, pH, carbon dioxide atmosphere and theaddition of serum, on the in-vitro activity of an antibiotic.In general, the in-vitro activity of roxithromycin isdiminished in the presence of human serum,3–10 butunaffected by the addition of 10% horse serum.5 However,an increase in inoculum size from 0.5–1 3 106 to 0.5–1 3 108

cfu/mL causes a doubling of the MICs of roxithromycin,erythromycin A, azithromycin and other macrolides.3,5,6

Felmingham et al.11 found that a carbon dioxideconcentration of 10% affected the in-vitro activity oferythromycin A and roxithromycin against anaerobes

(Bacteroides fragilis group, Prevotella melaninogenica,Prevotella bivia and Fusobacterium spp.), and the effectwas particularly marked against the B. fragilis group andF u s o b a c t e r i u m spp. Siebor & Kazmierczak5 also found that10% carbon dioxide reduced the potency of roxithromycinagainst aerobic bacteria and that the MICs of roxi-thromycin were doubled. Macrolide antibiotics are lessactive at low pH and Rosenblatt and Schoenknecht12

observed that incubation in the presence of 5% carbondioxide caused a fall in pH of 0.5–0.8 units. MICs ofroxithromycin were increased eight-fold at acid pHcompared with pH 7.0, and were halved at pH 8.0.3,5 Othermacrolides are affected in a similar way.

Spangler et al.13 tested the in-vitro activity of roxithro-mycin against anaerobic bacteria using the Oxyrase agardilution method (Oxyrase Inc., Mansfield, OH), whichprovides an anaerobic environment in the absence ofcarbon dioxide. The overall roxithromycin MIC50 andMIC90 were 0.5 mg/L and 16 mg/L, respectively, but roseto 2.0 and 64 mg/L, respectively, under standard anaerobicconditions in the presence of carbon dioxide. At a break-point of 8 mg/L,14 85% of the isolates were susceptible bythe Oxyrase method, compared with only 68% with thechamber method.

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Roxithromycin: review of its antimicrobial activity

A. Bryskier*

Hoechst Marion Roussel, Direction des Recherches Anti-Infectieux, Pharmacologie Clinique, 102 route de Noisy, 93235 Romainville, Cedex, France

Roxithromycin is a semi-synthetic 14-membered-ring macrolide antibiotic in which theerythronolide A lactone ring has been altered to prevent inactivation in the gastric milieu. Thein-vitro activity of roxithromycin is well documented and similar to that of other macrolideantibiotics. Roxithromycin is active against Gram-positive and Gram-negative cocci, Gram-positive bacilli and some Gram-negative bacilli, but has no significant effect on the pre-dominant faecal flora. It also displays good activity against atypical pathogens, such asMycobacterium avium complex, Helicobacter pylori and Borrelia spp. It penetrates andaccumulates within cells, such as macrophages and polymorphonuclear neutrophils (PMNs),where it is distributed between the cytosol and cellular granules. Once inside the cells, it isactive against intracellular pathogens, such as Legionella, Chlamydia, Mycobacterium,Rickettsia and Borrelia spp. Like other macrolides, roxithromycin displays a significant post-antibiotic effect which is dependent on the pathogens under study, the concentration ofroxithromycin and the duration of exposure. In vivo, roxithromycin is as effective or moreeffective than other macrolides in a wide range of infections.

*Tel: +33-149915121; Fax: +33-149915020.

© 1998 The British Society for Antimicrobial Chemotherapy

JAC

A. Bryskier

Determination of in-vitro susceptibility criteria

For Gram-positive species, interpretative criteria havebeen adopted in France (Comité Français de l’Antibio-gramme), Sweden and proposed in Germany and theUSA, though no definitive breakpoints have beenregistered (references 15 and 16; H. Grimm, data on file,Roussel Uclaf). In a French multicentre study,15 373clinical isolates of 12 species were tested for MIC andinhibition zones using a 15 mg roxithromycin disc (Oxoid,Basingstoke, UK). The roxithromycin breakpoint was 1–4 mg/L, corresponding to: susceptible, >22 mm (MIC < 1 mg/L); intermediate susceptibility, 17–21 mm (MIC2–4 mg/L); and resistant, ,17 mm (MIC . 4 mg/L).Olsson-Liljequist and the Swedish Subcommittee on Standardization of Methodology16 proposed breakpointsof <1 mg/L and >8 mg/L. The breakpoints recorded byzone diameters for different bacterial species were:staphylococci, >25 mm and <19 mm; enterococci, >25 mmand <12 mm; group A, B, and G streptococci, >20 mm and <15 mm, Streptococcus pneumoniae, >20 mm and<15 mm; Haemophilus influenzae, >25 mm and <10 mm;Moraxella catarrhalis, >25 mm and <20 mm. Jones et al.14

proposed interpretative criteria using NCCLS referencemethods.17,18 For Gram-positive cocci, they proposed roxi-thromycin breakpoints of 1–8 mg/L, corresponding to zonediameters of: >21 mm (susceptible), 10–20 mm (inter-mediate susceptibility) and <9 mm (resistant). Erwin &Jones19 proposed NCCLS susceptibility breakpoint recom-mendations for roxithromycin against H. influenzae of>16 mg/L (disc test correlate of >10 mm).

The in-vitro activity of roxithromycin against H. in -fluenzae closely resembles that of erythromycin A and

clarithromycin (MIC50 5 4–8 mg/L).6,20–22 According toJones,22 the zone diameter around a 15 mg disc indicatingroxithromycin susceptibility should be .10 mm in thepresence of carbon dioxide and HTM agar, though criteriafor resistance were not proposed.23 Cooper et al.24

suggest that current MICs and disc zone susceptibilitybreakpoints of <1 mg/L and >22 mm underestimate the clinical efficacy of roxithromycin against H. influenzaeand a zone diameter susceptibility breakpoint of .10 mm is predictive of a successful outcome in 78% ofcases.

Etest

The Etest method for determination of activity ofmacrolides against anaerobes was assessed by Spangler e ta l .2 5 Agar dilution and Etest MICs corresponded, to withinone dilution, in .99% of cases. Only 84–91% of Etest MICswere within one dilution of agar MICs for roxithromycinand other macrolides tested. In most cases, Etest MICswere lower than those observed by agar dilution.

In-vitro activity against common pathogens

The in-vitro activity of roxithromycin is well documented.In general, studies of more than ten isolates and usingbroth or agar dilution methods with bacterial inocula of104–106 cfu/mL are considered in this review. The naturalantibacterial spectrum of roxithromycin is essentially the same as that of other macrolides and covers Gram-positive cocci, Gram-negative cocci, Gram-positive bacilliand some Gram-negative bacilli.21,26–30 Numerous studieshave been conducted to determine the in-vitro activity ofroxithromycin against common pathogens.6,7,14,31–35

Gram-positive cocci

Staphylococcus spp. The in-vitro activity of roxithromycinagainst penicillin-susceptible and methicillin-susceptibleStaphylococcus aureus is similar to that of erythromycin Aand clarithromycin. Studies indicate that MICs range from0.01 to 4 mg/L, except when multiple resistance, includingresistance to methicillin, is a problem.6,7,36,37 At 2 mg/L,roxithromycin inhibited 100% of S. aureus clinical isolatessusceptible to benzylpenicillin and oxacillin.6,38,39 Erythro-mycin A-resistant isolates were not susceptible toroxithromycin, clarithromycin or azithromycin.21,40,41

The activity of roxithromycin against coagulase-negativestaphylococci in vitro is variable. Fleurette et al.42

determined the in-vitro activity of five macrolides against100 clinical isolates of coagulase-negative staphylococci.The MIC50 and MIC90 of roxithromycin were <0.006 mg/Land .128 mg/L, respectively. However, Rolston et al.38,43,44

found that roxithromycin, erythromycin A, clarithromycinand dirithromycin have little activity against Staphylo -

2

Figure. The structure of roxithromycin.


coccus epidermidis. Erythromycin-susceptible isolates arealso susceptible to roxithromycin but erythromycin-resistant isolates are not susceptible to other macrolides.Staphylococcus haemolyticus and Staphylococcus hominisare not susceptible to macrolides (MIC . 64 mg/L).Controversial results have been published byBauernfeind,37 who tested the in-vitro activity of roxithro-mycin and other macrolides against various coagulase-negative species. MIC50s ranged from 0.25 to 1 mg/L for S.haemolyticus, S. hominis, Staphylococcus cohnii, Staphylo -coccus simulans, Staphylococcus saprophyticus, Staphylo -coccus warneri, Staphylococcus hyicus, Staphylococcusauricularis, Staphylococcus xylosus and Staphylococcuscapitis. Guggenbichler et al.45 investigated the in-vitroactivity of roxithromycin and clarithromycin againsterythromycin A-resistant clinical isolates of staphylococci.At an MIC of 2 mg/L, 25% of the erythromycin A-resistantstrains were inhibited by clarithromycin and 11.6% byroxithromycin. Of 75 coagulase-negative staphylococciresistant to erythromycin A, 10.7% were inhibited byclarithromycin and 9.3% by roxithromycin at an MIC of 2 mg/L. Cross-resistance patterns differed between strainswith low-level (MIC > 4 mg/L) and high-level resistance(MIC > 256 mg/L) to erythromycin A.

Streptococcus spp. Several studies have shown that strepto-cocci are generally susceptible to macrolides.6,7,34,37,46–48

Roxithromycin displays similar in-vitro activity to erythro-mycin A and clarithromycin against Streptococcus pyo -genes, Streptococcus agalactiae, S. pneumoniae, Lancefieldgroup C, G and viridans group streptococci, with MIC50sand MIC90s of 0.1–1 mg/L.38,43,44 Le Noc et al.34 comparedthe older macrolides (erythromycin A, oleandomycin,josamycin and spiramycin) and found they all had bimodalactivity against S. pneumoniae. Roxithromycin was moreactive than josamycin and spiramycin.

When tested against clinical isolates of S. pneumoniaeresistant to penicillin G, the MIC50 and MIC90 ofroxithromycin were 0.25 mg/L and 4 mg/L, respectively.37

Knothe & Hauke49 recorded that only 1.5% of 710 S.pneumoniae isolates were resistant to roxithromycin (MIC> 8 mg/L) in Germany. The MIC50 and MIC90 were 0.125and 0.25 mg/L, respectively. R. N. Jones and M. E. Erwin(data on file, Roussel Uclaf) proposed the use of S.pneumoniae ATCC 49919 as a quality control whenmeasuring MICs of roxithromycin. MICs ranged from 0.06to 0.25 mg/L and a slight change in these values (onedilution increase) was detected in the presence of carbondioxide. The bactericidal activity of roxithromycin wasevaluated against S. pneumoniae clinical isolates using amodel simulating serum pharmacokinetic parameters.50

Roxithromycin reduced numbers of bacteria of 12 strainsby 99% in 2.61 6 1.35 h and of 11 strains by 99.9% in 3.246 1.44 h. No regrowth was seen.

Romeo et al.51 tested the in-vitro activity of roxi-thromycin, erythromycin A, josamycin and miokamycin

against the viridans group of streptococci (Streptococcusmutans, Streptococcus mitis, Streptococcus salivarius,Streptococcus milleri and Streptococcus sanguis). Roxi-thromycin and erythromycin A displayed the highestactivity (MIC50 ' 0.12 mg/L, MIC90 ' 1 mg/L) and few strains were highly resistant (MIC > 32 mg/L). Loza et al.52 demonstrated that roxithromycin was less activeagainst S. mitis RYC 49593, which has an effluxmechanism of resistance to the macrolides, than otherstrains.

Enterococcus spp. Numerous comparative studies againstenterococci have been carried out.6,8,34,35,36,43,44,47,53,54 LeNoc et al.34 compared the bacteriostatic and bactericidalactivity of roxithromycin with that of older macrolidesagainst erythromycin A-susceptible (MIC < 2 mg/L) andresistant Enterococcus faecalis. None of the macrolidesshowed significant bactericidal activity against thispathogen. Chin et al.47 compared the in-vitro activity ofroxithromycin and clarithromycin against erythromycinA-susceptible strains. MIC50s were 1 mg/L and 0.5 mg/Lfor roxithromycin and clarithromycin, respectively. Theroxithromycin and clarithromycin MICs for all erythro-mycin A-resistant strains were .32 mg/L.

Dette et al.8 found only moderate in-vitro activity ofmacrolides against Enterococcus faecium. The modal MICof roxithromycin was 6.15 mg/L. These results wereconfirmed by Tsuboi et al.54 The MIC50 and MIC90 ofroxithromycin against E. faecium were 6.25 and .100mg/L, respectively. Other studies confirmed that roxi-thromycin and erythromycin A were not active against E.faecium, Enterococcus raffinosus or Enterococcus casseli -flavus (MIC . 100 mg/L).53,55

Rolston et al.44 compared the in-vitro activity ofroxithromycin, clarithromycin, erythromycin A and diri-thromycin against E. faecalis. MIC90s of all the macrolideswere .64 mg/L. MIC50s were 4 mg/L for all the macrolidesexcept clarithromycin, which had an MIC50 of 8 mg/L. Themacrolides were poorly active against Enterococcusliquefaciens (MIC50 5 8 mg/L; MIC90 . 64 mg/L), and hadbimodal activity against Enterococcus avium (MIC50 50.25 mg/L; MIC90 5 128 mg/L).36 Roxithromycin showsgood activity against Enterococcus gallinarum (MIC50 51 mg/L; MIC90 5 2 mg/L) (Table I).55

Gram-positive bacilli

The antibacterial spectrum of roxithromycin covers mostCorynebacterium spp., Listeria monocytogenes andBacillus, Leuconostoc, Pediococcus and Lactobacillus spp.Corynebacterium jeikeium and Nocardia asteroides areexcluded since their MICs are .16 mg/L.34,37,38,39,43,44,55

The antibacterial activity of roxithromycin against L.monocytogenes is broadly similar to that of erythromycinA and azithromycin but less than that of clarithromycin,with most isolates being inhibited at concentrations of

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A. Bryskier

0.25–2 mg/L.21,32,34,38,43,44,47,55 One study showed that theMIC50 and MIC90 of roxithromycin against other Listeriaspp., such as Listeria inocua, Listeria seeligeri, Listeriawelshemeri and Listeria ivanovii, were 0.25 mg/L and 0.5mg/L respectively, but the number of strains used was toosmall to give a definitive conclusion about the activity ofroxithromycin against these microorganisms.37

Roxithromycin, like erythromycin A, dirithromycin andclarithromycin, is active against Bacillus spp. (MIC50sbetween 0.06 mg/L (dirithromycin) and 0.25 mg/L (roxi-thromycin and erythromycin A)).44 However, it has beenshown that macrolides have a bimodal range of activityagainst Bacillus spp.34

Roxithromycin, like all the macrolides except spira-mycin, shows good activity against Corynebacteriumdiphtheriae, with MICs of 0.03–0.5 mg/L.34 Rolston et al.44

reported that the MIC50 and MIC90 of roxithromycinagainst Corynebacterium hofmanii were 0.19 mg/L and3.12 mg/L, respectively.

Schülin et al.55 tested the in-vitro activity of roxi-thromycin against Pediococcus spp. and found MICs of0.12–0.25 mg/L. For Lactobacillus spp. and Leuconostoc

spp. the MIC50 and MIC90 were 0.25 mg/L and 0.12–0.25mg/L, respectively (Table II).

Gram-negative cocci

Neisseria meningitidis. The bacteriostatic and bactericidalactivity of roxithromycin and the older macrolides againstthis pathogen have been studied.34 Roxithromycin anderythromycin A have similar activity (MICs 5 0.06–0.5mg/L) and both are considered to be bactericidal (MBCs5 0.12–0.5 mg/L). However, other studies have recordedMICs of 0.3–4.0 mg/L.6,31,33,44

Gram-negative bacilli

Roxithromycin, like other macrolides, with the possibleexception of azithromycin, is not active against Entero-bacteriaceae,7,31 Pseudomonas aeruginosa, Acinetobacterspp., Stenotrophomonas spp. and other glucose-non-fermenting Gram-negative bacilli. However, it is activeagainst M. catarrhalis, Haemophilus spp., Pasteurella spp.,Bordetella pertussis and Eikenella spp. (Table III).

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Table I. Activity of roxithromycin against Gram-positive cocci

Bacterial species (n) MIC50 (mg/L) MIC90 (mg/L) Range (mg/L)

S. aureuspenicillin-susceptible (18)39 1 2 0.5–2penicillin-resistant (16)21 0.25 .128 0.12–.128methicillin-resistant (13)21 .128 .128 .128

S. epidermidis (15)21 32 .128 0.12–.128S. haemolyticus (14)37 0.5 1.0 0.25–1S. saprophyticus (24)39 0.5 32 0.25–32S. simulans (13)37 1.0 1.0 0.13–1S. hominis (10)37 0.5 1.0 0.25–1S. cohnii (11)37 0.25 0.5 0.25–1S. milleri (16)37 0.13 0.13 0.06–0.13S. pyogenes (38)55 0.06 0.06 0.03–16S. pneumoniae

penicillin-susceptible (20)37 0.13 0.25 0.06–1penicillin-resistant (17)37 1.0 2.0 0.25–2

S. agalactiae (38)37 0.13 0.25 0.13–0.25Streptococci, Lancefield group C, G(46)37 0.13 0.13 0.06–0.25E. faecalis (20)37 8 .64 2–.64E. faecalis â-lactamase-positive (10), 128 .128 8–.128

Van A (10), Van B (20)55

E. faecium (15)37 .64 .64 8–.64E. avium (11)55 0.25 128 0.03–>128E. casseliflavus (10)55 16 128 8–.128E. raffinosus (11)55 0.06 .128 0.015–>128E. gallinarum (10)55 1 2 0.12–2E. liquefaciens (10)37 8 .64 2–64


Moraxella catarrhalis. Studies evaluating the activity ofroxithromycin against this pathogen have included isolatesthat produce â-lactamase and those that do not.47,56–61

MIC90s of roxithromycin were in the range 0.12–1 mg/L.These studies also showed that the in-vitro activity ofroxithromycin was superior to those of erythromycin Aand josamycin.

Spencer & Wheat56 compared the in-vitro activity ofroxithromycin and erythromycin A against 188 strains ofM. catarrhalis. All isolates were susceptible to roxi-thromycin (MIC 5 0.06–0.25 mg/L; MIC50 5 0.125 mg/L;MIC90 5 0.25 mg/L). Roxithromycin was active againststrains producing BRO-1 and BRO-2 â-lactamases. The

MIC90 was somewhat lower than that reported by Hardy etal. (1 mg/L).21 However, this study included only 17strains. The activity of roxithromycin against â-lactamase-producing strains was confirmed by Liebowitz et al.58 in anexperimental in-vitro study.

Haemophilus influenzae. The activity of macrolidesagainst H. influenzae is not well established,62,63 andnumerous studies have been performed with roxithro-mycin.19,32,34,40,57,64–68 The in-vitro activity of roxithro-mycin, clarithromycin, and other macrolides against H.influenzae, as measured by standard susceptibility criteria,is sufficient to classify many isolates as fully resistant.

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Table II. Activity of roxithromycin against Gram-positive bacilli


L. monocytogenes (20)55 0.5 0.5 0.25–1Listeria spp. (14)37 1.0 1.0 0.13–0.5E. rhusopathiae7 – – 0.125C. diphtheriae (3)37 – – 0.03–0.06C. diphtheriae (410)191 0.03 0.03 0.016–2C. jeikeium (20)55 32 .128 0.25–.128Bacillus cereus (13)38 0.20 0.20 0.10–0.39Pediococcus spp. (5)55 – – 0.12–0.25Lactobacillus spp. (10)55 0.25 0.25 0.12–0.25Leuconostoc spp. (15)55 0.12 0.25 0.12–0.5Nocardia asteroides (21)39 128 128 0.25–.128

Table III. Activity of roxithromycin against Gram-negative bacilli


N. meningitidis (26)6 0.12 0.5 –N. gonorrhoeae

penicillin-susceptible (32)145 0.25 1.0 0.03–2penicillin-resistant, PPNG (32)145 1.0 1.0 0.06–2penicillin-resistant, non-PPNG (32)145 0.25 2.0 0.12–2.0

M. catarrhalisâ– and â1 (15)47 0.5 2 0.25–1â– and â1 (188)56 0.125 0.25 0.06–0.5â– and â1 (10)57 0.125 0.125 0.06–0.25â– and â1 (80)58 0.125 0.25 0.007–0.5

H. influenzae (22)21 4 8 2–8B. pertussis (75)72 0.5 0.5 0.12–0.5B. parapertussis (46)70 0.5 2 0.5–4P. multocida (22)46 8 32 2–.32E. corrodens (12)46 32 32 4–.32H. ducreyi (80)141 0.004 0.006 0.0002–0.125B. bronchiseptica (11)70 16 32 2–128

â–, â-lactamase negative; â1, â-lactamase-positive; PPNG, penicillinase-producing N. gonorrhoeae.

A. Bryskier

However, roxithromycin achieves high plasma concen-trations, which suggests that the criteria for susceptibilityought to be revised.14 Erwin & Jones19 proposed abreakpoint for roxithromycin of <16 mg/L for both â-lactamase-producing strains and non-â-lactamase-produc-ing isolates, which were similarly inhibited by roxi-thromycin. MIC50s against non-type b H. influenzae werehigher than those against type b strains (8 and 4 mg/L,respectively).65 Two studies have shown that roxithro-mycin displays bactericidal activity against H. influenzaewith low incidence of dissociated MBC/MIC ratios.34,69

Nicoletti et al.68 compared the in-vitro activity of roxi-thromycin, erythromycin A and ampicillin against H. in -fluenzae biotypes I (four strains), II (14 strains) and III (16strains), and various Haemophilus species. No differencein activity was observed against the three biotypes. TheMIC50s and MIC90s of roxithromycin against ampicillin-susceptible and ampicillin-resistant strains of Haemo -philus parainfluenzae were 0.19/1.56 mg/L and 0.39/1.56mg/L, respectively (Table IV).

Bordetella spp. In studies of the in-vitro activity of roxi-thromycin against 75 clinical isolates of B. pertussis,70,71 theMIC50s and MIC90s of roxithromycin and erythromycin Awere 0.25/0.5 mg/L and <0.12/<0.12 mg/L, respectively.70

The MIC90s of roxithromycin, erythromycin A, josamycin,clarithromycin, azithromycin and dirithromycin were 0.03,0.03, 0.06, <0.01, 0.03 and 0.03 mg/L, respectively.71

Against Bordetella parapertussis, MIC50 and MIC90 valueswere 0.5/0.12 mg/L and 0.25/0.25 mg/L for roxithromycinand erythromycin A, respectively.71 In a 5 year survey inNew Zealand, no reduction of in-vitro activity against B.pertussis was recorded.72 The MIC90s of roxithromycin,erythromycin A, josamycin, azithromycin, clarithromycinand dirithromycin were 0.25, 0.25, 1, 0.125, 0.25 and 0.125mg/L, respectively. Roxithromycin and erythromycin Aare poorly active against Bordetella bronchiseptica, withMIC50s and MIC90s of 16/32 mg/L and 8/32 mg/L,respectively.70

Pasteurella multocida. MICs of roxithromycin against P.multocida range between 0.5 and 2 mg/L and MBCs are2–16 mg/L.34,46

Eikenella corrodens. Goldstein et al.46 studied clinicalisolates of E. corrodens associated with dog bites andfound that roxithromycin was poorly active against thispathogen (MIC, 4–.32 mg/L; MIC50 and MIC90, 32 mg/L).

Anaerobes

The potential role of macrolides in anaerobic infections isstill controversial. Several studies have investigated theactivity of roxithromycin in these organisms.13,23,73–77

Dubreuil74 compared the in-vitro activity of roxithro-mycin against anaerobes with that of erythromycin A; B. fragilis ATCC 25285 was used as a control. At aconcentration of 4 mg/L, roxithromycin and erythromycinA inhibited 59% and 58% of B. fragilis (sensu stricto),respectively. Roxithromycin was less active against Bac -teroides thetaiotaomicron but inhibited two-thirds ofBacteroides distanosis isolates while Porphyromonas spp.and Prevotella spp. were more susceptible to roxithro-mycin than erythromycin A. All 103 strains were inhibitedby 2 mg/L of roxithromycin and 4 mg/L of erythromycin A.P. melaninogenica and all Mobiluncus spp. were sus-ceptible to roxithromycin (MICs , 0.25 mg/L). Half of thestrains of Fusobacterium spp. were resistant to roxi-thromycin, and F. nucleatum strains were slightly moresusceptible than other species of this genus (MIC50 ' 2mg/L) but Fusobacterium varium and Fusobacteriummortiferum strains were resistant (MIC50 . 64 mg/L).Veillonella spp. were poorly susceptible to roxithromycin(MIC50 5 16 mg/L) but, of the 124 Peptococcus strainstested, only two were highly resistant (MIC . 64 mg/L;MIC50 5 4 mg/L). MIC50s of roxithromycin againstPeptostreptococcus and Clostridium perfringens were0.125 and 2 mg/L, respectively.

Clostridium difficile strains may be divided into twogroups on the basis of susceptibility to roxithromycin:76 asensitive group (MIC < 2 mg/L) and a highly resistantgroup (MIC . 64 mg/L). Other clostridia were generallysusceptible to roxithromycin (MIC90 ' 2 mg/L). Resistantstrains were mainly Clostridium ramosum and Clostridiuminnocuum. Eubacterium aerofaciens and Eubacteriumlimosum were inhibited by roxithromycin at a concen-tration of 2 mg/L, whereas propionibacteria, bifidobacteria

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Table IV. Activity of roxithromycin against species of Haemophilus68


H. influenzae biotype I (3) 0.19 0.78 0.19–0.78H. influenzae biotype I (9) 0.19 0.78 0.05–1.56H. influenzae biotype III (10) 0.39 0.78 0.05–1.56H. parainfluenzae (11) 0.19 1.56 0.05–3.12H. paraphrophilus (12) 0.19 0.78 0.09–3.12H. aphrophilus (2) – – 0.05–0.19


and Actinomyces spp. were all susceptible to roxithro-mycin (MIC < 1 mg/L) (Table V).

Intracellular pathogens

Intracellular concentrations. As roxithromycin penetratescells and accumulates within them, 78 it might be useful fortreating infections caused by susceptible intracellularpathogens, such as Legionella, Chlamydia and Rickettsiaspp., and Rickettsia-like spp. (Bartonella, formerlyRochalimaea spp.), Mycobacterium spp. and Brucella spp.

Carlier et al.79 studied the intracellular accumulationand subcellular distribution of 14C-labelled roxithromycinand erythromycin A in J-774 macrophages and poly-morphonuclear neutrophils (PMN). They observed abimodal distribution of both compounds in macrophagesand approximately one-half of the amount of each drugwas soluble located presumably in the cytosol; theremaining half was associated with granules. In humanPMN, approximately one-third of intracellular roxithro-mycin was associated with azurophilic granules. Theseresults agree with those reported by Hand et al.,80 whoshowed that roxithromycin was accumulated by PMNcytoplasts with an intracellular/extracellular (I/E) ratiotwo-thirds of that in intact PMN (13.8 compared with28.8).

In recent studies,81,82 it has been shown that roxithro-mycin is rapidly taken up by human neutrophils (within30–60 min) and maximal I/E values are approximately 100and 30 for roxithromycin and erythromycin A, res-pectively. Roxithromycin, like erythromycin A and clari-thromycin (but not azithromycin), is rapidly released fromcells (80% within 1 h). Recent data83 suggest that phos-

phorylation by protein kinase A leads to increasedmacrolide transport.

The concentration of roxithromycin in cells recoveredby bronchoalveolar lavage (22 6 10 mg/L) is twice thatfound in plasma (11 6 6 mg/L) and 12 times that inepithelial lining fluid (1.8 6 7 mg/L).84 Other authors havereported I/E ratios of 16.2–21.9 and 30.85–87 The I/E ratiosrecorded by Carlier et al.79 in the alveolar macrophages ofnon-smokers and smokers were 61 6 7 and 190 6 21,respectively. In human PMN the ratio was 14 6 3. Roxi-thromycin is also active intracellularly against pathogenswithin phagocytes.87–89

Legionella pneumophila. Several studies of the effects ofroxithromycin against L. pneumophila have beenpublished.90–96 Dournon et al.93 compared the in-vitroactivity of roxithromycin with that of three othermacrolides—erythromycin A, spiramycin and josamycin—against L. pneumophila. The results were corrected to takeinto account the possible inhibitory effect of charcoal-supplemented agar (BCEY) used in the study ofantibacterial activity. Corrected MICs were 0.04, 0.06, 0.17and 1.20 mg/L for roxithromycin, erythromycin A,josamycin and spiramycin, respectively.

Liebers et al.97 compared agar dilution and micro-dilution susceptibility testing for eight antimicrobialagents, including four macrolide antibiotics, against 48clinical isolates of L. pneumophila. For the agar dilutiontests charcoal-free agar (BSYE) and BCEY were used.The MIC50s and MIC90s of roxithromycin were 0.25–0.06mg/L and 0.5–0.06 mg/L for BCEY and BSYE, res-pectively. Inhibitory and bactericidal concentrations ofroxithromycin against 48 strains of L. pneumophila using a

7

Table V. Activity of roxithromycin against anaerobic bacilli74


B. fragilis (148) 4 >64 0.25–>64B. thetaiotaomicron (46) 32 64 1–>64B. distanosis (25) 2 16 0.25–>64P. melaninogenica (82) 0.125 0.5 0.003–2Mobiluncus spp. (20) 0.016 0.03 0.004–0.25F. nucleatum (17) 2 64 0.25–>64F. varium and F. mortiferum (10) – – 64Veillonella spp. (7) 16 32 16–64Peptococcus spp. (124) 4 4 0.125–>64Peptostreptococcus spp. (38) 0.125 1 0.03–64C. perfringens (133) 2 4 0.25–8C. difficile (26) 1 >64 0.25–>64Eubacterium spp. (28) 0.125 2 0.06–>64Propionibacterium spp. (27) 0.06 0.25 0.03–1Actinomyces spp. (13) 0.06 1 0.06–1Bifidobacterium spp. (13) 0.06 1 0.06–1

A. Bryskier

microdilution technique were: MIC50, 0.125 mg/l; MBC50,0.25 mg/L; MIC90, 0.25 mg/L; MBC90, 4.0 mg/L. A detailedstudy of macrolides against Legionella spp. (referencestrains) was also carried out using BSYE agar.90 MICswere 0.25 mg/L for L. pneumophila (serotypes 1–6),Legionella micdadei, Legionella dumoffii, Legionellalongbeachae (serotypes 1 and 2) and Legionella wads -worthii. Against Legionella bozemanii and Legionellagormanii, MICs were 0.5 mg/L and 0.06 mg/L, res-pectively. These results were confirmed by Jones &Barry.91

The in-vitro activity of roxithromycin against Legionellaspecies has also been assessed by Stout et al. (Stout, J. E.,Arnold, A., Ta, A. and Yu, V. L., data on file, RousselUclaf) using buffered yeast-extract broth supplementedwith L-cysteine, ferric pyrophosphate and α-ketoglutarate,and 48–72 h incubation. The broth dilution MICs andMBCs of roxithromycin (0.06–0.25 mg/L and 1–8 mg/L,respectively) were similar to those of erythromycin A. Inthe HL-60 tissue culture model (promyelocytic leukaemiccell line, ATCC), roxithromycin demonstrated significantactivity against Legionella spp. at 8 3 MIC (Table VI).

Chlamydia spp. The genus Chlamydia encompasses threespecies—Chlamydia trachomatis, Chlamydia psittaci andChlamydia pneumoniae. Chlamydiae are obligate intra-cellular parasites which accumulate in cytoplasmicvacuoles, where they undergo a complex transformationfrom elementary bodies to reticular bodies.98 MICdeterminations are carried out in tissue culture andnumerous cell lines have been used, including non-phago-cytic cells (HeLa, McCoy, HEp-2) and macrophages (J-774). However, it is difficult to compare results obtainedwith the macrolides because of the different methodologiesused by investigators.

Cevenini et al.99–101 used McCoy cell monolayers infectedwith C. trachomatis LGV 2 serotype and reported roxi-thromycin MICs of 0.05–0.8 mg/L, with MBCs in the samerange. Kato et al.102 compared the antichlamydial activity ofroxithromycin, midecamycin, rokitamycin and spiramycinagainst ten clinical isolates of C. trachomatis. Roxithro-mycin was more effective than midecamycin and spiramycin, and as effective as rokitamycin. MICs rangedbetween <0.03 and 0.125 mg/L. Samra et al.103 also used theMcCoy cell line, and compared the activity of roxithro-mycin, erythromycin A, doxycycline and tetracyclineagainst 50 clinical isolates of C. trachomatis. Sixty-four percent of the isolates were inhibited by 0.06 mg/L of roxi-thromycin and 100% by 0.12 mg/L; 100% of isolates wereinhibited by 0.25 mg/L of erythromycin A and doxycycline,and by 0.5 mg/L of tetracycline. Roxithromycin exhibitedbactericidal activity compared with erythromycin A, doxy-cycline and tetracycline, which were bacteriostatic.

Orfila & Haider104,105 compared the in-vitro activity ofmacrolides against C. pneumoniae; the lowest MIC (0.05mg/L) was obtained with roxithromycin and the highest (1mg/L) with erythromycin A. In J-774 macrophage cells,the accumulation of erythromycin A and roxithromycin inC. trachomatis-infected cells was similar to that in unin-fected cells. Roxithromycin showed greater activity thanerythromycin A against C. trachomatis and was aseffective against C. pneumoniae in the J-774 macrophagemodel. Fewer than 1% of the cells were infected afterexposure to 5 mg/L of the macrolides for 60 h (C.trachomatis) or 74 h (C. pneumoniae).106

Fenelon et al.,107 using McCoy cells, found an MIC ofroxithromycin of 0.25 mg/L against C. pneumoniae strainTW183. Bowie et al.108 determined the in-vitro activity ofroxithromycin against ten clinical isolates of C. tracho -matis using cycloheximide-treated McCoy cell mono-

8

Table VI. Activity of roxithromycin against Legionella spp.90

Species Serogroup 104 cfu/spot 106 cfu/spot

L. pneumophila 1 ATCC 33152 0.0625 0.251 ATCC 33153 0.0625 0.252 ATCC 33154 0.0625 0.253 ATCC 33155 0.0625 0.254 ATCC 33156 0.0625 0.255 ATCC 33216 0.125 0.256 ATCC 33125 0.125 0.50

L. micdadei ATCC 33218 0.0625 0.50L. dumoffii ATCC 33219 0.25 0.25L. longbeachae 1 ATCC 33462 <0.03 0.25

2 ATCC 33484 <0.03 0.125L. gormanii ATCC 33297 <0.03 0.0625L. jordanis ATCC 33623 <0.03 0.25L. wadsworthii ATCC 33877 <0.03 0.25


layers. The MIC50 and MIC90 of roxithromycin were 0.5and 1.0 mg/L, respectively. Several other studies haveconfirmed these results.109–114

Three studies have investigated the activity of roxi-thromycin against C. psittaci (reference 115; S. Richmond(two studies), data on file, Roussel Uclaf). S. Richmond(data on file, Roussel Uclaf) determined the MIC andminimum lethal concentration (MLC) of roxithromycinand erythromycin A against a duck strain of C. psittaci in acycloheximide-treated McCoy cell line. The MICs andMLCs were 0.1/.32 mg/L and 0.025/1.6 mg/L forerythromycin A and roxithromycin, respectively. Orfila et al.115 compared the in-vitro activity of roxithromycin,erythromycin A, josamycin and other antibacterialsagainst a test strain of C. psittaci using a McCoy cell linesupplemented with fetal calf serum; they found thatroxithromycin and erythromycin A were similarlyeffective (Table VII).

Mycobacterium spp. Mycobacteria may be divided intothree categories: Mycobacterium tuberculosis, Myco -bacterium leprae and atypical mycobacteria such asMycobacterium aviumcomplex (MAC).

None of the currently available 14- and 15-memberedring macrolides show activity against M. tuberculosis, withMICs being .64 mg/L.116 The MICs of roxithromycinagainst Mycobacterium bovis BCG were 0.5–4 mg/L at pH6.8 and 0.25–2 mg/L at pH 7.4. MICs for all isolates (M.tuberculosis, Mycobacterium africanum, M. bovis) were inthe range 32–.64 mg/L at pH 6.8 and 16–32 mg/L at pH7.4.116

Franzblau and colleague117,118 determined the anti-bacterial activity of roxithromycin, clarithromycin,azithromycin and erythromycin A against M. leprae bymeasuring intracellular ATP, a radiospirometric assay ofpalmitate oxidation, and the rate of phenolic glycolipid Isynthesis.

In this in-vitro test, roxithromycin and clarithromycinwere each more potent than erythromycin A or azithro-mycin, and exhibited greatest activity in increasing the rateof ATP decay and reducing rates of palmitate oxidation.Roxithromycin and other macrolides were administered inthe diet of Balb/c mice at 0.01% (w/w). Neither erythro-mycin A nor roxithromycin inhibited growth of M. lepraein mouse footpads. In contrast, Gelber119 found thatroxithromycin and clarithromycin were bactericidal in themurine footpad model.

Several studies have been performed to test the activityof roxithromycin against MAC.120,121–130 Casal et al.,124

using Middlebrook 7H10 agar, studied the in-vitro activityof roxithromycin alone or in combination with rifampicinagainst 20 isolates of M. avium. MICs ranged from 2 to 16mg/L. Rifampicin and roxithromycin acted synergically:when 2 mg/L rifampicin was added, the MIC of roxi-thromycin fell to 0.25 mg/L. Naik & Ruck130 tested the in-vitro activity of 12 macrolide compounds against 28 M. avium strains isolated from AIDS patients. In-vitroactivity was determined by the conventional proportionmethod and the radiometric method (BACTEC) method.The MIC50 and MIC90 of roxithromycin were 8 and 16mg/L, respectively, while those of azithromycin, erythro-mycin A and clarithromycin were 16/32 mg/L, 32/64 mg/Land 2/4 mg/L, respectively. Maugein et al.125 also studiedthe in-vitro activity of roxithromycin and erythromycin Aagainst 20 isolates of M. avium using a conventionalmethod; the MIC50 and MIC90 of roxithromycin were 8/16mg/L and 16/32 mg/L using 7H9 and Löwenstein agarmedium, respectively, while those of erythromycin A were16/64 mg/L and 32/>64 mg/L. Gévaudan et al.120 recordedmean MICs of 4 mg/L (range 4–16 mg/L) of roxithromycinand 8 mg/L (range 8–32 mg/L) of azithromycin. They alsoobserved that roxithromycin and amikacin acted synergic-ally. Bermudez & Young122 found that this synergyincreased tumour necrosis factor (TNF) concentrations.

9

Table VII. Activity of roxithromycin against atypical microorganisms

Organism (n) MIC50 (mg/L) MIC90 (mg/L) Range (mg/L)

C. trachomatis (50)103 0.06 0.125 0.03–0.125C. trachomatis (10)100 – – 0.03–0.125C. trachomatis (10)108 – – 0.5–2.0C. pneumoniae (RS)115 – – 0.05–0.125C. psittaci (RS)115 – – 0.025–2.0M. pneumoniae (20)148 0.03 0.03 0.008–0.03M. hominis (ND)110 8 16 8–16Mycoplasma genitalium (7)187 – – <0.01U. urealyticum (ND)110 0.25 0.25 0.125–0.25U. urealyticum (100)146 0.25 0.5 0.125–2Mycobacterium avium complex (ND)120 – – 4–16

ND, not determined; RS, reference strains.

A. Bryskier

Rastogi et al.131 determined roxithromycin MICs againstMAC clinical isolates using the BACTEC method at twopH values. MICs obtained at pH 7.4 (0.5–2.0 mg/L) wereone or two dilutions lower or higher than those obtained atpH 6.8 (1–8 mg/L) and may indicate that the measuredMIC is influenced by pH. Rastogi et al.126 also examinedcombinations of roxithromycin with other antibacterialagents. They found that the antibacterial activity ofroxithromycin was enhanced against all ten strains testedwhen the drug was combined with ethambutol, in threestrains with rifampicin or clofazimine, in two strains withamikacin, and in one strain with ofloxacin. Casal et al.123

found that addition of rifabutin reduced the MIC ofroxithromycin to 0.01–0.5 mg/L.

Roxithromycin was tested against 25 MAC strainsisolated from patients with AIDS and disseminated MACdisease.129 A broth radiometric macrodilution method wasused to measure the in-vitro activity of roxithromycin andother agents (pH approximately 6.8). The range of activitywas ,2–32 mg/L and the combination of roxithromycinand ethambutol was additive or synergic. In the macro-phage test system, the intracellular activity of roxithro-mycin was strain-dependent. Against MAC 100, roxi-thromycin was bactericidal at concentrations of 1–64mg/L. Against MAC 101 and MAC 109, roxithromycinwas bacteriostatic at concentrations of <8 mg/L (MAC101) and 32 mg/L (MAC 109).

Rastogi et al.127 screened the intracellular activity of roxithromycin in human macrophages and its further potentiation by other antibacterial agents. Roxithromycinused alone was bactericidal against the five MAC isolates.The bactericidal effect of roxithromycin in combinationwith rifampicin against all five strains tested was greaterthan that of any of the drugs alone. In another study thecombination of roxithromycin with ethambutol and levo-floxacin was also found to be synergic.128 These datacorrelate well with the therapeutic efficacy of roxithromycinobserved in animal models of MAC infections.132

Other atypical mycobacteria. Potentially useful roxithro-mycin MICs were obtained at pH 7.4 and 6.8 for Myco -bacterium scrofulaceum (1.0 and 0.5 mg/L, respectively),Mycobacterium sulzgai (4.0 and 1.0 mg/L), Mycobacteriummalmoenese (2 and 0.5 mg/L), Mycobacterium xenopi(0.5 and 0.25 mg/L) and Mycobacterium kansasii (1 and 0.5 mg/L), but not for Mycobacterium simiae (32 and 8.0 mg/L). Roxithromycin was more active at pH 7.4 than at pH 6.8.131 Brown et al.133 evaluated the in-vitroefficacy of roxithromycin against reference isolates ofrapidly growing mycobacteria. Roxithromycin inhibited.90% of isolates of Mycobacterium abscessus, Myco -bacterium chelonae, M. chelonae-like organisms andMycobacterium peregrinum at a concentration of 2 mg/L.Mycobacterium fortuitum was less susceptible, with only 29% of isolates being susceptible to roxithromycin (2 mg/L). Roxithromycin had minimal activity against 20

isolates of Mycobacterium marinum.134 Maugein et al.125

showed that roxithromycin was slightly more active thanerythromycin A against Mycobacterium xenopi. Roxithro-mycin MIC50s and MIC90s on 7H9 and Löwenstein mediawere 0.12/0.25 mg/L and 0.25/0.5 mg/L, respectively.

Rickettsiae. Recent reviews have dealt with Rickettsia andCoxiella spp.135,136 In vitro, MICs of roxithromycin forRickettsia rickettsii and Rickettsia conorii were 1.0 mg/L,whereas those of erythromycin A and spiramycin were 8.0and 32.0 mg/L, respectively. Roxithromycin and erythro-mycin A also have good activity against Rickettsia pro -wazekii and Rickettsia tsutsugamuchi (B. Hanson & D. J.Silverman, data on file, Roussel Uclaf).

Bartonella (Rochalimaea) henselae is a newly identifiedrickettsial pathogen that causes bacillary angiomatosis andvisceral peliosis. In-vitro reports indicate that macrolidesare active against this organism (MIC 5 0.25 mg/L),137 andthese data have been validated clinically for roxithromycinagainst Bartonella quintana and Bartonella elizabethae,with MICs of 0.125 and 0.06 mg/L, respectively.82,134

B r u c e l l a s p p . Garcia-Rodriguez et al.1 3 8 tested the in-vitroactivity of five macrolide antibiotics, including roxithro-mycin, against reference strains of Brucella melitensis,Brucella abortus, Brucella neotomae, Brucella suis, B r u c e l l ac a n i s a n d Brucella ovis, and 46 clinical isolates. The MIC5 0

and MIC9 0 of roxithromycin were 8 and 16 mg/L,respectively, with MICs ranging from 0.1 to 32 mg/L. In amurine brucellosis infection, roxithromycin was given orally(50 mg/kg) alone or in combination with streptomycin (75 mg/kg) for 14 days. A significant reduction in B .m e l i t e n s i s (MIC 5 3.31 mg/L) numbers in the spleen wasrecorded with both regimens. The mean log1 0 cfu/g ofspleen was 3.64 in the roxithromycin-treated mice and 2.6 inthe mice treated with the combination regimen. In theuntreated control animals the value was 5.7.1 3 9

Sexually transmitted pathogens

Sanson-Le Pors et al.140 tested the in-vitro activity ofroxithromycin against Haemophilus ducreyi and recordedMICs of 0.016–0.06 mg/L. Miller et al.141 reported MIC50s/MIC90s of 0.001/0.004 mg/L, 0.004/0.005 mg/L and 0.004/0.015 mg/L for roxithromycin, erythromycin A and clari-thromycin, respectively. Lukehart & Baker-Zander142

found that roxithromycin and erythromycin A hadsignificant activity against Treponema pallidum.

Comparative studies of the in-vitro activity of roxi-thromycin and erythromycin A against clinical isolates ofGardnerella vaginalis showed MICs of 0.008–0.016mg/L.51,143,144 MIC90s were identical for roxithromycin,erythromycin A and clarithromycin (0.12 mg/L).143 MICsof roxithromycin rose as the bacterial inoculum sizeincreased (103 cfu/mL, 0.003 mg/L; 105 cfu/mL, 0.01 mg/L;107 cfu/mL, 0.04 mg/L).51

10


Both roxithromycin and erythromycin A show goodactivity against Ureaplasma urealyticum.99,145–147 However,differences in methodology make comparisons betweenstudies difficult. Ridgway145 found MICs of roxithromycinand erythromycin A of 0.125–0.5 mg/L, whereas otherinvestigators have reported MICs of 0.1–4.0 mg/L overallfor both compounds. Bébéar et al.146 reported values of 0.2and 1.0 mg/L for roxithromycin and erythromycin A,respectively, and roxithromycin MIC50 and MIC90 of0.25/1.0 mg/L.

Like all 14- and 15-membered ring macrolides, roxi-thromycin is not active against Mycoplasma hominis (MIC. 32 mg/L).

The in-vitro activity of roxithromycin against Neisseriagonorrhoeae has been determined in a number ofstudies.32,34,37 MICs range between 0.25 and 4 mg/L, withan MIC50 and MIC90 of 0.7 and 3 mg/L, respectively. N. gonorrhoeae isolates resistant to penicillin G were twoto four times less susceptible than the penicillin-susceptiblestrains, with MIC50s and MIC90s of 0.12–1 mg/L comparedwith 0.12–0.25 mg/L.37,145

Other pathogens

Mycoplasma pneumoniae. The in-vitro activity of roxi-thromycin, erythromycin A, and josamycin was assessedagainst 100 strains of M. pneumoniae. The geometric meanMICs were 0.27, 1.97 and 0.12 mg/L, respectively; theMIC50 and MIC90 were 0.03 mg/L.146,148 Hara et al.90 in-vestigated the in-vitro activity of roxithromycin anderythromycin A against 18 clinical isolates of M. pneu -moniae and reported geometric mean MICs of 0.01 mg/Land 0.0039 mg/L, respectively. Palu et al.147 comparedeight macrolides against ten strains of M. pneumoniae andreported MICs of <0.01 mg/L for roxithromycin, erythro-mycin A and miokamycin and 0.05 mg/L for oleando-mycin.

Borrelia spp. Lyme disease is the most commonly reportedtick-borne disease in Europe and the USA. In-vitro andin-vivo studies have been carried out to assess the efficacyof roxithromycin in the treatment of the disease and haveshown that isolates of Borrelia burgdorferi are highlysusceptible to the new macrolides (MIC ' 0.03mg/L).149–153 Sambri et al.149 tested roxithromycin andother antibacterial agents against six clinical isolates of B.burgdorferi and one of Borrelia hermsii. MBCs of roxi-thromycin for all isolates were 0.125 mg/L. Gasser et al.153

found a roxithromycin MIC of 0.031 mg/L for B.burgdorferi ATCC 35210. Hansen et al.151 showed that allstrains of B. burgdorferi were highly susceptible to roxi-thromycin in vitro, with a median MBC of 0.12 mg/L. In ananimal (gerbil) model systemic B. burgdorferi infectionwas eradicated within 10 days’ treatment with roxithro-mycin at doses of .25 mg/kg/day. Preac-Mursic et al.150

tested the antibacterial activity of roxithromycin, erythro-mycin A, clarithromycin and azithromycin against B.burgdorferi in vitro and in vivo. In vitro, all macrolidesdisplayed excellent activity (roxithromycin MIC50 5 0.015,MIC90 = 0.03 mg/L). However, roxithromycin was noteffective in the gerbil model.

Early investigations revealed relative homogeneity ofprotein profiles and antigenic reactions among Americanisolates of B. burgdorferi and heterogeneity amongEuropean isolates.154 B. burgdorferi sensu lato has beensubdivided into three genospecies:155 B. burgdorferi sensustricto, Borrelia garinii and Borrelia afzelii. Recentfindings suggest that the genospecies are associated withdifferent clinical manifestations (arthritis, neurologicalsymptoms and acrodermatitis chronica atrophicans,respectively).156 Péter & Bretz152 investigated the in-vitroactivity of seven antibacterial agents, including roxithro-mycin, against these three subspecies. MICs of roxithro-mycin were 0.062 mg/L, 0.015 mg/L and 0.125–0.062 mg/L,respectively, and roxithromycin was bacteriostatic formost isolates. Roxithromycin was more effective againstB. burgdorferi sensu stricto and B. garinii than B. afzelii. Inanother study the combination of roxithromycin andminocycline was synergic against all three B. burgdorferigenospecies.157

Helicobacter pylori. Eradication of H. pylori cures gastritisand prevents duodenal ulcer relapse. However, there areseveral drawbacks to the 2 week triple-drug therapy usedto eradicate H. pylori, and macrolide antibiotics may be analternative. Czinn et al.158 compared the in-vitro activitiesof roxithromycin, erythromycin A and azithromycinagainst ten strains of H. pylori. Overall MICs ranged from0.06 to 0.5 mg/L. The MIC50 and MIC90 of roxithromycinagainst H. pylori were 0.12 and 0.25 mg/L, respectively(MIC range 0.12–0.25 mg/L).30,159 Mégraud et al.160

determined the killing curves of roxithromycin alone or incombination with amoxycillin and/or lansoprazole. Roxi-thromycin at >1 mg/L had a bactericidal effect (reductionof 3 log10 cfu/mL) after 24 h. When a subinhibitoryconcentration of amoxycillin (0.001 mg/L) was added, anadditive effect was observed. Combination of the proton-pump inhibitor lansoprazole, amoxycillin and roxithro-mycin was also found to be additive or synergic but neverantagonistic. Cross-resistance between all macrolides wasobserved for clarithromycin-resistant isolates.

Campylobacter spp. Microorganisms of the genus Campy -lobacter are increasingly common in enteric disease,usually causing non-invasive diarrhoea which occasionallyrequires antibacterial therapy. Goosens et al.161 comparedthe in-vitro activity of roxithromycin and erythromycin Aagainst Campylobacter jejuni. The MIC50 and MIC90 ofroxithromycin were 1 and 4 mg/L, respectively (range0.25–8 mg/L). These results are similar to those obtainedby Barlam & Neu31 MICs of azithromycin, clarithromycin,

11

A. Bryskier

roxithromycin and erythromycin A were determined for36 quinolone-susceptible and 106 quinolone-resistantstrains of C. jejuni. MIC90s were 0.5, 4, 16 and 4 mg/L,respectively. No difference in activity was found betweenmacrolides against quinolone-susceptible and quinolone-resistant strains.162 Resistance to roxithromycin remainedstable between 1988 and 1992 (MIC50 5 2 mg/L) andcomprises approximately 10% of strains for a breakpointMIC of >8 mg/L.163 The MIC50s of roxithromycin forCampylobacter upsaliensis and Campylobacter fetus sub-species fetus were 3.12 and 1.56 mg/L, respectively.164

Vibrio cholerae. Macrolides can be used in the treatmentof cholera in children.165 The MIC50 and MIC90 for 50clinical isolates of V. cholerae serovar Ogawa of Africanorigin were 6.2 and 15.5 mg/L, respectively (Table VIII).

Faecal flora

The ecological impact on the intestinal flora ofroxithromycin given orally at a dose of 300 mg was studiedin six volunteers.166 The faecal concentrations of roxi-thromycin were in the range of 100–200 mg/kg of faeces.Changes in the faecal flora were limited to a decrease inoverall counts of Enterobacteriaceae. Other intestinalflora, including anaerobes, were not significantly affectedand no overgrowth of P. aeruginosa , staphylococci, fungior highly erythromycin-resistant strains of Enterobac-teriaceae was observed. In six volunteers receivingrepeated doses of roxithromycin (150 mg every 12 h for 29doses), no abnormal growth of C. difficile was observed.167

Post-antibiotic effect

Kuenzi et al.168 performed a study involving H. influenzae,S. aureus, S. pyogenes and S. pneumoniae. Like erythro-mycin A, roxithromycin showed a time-dependent post-antibiotic effect (PAE). S. pneumoniae ATCC 27336(MIC , 0.06–0.125 mg/L) was exposed for 2 h to 7 mg/L ofroxithromycin. Subcultures were taken into fresh drug-free broth. Analysis of regrowth revealed a PAE of 5.2 h.Further experiments showed that the PAE was dependent

on both the concentration of the drug and the duration ofexposure. Similar results were obtained with erythromycinA and clindamycin after exposure for 1 h; concentrationssimilar to the MIC resulted in PAEs of 1–2 h. In contrast, 1and 2 h exposure to 5–10 3 MIC were followed by PAEsof 3.2 and 5.3 h (erythromycin A), 2.5 and 4.9 h(clindamycin) and 2.6 h and 4.4 h (roxithromycin).Corresponding PAEs for a 6 h exposure were 6.3 h forerythromycin A and roxithromycin, and 6.9 h forclindamycin. Roxithromycin concentrations of 50–100 3MIC produced a maximal PAE of 7.9 h following exposurefor 6 h. Similar PAEs of up to 1.5 h were observed when S.pyogenes Abs 86-29 was exposed to 0.5–1.0 3 MICs of thethree drugs for 1 and 6 h. In contrast, 6 h exposure to 5–103 MIC of roxithromycin resulted in PAEs of 6–7 h. PAEsof 1.5–2.5 h were observed following 6 h exposure of S.aureus to 0.5–1 3 MIC; exposure to 5–10 3 MIC producedPAEs of 2.5–5.2 h depending on exposure time.

Exposure of H. influenzaeto the MIC for 2 h produced nosignificant PAE. However, a maximal PAE of 2–4 h wasobtained after 1–2 h exposure to 10 3 MIC of roxithromycin and erythromycin A. Exposure to 10 3 MICof clindamycin for 1–2 h produced a PAE of only 1–2 h.

Castillo et al.169 determined the duration of the PAE ofclarithromycin, erythromycin A, and roxithromycin invitro against 12 clinical isolates of S. aureus and S.epidermidis, and found that roxithromycin PAEs lasted0.9–2.6 h.

Hamilton-Miller & Shah170 showed that the PAE ofroxithromycin against Lancefield group A streptococciwas similar to that of erythromycin A and miokamycin,but inferior to that of miokamycin against group B streptococci and erythromycin A-sensitive enterococcalisolates.

Post-exposure, sub-MIC concentrations may enhancethe duration of macrolide PAEs. Exposure of S. pyogenestosub-MIC concentrations (0.1, 0.2 and 0.3 3 MIC) of roxi-thromycin during the PAE phase increased the PAEduration from 5 h to 5.6, 9.8 and 10.4 h respectively.171 It hasbeen suggested that subinhibitory concentrations of anti-bacterial agents reduce the virulence of some bacterialspecies. In vitro, roxithromycin completely inhibitedcoagulase and b-haemolysin production by S. aureus and

12

Table VIII. Activity of roxithromycin against gastroenteric pathogens

Organism (n) MIC50 (mg/L) MIC90 (mg/L) Range (mg/L)

C. jejuni (100)164 3.12 6.25 0.39–25Campylobacter coli (50)164 3.12 12.5 0.39–50C. upsaliensis (20)164 3.12 12.5 0.19–12.5C. fetus (20)164 1.56 3.12 0.39–3.12V. cholerae (30)165 6.2 15.5Helicobacter pylori (33)161 – – 0.25


lecithinase and deoxyribonuclease were partially in-hibited.172

In-vivo activities

Non-discriminative infections

Systemic infections. Numerous studies on the effectivenessof roxithromycin in systemic infections have beenperformed (references 3, 7, 54 and 90; N. Klesel & G.Seibert, data on file, Roussel Uclaf). Chantot et al.7 com-pared the efficacy of roxithromycin and erythromycin Afollowing intraperitoneal or oral administration to CharlesRiver CD1 mice. The overall in-vivo activity of roxithro-mycin was three to six times higher than that of erythro-mycin A, irrespective of in-vitro activity (e.g. for infectionswith S. aureus Giorgio, PD50s were 23 and 60 mg/kg forroxithromycin and erythromycin A, respectively).

The antibacterial activity of roxithromycin was alsocompared with that of erythromycin A in mice inoculatedintraperitoneally with S. aureus, S. pyogenes, S. agalactiae,L. monocytogenes, Erysipelothrix rhusopathiae (MIC 50.125 mg/L) or Pasteurella multocida. The in-vitro MICs ofroxithromycin and erythromycin A were equivalent over-all but animals treated with roxithromycin had improvedsurvival, as shown by the lower ED50s compared withthose treated with the comparators. The therapeutic ratioof the ED50 of erythromycin A and roxithromycin suggeststhat identical effects are obtained in susceptible bacteriawith doses of roxithromycin six to 14 times lower thanthose of erythromycin A (N. Klesel & G. Seibert, data onfile, Roussel Uclaf).

The in-vivo efficacy of oral roxithromycin, erythro-mycin A, josamycin and rokitamycin were compared inexperimental staphylococcal infections (S. aureus Smith)in Std/ddy mice (inoculum of 1.86 3 108 cells/mousewithout mucin).54 ED50s were 0.76, 4.0, 6.63 and 6.94mg/mouse for roxithromycin, erythromycin A, josamycinand rokitamycin, respectively. Nishino et al.3 recordedsimilar results when they compared the efficacy of roxi-thromycin, erythromycin A, josamycin and rokitamycinagainst other bacterial species (S. aureus, S. pneumoniaeIII and S. pyogenes C-203).

Muraoka et al.53 compared the in-vitro and in-vivoactivity of roxithromycin, erythromycin A, josamycin and rokitamycin against Gram-positive cocci. ICR micewere challenged intraperitoneally with a 5% mucinsuspension of various isolates of S. aureus (Smith, TMS 27,TMS 298, TMS 299), S. pyogenes (TMS 1, TMS 22) and S. pneumoniae (TMS 43, TMS 51). ED50s (Van derWaerden method) were determined from the number of mice surviving 7 days after inoculation. Roxithromycinwas highly effective, two to 50 times more so than othermacrolides. Even when other macrolides showed higherin-vitro efficacy, roxithromycin was more effective in vivo.

Experimental pneumonia. Tsuboi et al.54 compared thecure rate provided by roxithromycin and erythromycin Ain mice infected with S. pneumoniae (HL-438) by intra-nasal inoculation. The number of microorganisms found inthe lungs of mice 48 h after treatment with roxithromycinwas very low. In mice treated with erythromycin A thenumber fell initially and rose after 72 h. Concentrations inserum and tissue (lung, liver) were determined bymicrobiological assay after a single oral administration of 2mg/mouse (100 mg/kg). The tissue distribution and plasmalevels of roxithromycin in mice were five to ten timeshigher than those of erythromycin A.

Muraoka et al.53 also tested the in-vivo efficacy of roxi-thromycin and erythromycin A in ICR mice with experi-mental S. pneumoniae infection. Antibiotic treatment wasstarted 6 h following intranasal challenge and two furtherdoses were given 30 and 54 h after the challenge. In theroxithromycin group there was a marked decrease in thenumber of viable organisms in the lungs when firstmeasured at 24 h and later at 48 h compared with theerythromycin A group. All the animals in the erythro-mycin A group died of septicaemia.

Subcutaneous infections. Roxithromycin was more activethan erythromycin A in preventing subcutaneous infec-tions caused by S. aureus 265 and S. aureus BB.3

Specific experimental infections

Legionella pneumophila. The in-vivo activity of oralroxithromycin was compared with that of erythromycin A,rifampicin, josamycin and rokitamycin against experi-mental Legionella pneumophila infections in guinea pigs.92

Five male guinea pigs (body weight 280–320 g) wereinfected with L. pneumophila serogroup 1 by intratrachealinoculation of 1.9 3 102–1.9 3 108 cfu/animal. The LD50

was calculated by the Behrens–Kärber method.173 Eachanimal was given ten times the LD50 in 0.5 mL. After 24 h,treatment was started with two daily doses for 7 days (allcompounds). None of the animals in the roxithromycin (10mg/kg/day) or rifampicin groups (7.5 mg/kg/day) had diedby day 10. In the erythromycin A group (20 mg/kg/day)the survival rate at day 5 was 60%. All animals in thejosamycin group (20 mg/kg/day) and the rokitamycingroup (10 mg/kg/day) died by day 9 and day 6, res-pectively.

Mycoplasma pneumoniae. Hara et al.90 reported the in-vitro and in-vivo activities of oral roxithromycin anderythromycin A against M. pneumoniae. Young goldenhamsters (ten in each group) were challenged by theintranasal route with 30 mL of a suspension of 9.2 3 107

cfu/mL M. pneumoniae. Antibiotic treatment was begun 7days after challenge (5 mg/hamster once daily for 14 days).The results demonstrated similar, good activity in bothtreatment groups and the number of viable bacterial

13

A. Bryskier

colonies in the lungs was reduced after 3 days in bothgroups.

Chlamydia trachomatis salpingitis. Zana et al.174 used amouse model of acute chlamydial salpingitis to evaluatethe efficacy of roxithromycin in preventing irreversible in-flammatory damage leading to tubal infertility. FemaleC3H/He mice were inoculated with C. trachomatis andgiven roxithromycin subcutaneously. The protective effectof roxithromycin was assessed in terms of fertility para-meters. When therapy was initiated on day 7 and giventwice daily (25 mg/kg) all the mice remained fertile; whentreatment was initiated on day 10 and given in a singledaily dose of 50 or 100 mg/kg, 90% and 70% of the mice,respectively, remained fertile.

Antiparasitic activity

Toxoplasmosis. Macrolides, including roxithromycin,inhibit Toxoplasma gondii tachyzoites in vitro, but a sig-nificant effect is only obtained at high concentrations.175,176

Roxithromycin protected mice against infection with thevirulent and lethal RH strain and C-56 strains of T.gondii.177 In a model of toxoplasma encephalitis in mice, asurvival rate of 80–100% was observed compared with100% mortality in untreated controls.178 Furthermore,using murine peritoneal macrophages infected with thevirulent RH strains of T. gondii, the concentrationproducing 50% inhibition of growth (IC50) was calculatedas 54, 140, 147 and 246 mmol/L for roxithromycin, azithro-mycin, clarithromycin and spiramycin, respectively.179

In a model of dual infections in immunosuppressed rats,Brun-Pascaud et al.180 demonstrated that roxithromycinwas selectively prophylactic against toxoplasmosis. Roxi-thromycin (400 mg/kg) combined with dapsone (25 or 50 mg/kg) was as effective as pyrimethamine (3 mg/kg) in preventing toxoplasmosis in immunosuppressed rats.Roxithromycin (200 mg/kg) combined with sulpha-methoxazole (20 mg/kg) was able to prevent toxoplasmosisand pneumocystosis in immunosuppressed rats.1 8 1

Other parasites

Wéry & Demedts182 have investigated the activity of roxi-thromycin and metronidazole against Entamoeba histo -lytica in polyxenic culture, using Jones’ medium. Growthwas completely inhibited after 4 days’ exposure to roxi-thromycin (100 mg/L). At lower doses, roxithromycin(1.25–20 mg/L) partially inhibited E. histolytica growth.These authors also found that erythromycin A, roxithro-mycin and metronidazole did not completely inhibit thegrowth of Trichomonas vaginalis in axenic culture usingKupferberg medium. Studies of the susceptibility ofclinical isolates of Plasmodium falciparum indicate asynergic relationship between roxithromycin and amodia-quine.183 Clinically, in AIDS patients with CD4+ counts of

<100, roxithromycin was effective in cryptosporidiumdiarrhoea.184,185

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Roxithromycin: review of its antimicrobial activity