Roxithromycin Review of Its Antimicrobial Activity

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

erythronolide A lactone ring has been altered to prevent inactivation in the gastric milieu. The
in-vitro activity of roxithromycin is well documented and similar to that of other macrolide
antibiotics. 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 as
Mycobacterium avium complex, Helicobacter pylori and Borrelia spp. It penetrates and
accumulates within cells, such as macrophages and polymorphonuclear neutrophils (PMNs),
where it is distributed between the cytosol and cellular granules. Once inside the cells, it is
active 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 of
roxithromycin and the duration of exposure. In vivo, roxithromycin is as effective or more
effective than other macrolides in a wide range of infections.
Introduction (Bacteroides fragilis group, Prevotella melaninogenica,

Prevotella bivia and Fusobacterium spp.), and the effect
Roxithromycin is a semi-synthetic 14-membered ring was particularly marked against the B. fragilis group and
macrolide antibiotic in which the erythronolide A lactone Fusobacterium spp. Siebor & Kazmierczak5 also found that
ring has been modified to prevent inactivation by gastric 10% carbon dioxide reduced the potency of roxithromycin
acid.1 Roxithromycin differs from erythromycin A by the against aerobic bacteria and that the MICs of roxi-
replacement of the 9-keto group by an etheroxime side thromycin were doubled. Macrolide antibiotics are less
chain (Figure).2 active at low pH and Rosenblatt and Schoenknecht12
observed that incubation in the presence of 5% carbon
Factors influencing in-vitro activity dioxide caused a fall in pH of 0.5–0.8 units. MICs of
roxithromycin were increased eight-fold at acid pH
It is common practice to determine the influence of a compared with pH 7.0, and were halved at pH 8.0.3,5 Other
number of factors, such as culture medium, bacterial macrolides are affected in a similar way.
inoculum size, pH, carbon dioxide atmosphere and the Spangler et al. 13 tested the in-vitro activity of roxithro-
addition of serum, on the in-vitro activity of an antibiotic. mycin against anaerobic bacteria using the Oxyrase agar
In general, the in-vitro activity of roxithromycin is dilution method (Oxyrase Inc., Mansfield, OH), which
diminished in the presence of human serum,3–10 but provides an anaerobic environment in the absence of
unaffected by the addition of 10% horse serum.5 However, carbon dioxide. The overall roxithromycin MIC50 and
an increase in inoculum size from 0.5–1 3 106 to 0.5–1 3 108 MIC90 were 0.5 mg/L and 16 mg/L, respectively, but rose
cfu/mL causes a doubling of the MICs of roxithromycin, to 2.0 and 64 mg/L, respectively, under standard anaerobic
erythromycin A, azithromycin and other macrolides.3,5,6 conditions in the presence of carbon dioxide. At a break-
Felmingham et al.11 found that a carbon dioxide point of 8 mg/L,14 85% of the isolates were susceptible by
concentration of 10% affected the in-vitro activity of the Oxyrase method, compared with only 68% with the
erythromycin A and roxithromycin against anaerobes chamber method.
*Tel: +33-149915121; Fax: +33-149915020.
1
© 1998 The British Society for Antimicrobial Chemotherapy
A. Bryskier
clarithromycin (MIC50 5 4–8 mg/L).6,20–22 According to

Jones,22 the zone diameter around a 15 mg disc indicating
roxithromycin susceptibility should be .10 mm in the
presence of carbon dioxide and HTM agar, though criteria
for resistance were not proposed.23 Cooper et al.24
suggest that current MICs and disc zone susceptibility
breakpoints of <1 mg/L and >22 mm underestimate
the clinical efficacy of roxithromycin against H. influenzae
and a zone diameter susceptibility breakpoint of
.10 mm is predictive of a successful outcome in 78% of
cases.
Etest
The Etest method for determination of activity of
macrolides against anaerobes was assessed by Spangler et
al.25 Agar dilution and Etest MICs corresponded, to within
one dilution, in .99% of cases. Only 84–91% of Etest MICs
were within one dilution of agar MICs for roxithromycin
Figure. The structure of roxithromycin. and other macrolides tested. In most cases, Etest MICs
were lower than those observed by agar dilution.
Determination of in-vitro susceptibility

criteria In-vitro activity against common pathogens
For Gram-positive species, interpretative criteria have The in-vitro activity of roxithromycin is well documented.
been adopted in France (Comité Français de l’Antibio- In general, studies of more than ten isolates and using
gramme), Sweden and proposed in Germany and the broth or agar dilution methods with bacterial inocula of
USA, though no definitive breakpoints have been 104–106 cfu/mL are considered in this review. The natural
registered (references 15 and 16; H. Grimm, data on file, antibacterial spectrum of roxithromycin is essentially
Roussel Uclaf). In a French multicentre study,15 373 the same as that of other macrolides and covers Gram-
clinical isolates of 12 species were tested for MIC and positive cocci, Gram-negative cocci, Gram-positive bacilli
inhibition zones using a 15 mg roxithromycin disc (Oxoid, and some Gram-negative bacilli.21,26–30 Numerous studies
Basingstoke, UK). The roxithromycin breakpoint was have been conducted to determine the in-vitro activity of
1–4 mg/L, corresponding to: susceptible, >22 mm (MIC roxithromycin against common pathogens.6,7,14,31–35
< 1 mg/L); intermediate susceptibility, 17–21 mm (MIC
2–4 mg/L); and resistant, ,17 mm (MIC . 4 mg/L).
Gram-positive cocci
Olsson-Liljequist and the Swedish Subcommittee on
Standardization of Methodology16 proposed breakpoints Staphylococcus spp. The in-vitro activity of roxithromycin
of <1 mg/L and >8 mg/L. The breakpoints recorded by against penicillin-susceptible and methicillin-susceptible
zone diameters for different bacterial species were: Staphylococcus aureus is similar to that of erythromycin A
staphylococci, >25 mm and <19 mm; enterococci, >25 mm and clarithromycin. Studies indicate that MICs range from
and <12 mm; group A, B, and G streptococci, >20 mm 0.01 to 4 mg/L, except when multiple resistance, including
and <15 mm, Streptococcus pneumoniae, >20 mm and resistance to methicillin, is a problem.6,7,36,37 At 2 mg/L,
<15 mm; Haemophilus influenzae, >25 mm and <10 mm; roxithromycin inhibited 100% of S. aureus clinical isolates
Moraxella catarrhalis, >25 mm and <20 mm. Jones et al.14 susceptible to benzylpenicillin and oxacillin.6,38,39 Erythro-
proposed interpretative criteria using NCCLS reference mycin A-resistant isolates were not susceptible to
methods.17,18 For Gram-positive cocci, they proposed roxi- roxithromycin, clarithromycin or azithromycin.21,40,41
thromycin breakpoints of 1–8 mg/L, corresponding to zone The activity of roxithromycin against coagulase-negative
diameters of: >21 mm (susceptible), 10–20 mm (inter- staphylococci in vitro is variable. Fleurette et al.42
mediate susceptibility) and <9 mm (resistant). Erwin & determined the in-vitro activity of five macrolides against
Jones19 proposed NCCLS susceptibility breakpoint recom- 100 clinical isolates of coagulase-negative staphylococci.
mendations for roxithromycin against H. influenzae of The MIC50 and MIC90 of roxithromycin were <0.006 mg/L
>16 mg/L (disc test correlate of >10 mm). and .128 mg/L, respectively. However, Rolston et al. 38,43,44
The in-vitro activity of roxithromycin against H. in - found that roxithromycin, erythromycin A, clarithromycin
fluenzae closely resembles that of erythromycin A and and dirithromycin have little activity against Staphylo -
2
coccus epidermidis. Erythromycin-susceptible isolates are against the viridans group of streptococci (Streptococcus
also susceptible to roxithromycin but erythromycin- mutans, Streptococcus mitis, Streptococcus salivarius,
resistant isolates are not susceptible to other macrolides. Streptococcus milleri and Streptococcus sanguis). Roxi-
Staphylococcus haemolyticus and Staphylococcus hominis thromycin and erythromycin A displayed the highest
are not susceptible to macrolides (MIC . 64 mg/L). activity (MIC50 ' 0.12 mg/L, MIC90 ' 1 mg/L) and
Controversial results have been published by few strains were highly resistant (MIC > 32 mg/L). Loza
Bauernfeind,37 who tested the in-vitro activity of roxithro- et al.52 demonstrated that roxithromycin was less active
mycin and other macrolides against various coagulase- against S. mitis RYC 49593, which has an efflux
negative species. MIC50s ranged from 0.25 to 1 mg/L for S. mechanism of resistance to the macrolides, than other
haemolyticus, S. hominis, Staphylococcus cohnii, Staphylo - strains.
coccus simulans, Staphylococcus saprophyticus, Staphylo -
coccus warneri, Staphylococcus hyicus, Staphylococcus Enterococcus spp. Numerous comparative studies against
auricularis, Staphylococcus xylosus and Staphylococcus enterococci have been carried out.6,8,34,35,36,43,44,47,53,54 Le
capitis. Guggenbichler et al.45 investigated the in-vitro Noc et al.34 compared the bacteriostatic and bactericidal
activity of roxithromycin and clarithromycin against activity of roxithromycin with that of older macrolides
erythromycin A-resistant clinical isolates of staphylococci. against erythromycin A-susceptible (MIC < 2 mg/L) and
At an MIC of 2 mg/L, 25% of the erythromycin A-resistant resistant Enterococcus faecalis. None of the macrolides
strains were inhibited by clarithromycin and 11.6% by showed significant bactericidal activity against this
roxithromycin. Of 75 coagulase-negative staphylococci pathogen. Chin et al.47 compared the in-vitro activity of
resistant to erythromycin A, 10.7% were inhibited by roxithromycin and clarithromycin against erythromycin
clarithromycin and 9.3% by roxithromycin at an MIC of A-susceptible strains. MIC50s were 1 mg/L and 0.5 mg/L
2 mg/L. Cross-resistance patterns differed between strains for roxithromycin and clarithromycin, respectively. The
with low-level (MIC > 4 mg/L) and high-level resistance roxithromycin and clarithromycin MICs for all erythro-
(MIC > 256 mg/L) to erythromycin A. mycin A-resistant strains were .32 mg/L.
Dette et al.8 found only moderate in-vitro activity of
Streptococcus spp. Several studies have shown that strepto- macrolides against Enterococcus faecium. The modal MIC
cocci are generally susceptible to macrolides.6,7,34,37,46–48 of roxithromycin was 6.15 mg/L. These results were
Roxithromycin displays similar in-vitro activity to erythro- confirmed by Tsuboi et al.54 The MIC50 and MIC90 of
mycin A and clarithromycin against Streptococcus pyo - roxithromycin against E. faecium were 6.25 and .100
genes, Streptococcus agalactiae, S. pneumoniae, Lancefield mg/L, respectively. Other studies confirmed that roxi-
group C, G and viridans group streptococci, with MIC50s thromycin and erythromycin A were not active against E.
and MIC 90s of 0.1–1 mg/L.38,43,44 Le Noc et al. 34 compared faecium, Enterococcus raffinosus or Enterococcus casseli -
the older macrolides (erythromycin A, oleandomycin, flavus (MIC . 100 mg/L).53,55
josamycin and spiramycin) and found they all had bimodal Rolston et al.44 compared the in-vitro activity of
activity against S. pneumoniae. Roxithromycin was more roxithromycin, clarithromycin, erythromycin A and diri-
active than josamycin and spiramycin. thromycin against E. faecalis. MIC90s of all the macrolides
When tested against clinical isolates of S. pneumoniae were .64 mg/L. MIC50s were 4 mg/L for all the macrolides
resistant to penicillin G, the MIC50 and MIC90 of except clarithromycin, which had an MIC50 of 8 mg/L. The
roxithromycin were 0.25 mg/L and 4 mg/L, respectively.37 macrolides were poorly active against Enterococcus
Knothe & Hauke49 recorded that only 1.5% of 710 S. liquefaciens (MIC50 5 8 mg/L; MIC90 . 64 mg/L), and had
pneumoniae isolates were resistant to roxithromycin (MIC bimodal activity against Enterococcus avium (MIC50 5
> 8 mg/L) in Germany. The MIC50 and MIC 90 were 0.125 0.25 mg/L; MIC90 5 128 mg/L).36 Roxithromycin shows
and 0.25 mg/L, respectively. R. N. Jones and M. E. Erwin good activity against Enterococcus gallinarum (MIC50 5
(data on file, Roussel Uclaf) proposed the use of S. 1 mg/L; MIC90 5 2 mg/L) (Table I).55
pneumoniae ATCC 49919 as a quality control when
measuring MICs of roxithromycin. MICs ranged from 0.06
Gram-positive bacilli
to 0.25 mg/L and a slight change in these values (one
dilution increase) was detected in the presence of carbon The antibacterial spectrum of roxithromycin covers most
dioxide. The bactericidal activity of roxithromycin was Corynebacterium spp., Listeria monocytogenes and
evaluated against S. pneumoniae clinical isolates using a Bacillus, Leuconostoc, Pediococcus and Lactobacillus spp.
model simulating serum pharmacokinetic parameters.50 Corynebacterium jeikeium and Nocardia asteroides are
Roxithromycin reduced numbers of bacteria of 12 strains excluded since their MICs are .16 mg/L.34,37,38,39,43,44,55
by 99% in 2.61 6 1.35 h and of 11 strains by 99.9% in 3.24 The antibacterial activity of roxithromycin against L.
6 1.44 h. No regrowth was seen. monocytogenes is broadly similar to that of erythromycin
Romeo et al.51 tested the in-vitro activity of roxi- A and azithromycin but less than that of clarithromycin,
thromycin, erythromycin A, josamycin and miokamycin with most isolates being inhibited at concentrations of
3
A. Bryskier
Table I. Activity of roxithromycin against Gram-positive cocci
Bacterial species (n) MIC50 (mg/L) MIC90 (mg/L) Range (mg/L)
S. aureus
penicillin-susceptible (18)39 1 2 0.5–2
penicillin-resistant (16)21 0.25 .128 0.12–.128
methicillin-resistant (13)21 .128 .128 .128
S. epidermidis (15)21 32 .128 0.12–.128
S. haemolyticus (14)37 0.5 1.0 0.25–1
S. saprophyticus (24)39 0.5 32 0.25–32
S. simulans (13)37 1.0 1.0 0.13–1
S. hominis (10)37 0.5 1.0 0.25–1
S. cohnii (11)37 0.25 0.5 0.25–1
S. milleri (16)37 0.13 0.13 0.06–0.13
S. pyogenes (38)55 0.06 0.06 0.03–16
S. pneumoniae
penicillin-susceptible (20)37 0.13 0.25 0.06–1
penicillin-resistant (17)37 1.0 2.0 0.25–2
S. agalactiae (38)37 0.13 0.25 0.13–0.25
Streptococci, Lancefield group C, G(46)37 0.13 0.13 0.06–0.25
E. faecalis (20)37 8 .64 2–.64
E. faecalis β-lactamase-positive (10), 128 .128 8–.128
Van A (10), Van B (20)55
E. faecium (15)37 .64 .64 8–.64
E. avium (11)55 0.25 128 0.03–>128
E. casseliflavus (10)55 16 128 8–.128
E. raffinosus (11)55 0.06 .128 0.015–>128
E. gallinarum (10)55 1 2 0.12–2
E. liquefaciens (10)37 8 .64 2–64
0.25–2 mg/L.21,32,34,38,43,44,47,55 One study showed that the spp. the MIC50 and MIC90 were 0.25 mg/L and 0.12–0.25
MIC50 and MIC 90 of roxithromycin against other Listeria mg/L, respectively (Table II).
spp., such as Listeria inocua, Listeria seeligeri, Listeria
welshemeri and Listeria ivanovii, were 0.25 mg/L and 0.5 Gram-negative cocci
mg/L respectively, but the number of strains used was too
small to give a definitive conclusion about the activity of Neisseria meningitidis. The bacteriostatic and bactericidal
roxithromycin against these microorganisms.37 activity of roxithromycin and the older macrolides against
Roxithromycin, like erythromycin A, dirithromycin and this pathogen have been studied.34 Roxithromycin and
clarithromycin, is active against Bacillus spp. (MIC50s erythromycin A have similar activity (MICs 5 0.06–0.5
between 0.06 mg/L (dirithromycin) and 0.25 mg/L (roxi- mg/L) and both are considered to be bactericidal (MBCs
thromycin and erythromycin A)).44 However, it has been 5 0.12–0.5 mg/L). However, other studies have recorded
shown that macrolides have a bimodal range of activity MICs of 0.3–4.0 mg/L.6,31,33,44
against Bacillus spp.34
Roxithromycin, like all the macrolides except spira-
Gram-negative bacilli
mycin, shows good activity against Corynebacterium
diphtheriae, with MICs of 0.03–0.5 mg/L.34 Rolston et al. 44 Roxithromycin, like other macrolides, with the possible
reported that the MIC50 and MIC90 of roxithromycin exception of azithromycin, is not active against Entero-
against Corynebacterium hofmanii were 0.19 mg/L and bacteriaceae,7,31 Pseudomonas aeruginosa, Acinetobacter
3.12 mg/L, respectively. spp., Stenotrophomonas spp. and other glucose-non-
Schülin et al.55 tested the in-vitro activity of roxi- fermenting Gram-negative bacilli. However, it is active
thromycin against Pediococcus spp. and found MICs of against M. catarrhalis, Haemophilus spp., Pasteurella spp.,
0.12–0.25 mg/L. For Lactobacillus spp. and Leuconostoc Bordetella pertussis and Eikenella spp. (Table III).
4
Table II. Activity of roxithromycin against Gram-positive bacilli
L. monocytogenes (20)55 0.5 0.5 0.25–1

Listeria spp. (14)37 1.0 1.0 0.13–0.5
E. rhusopathiae7 – – 0.125
C. diphtheriae (3)37 – – 0.03–0.06
C. diphtheriae (410)191 0.03 0.03 0.016–2
C. jeikeium (20)55 32 .128 0.25–.128
Bacillus cereus (13)38 0.20 0.20 0.10–0.39
Pediococcus spp. (5)55 – – 0.12–0.25
Lactobacillus spp. (10)55 0.25 0.25 0.12–0.25
Leuconostoc spp. (15)55 0.12 0.25 0.12–0.5
Nocardia 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 0.03–2
penicillin-resistant, PPNG (32)145 1.0 1.0 0.06–2
penicillin-resistant, non-PPNG (32)145 0.25 2.0 0.12–2.0
M. catarrhalis
β– and β1 (15)47 0.5 2 0.25–1
β– and β1 (188)56 0.125 0.25 0.06–0.5
β– and β1 (10)57 0.125 0.125 0.06–0.25
β– and β1 (80)58 0.125 0.25 0.007–0.5
H. influenzae (22)21 4 8 2–8
B. pertussis (75)72 0.5 0.5 0.12–0.5
B. parapertussis (46)70 0.5 2 0.5–4
P. multocida (22)46 8 32 2–.32
E. corrodens (12)46 32 32 4–.32
H. ducreyi (80)141 0.004 0.006 0.0002–0.125
B. bronchiseptica (11)70 16 32 2–128
β–, β-lactamase negative; β1, β-lactamase-positive; PPNG, penicillinase-producing N. gonorrhoeae.
Moraxella catarrhalis. Studies evaluating the activity of MIC90 was somewhat lower than that reported by Hardy et
roxithromycin against this pathogen have included isolates al. (1 mg/L).21 However, this study included only 17
that produce β-lactamase and those that do not.47,56–61 strains. The activity of roxithromycin against β-lactamase-
MIC90s of roxithromycin were in the range 0.12–1 mg/L. producing strains was confirmed by Liebowitz et al.58 in an
These studies also showed that the in-vitro activity of experimental in-vitro study.
roxithromycin was superior to those of erythromycin A
and josamycin. Haemophilus influenzae. The activity of macrolides
Spencer & Wheat56 compared the in-vitro activity of against H. influenzae is not well established,62,63 and
roxithromycin and erythromycin A against 188 strains of numerous studies have been performed with roxithro-
M. catarrhalis. All isolates were susceptible to roxi- mycin.19,32,34,40,57,64–68 The in-vitro activity of roxithro-
thromycin (MIC 5 0.06–0.25 mg/L; MIC50 5 0.125 mg/L; mycin, clarithromycin, and other macrolides against H.
MIC90 5 0.25 mg/L). Roxithromycin was active against influenzae, as measured by standard susceptibility criteria,
strains producing BRO-1 and BRO-2 β-lactamases. The is sufficient to classify many isolates as fully resistant.
5
A. Bryskier
However, roxithromycin achieves high plasma concen- Eikenella corrodens. Goldstein et al.46 studied clinical
trations, which suggests that the criteria for susceptibility isolates of E. corrodens associated with dog bites and
ought to be revised.14 Erwin & Jones19 proposed a found that roxithromycin was poorly active against this
breakpoint for roxithromycin of <16 mg/L for both β- pathogen (MIC, 4–.32 mg/L; MIC50 and MIC90, 32 mg/L).
lactamase-producing strains and non-β-lactamase-produc-
ing isolates, which were similarly inhibited by roxi-
Anaerobes
thromycin. MIC 50s against non-type b H. influenzae were
higher than those against type b strains (8 and 4 mg/L, The potential role of macrolides in anaerobic infections is
respectively).65 Two studies have shown that roxithro- still controversial. Several studies have investigated the
mycin displays bactericidal activity against H. influenzae activity of roxithromycin in these organisms.13,23,73–77
with low incidence of dissociated MBC/MIC ratios.34,69 Dubreuil74 compared the in-vitro activity of roxithro-
Nicoletti et al.68 compared the in-vitro activity of roxi- mycin against anaerobes with that of erythromycin A;
thromycin, erythromycin A and ampicillin against H. in - B. fragilis ATCC 25285 was used as a control. At a
fluenzae biotypes I (four strains), II (14 strains) and III (16 concentration of 4 mg/L, roxithromycin and erythromycin
strains), and various Haemophilus species. No difference A inhibited 59% and 58% of B. fragilis (sensu stricto),
in activity was observed against the three biotypes. The respectively. Roxithromycin was less active against Bac -
MIC50s and MIC90s of roxithromycin against ampicillin- teroides thetaiotaomicron but inhibited two-thirds of
susceptible and ampicillin-resistant strains of Haemo - Bacteroides distanosis isolates while Porphyromonas spp.
philus parainfluenzae were 0.19/1.56 mg/L and 0.39/1.56 and Prevotella spp. were more susceptible to roxithro-
mg/L, respectively (Table IV). mycin than erythromycin A. All 103 strains were inhibited
by 2 mg/L of roxithromycin and 4 mg/L of erythromycin A.
Bordetella spp. In studies of the in-vitro activity of roxi- P. melaninogenica and all Mobiluncus spp. were sus-
thromycin against 75 clinical isolates of B. pertussis,70,71 the ceptible to roxithromycin (MICs , 0.25 mg/L). Half of the
MIC50s and MIC 90s of roxithromycin and erythromycin A strains of Fusobacterium spp. were resistant to roxi-
were 0.25/0.5 mg/L and <0.12/<0.12 mg/L, respectively.70 thromycin, and F. nucleatum strains were slightly more
The MIC90s of roxithromycin, erythromycin A, josamycin, susceptible than other species of this genus (MIC50 ' 2
clarithromycin, azithromycin and dirithromycin were 0.03, mg/L) but Fusobacterium varium and Fusobacterium
0.03, 0.06, <0.01, 0.03 and 0.03 mg/L, respectively.71 mortiferum strains were resistant (MIC50 . 64 mg/L).
Against Bordetella parapertussis, MIC50 and MIC 90 values Veillonella spp. were poorly susceptible to roxithromycin
were 0.5/0.12 mg/L and 0.25/0.25 mg/L for roxithromycin (MIC50 5 16 mg/L) but, of the 124 Peptococcus strains
and erythromycin A, respectively.71 In a 5 year survey in tested, only two were highly resistant (MIC . 64 mg/L;
New Zealand, no reduction of in-vitro activity against B. MIC50 5 4 mg/L). MIC50s of roxithromycin against
pertussis was recorded.72 The MIC90s of roxithromycin, Peptostreptococcus and Clostridium perfringens were
erythromycin A, josamycin, azithromycin, clarithromycin 0.125 and 2 mg/L, respectively.
and dirithromycin were 0.25, 0.25, 1, 0.125, 0.25 and 0.125 Clostridium difficile strains may be divided into two
mg/L, respectively. Roxithromycin and erythromycin A groups on the basis of susceptibility to roxithromycin:76 a
are poorly active against Bordetella bronchiseptica, with sensitive group (MIC < 2 mg/L) and a highly resistant
MIC50s and MIC90s of 16/32 mg/L and 8/32 mg/L, group (MIC . 64 mg/L). Other clostridia were generally
respectively.70 susceptible to roxithromycin (MIC 90 ' 2 mg/L). Resistant
strains were mainly Clostridium ramosum and Clostridium
Pasteurella multocida. MICs of roxithromycin against P. innocuum. Eubacterium aerofaciens and Eubacterium
multocida range between 0.5 and 2 mg/L and MBCs are limosum were inhibited by roxithromycin at a concen-
2–16 mg/L.34,46 tration of 2 mg/L, whereas propionibacteria, bifidobacteria
Table IV. Activity of roxithromycin against species of Haemophilus68
H. influenzae biotype I (3) 0.19 0.78 0.19–0.78

H. influenzae biotype I (9) 0.19 0.78 0.05–1.56
H. influenzae biotype III (10) 0.39 0.78 0.05–1.56
H. parainfluenzae (11) 0.19 1.56 0.05–3.12
H. paraphrophilus (12) 0.19 0.78 0.09–3.12
H. aphrophilus (2) – – 0.05–0.19
6
and Actinomyces spp. were all susceptible to roxithro- phorylation by protein kinase A leads to increased
mycin (MIC < 1 mg/L) (Table V). macrolide transport.
The concentration of roxithromycin in cells recovered
by bronchoalveolar lavage (22 6 10 mg/L) is twice that
Intracellular pathogens
found in plasma (11 6 6 mg/L) and 12 times that in
Intracellular concentrations. As roxithromycin penetrates epithelial lining fluid (1.8 6 7 mg/L).84 Other authors have
cells and accumulates within them, 78 it might be useful for reported I/E ratios of 16.2–21.9 and 30.85–87 The I/E ratios
treating infections caused by susceptible intracellular recorded by Carlier et al.79 in the alveolar macrophages of
pathogens, such as Legionella, Chlamydia and Rickettsia non-smokers and smokers were 61 6 7 and 190 6 21,
spp., and Rickettsia-like spp. (Bartonella, formerly respectively. In human PMN the ratio was 14 6 3. Roxi-
Rochalimaea spp.), Mycobacterium spp. and Brucella spp. thromycin is also active intracellularly against pathogens
Carlier et al.79 studied the intracellular accumulation within phagocytes.87–89
and subcellular distribution of 14C-labelled roxithromycin
and erythromycin A in J-774 macrophages and poly- Legionella pneumophila. Several studies of the effects of
morphonuclear neutrophils (PMN). They observed a roxithromycin against L. pneumophila have been
bimodal distribution of both compounds in macrophages published.90–96 Dournon et al.93 compared the in-vitro
and approximately one-half of the amount of each drug activity of roxithromycin with that of three other
was soluble located presumably in the cytosol; the macrolides—erythromycin A, spiramycin and josamycin—
remaining half was associated with granules. In human against L. pneumophila. The results were corrected to take
PMN, approximately one-third of intracellular roxithro- into account the possible inhibitory effect of charcoal-
mycin was associated with azurophilic granules. These supplemented agar (BCEY) used in the study of
results agree with those reported by Hand et al.,80 who antibacterial activity. Corrected MICs were 0.04, 0.06, 0.17
showed that roxithromycin was accumulated by PMN and 1.20 mg/L for roxithromycin, erythromycin A,
cytoplasts with an intracellular/extracellular (I/E) ratio josamycin and spiramycin, respectively.
two-thirds of that in intact PMN (13.8 compared with Liebers et al.97 compared agar dilution and micro-
28.8). dilution susceptibility testing for eight antimicrobial
In recent studies,81,82 it has been shown that roxithro- agents, including four macrolide antibiotics, against 48
mycin is rapidly taken up by human neutrophils (within clinical isolates of L. pneumophila. For the agar dilution
30–60 min) and maximal I/E values are approximately 100 tests charcoal-free agar (BSYE) and BCEY were used.
and 30 for roxithromycin and erythromycin A, res- The MIC50s and MIC90s of roxithromycin were 0.25–0.06
pectively. Roxithromycin, like erythromycin A and clari- mg/L and 0.5–0.06 mg/L for BCEY and BSYE, res-
thromycin (but not azithromycin), is rapidly released from pectively. Inhibitory and bactericidal concentrations of
cells (80% within 1 h). Recent data83 suggest that phos- roxithromycin against 48 strains of L. pneumophila using a
Table V. Activity of roxithromycin against anaerobic bacilli74
B. fragilis (148) 4 >64 0.25–>64

B. thetaiotaomicron (46) 32 64 1–>64
B. distanosis (25) 2 16 0.25–>64
P. melaninogenica (82) 0.125 0.5 0.003–2
Mobiluncus spp. (20) 0.016 0.03 0.004–0.25
F. nucleatum (17) 2 64 0.25–>64
F. varium and F. mortiferum (10) – – 64
Veillonella spp. (7) 16 32 16–64
Peptococcus spp. (124) 4 4 0.125–>64
Peptostreptococcus spp. (38) 0.125 1 0.03–64
C. perfringens (133) 2 4 0.25–8
C. difficile (26) 1 >64 0.25–>64
Eubacterium spp. (28) 0.125 2 0.06–>64
Propionibacterium spp. (27) 0.06 0.25 0.03–1
Actinomyces spp. (13) 0.06 1 0.06–1
Bifidobacterium spp. (13) 0.06 1 0.06–1
7
A. Bryskier
microdilution technique were: MIC50, 0.125 mg/l; MBC50, Cevenini et al.99–101 used McCoy cell monolayers infected
0.25 mg/L; MIC90, 0.25 mg/L; MBC90, 4.0 mg/L. A detailed with C. trachomatis LGV 2 serotype and reported roxi-
study of macrolides against Legionella spp. (reference thromycin MICs of 0.05–0.8 mg/L, with MBCs in the same
strains) was also carried out using BSYE agar.90 MICs range. Kato et al.102 compared the antichlamydial activity of
were 0.25 mg/L for L. pneumophila (serotypes 1–6), roxithromycin, midecamycin, rokitamycin and spiramycin
Legionella micdadei, Legionella dumoffii, Legionella against ten clinical isolates of C. trachomatis. Roxithro-
longbeachae (serotypes 1 and 2) and Legionella wads - mycin was more effective than midecamycin and
worthii. Against Legionella bozemanii and Legionella spiramycin, and as effective as rokitamycin. MICs ranged
gormanii, MICs were 0.5 mg/L and 0.06 mg/L, res- between <0.03 and 0.125 mg/L. Samra et al.103 also used the
pectively. These results were confirmed by Jones & McCoy cell line, and compared the activity of roxithro-
Barry.91 mycin, erythromycin A, doxycycline and tetracycline
The in-vitro activity of roxithromycin against Legionella against 50 clinical isolates of C. trachomatis. Sixty-four per
species has also been assessed by Stout et al. (Stout, J. E., cent of the isolates were inhibited by 0.06 mg/L of roxi-
Arnold, A., Ta, A. and Yu, V. L., data on file, Roussel thromycin and 100% by 0.12 mg/L; 100% of isolates were
Uclaf) using buffered yeast-extract broth supplemented inhibited by 0.25 mg/L of erythromycin A and doxycycline,
with L-cysteine, ferric pyrophosphate and α-ketoglutarate, and by 0.5 mg/L of tetracycline. Roxithromycin exhibited
and 48–72 h incubation. The broth dilution MICs and bactericidal activity compared with erythromycin A, doxy-
MBCs of roxithromycin (0.06–0.25 mg/L and 1–8 mg/L, cycline and tetracycline, which were bacteriostatic.
respectively) were similar to those of erythromycin A. In Orfila & Haider104,105 compared the in-vitro activity of
the HL-60 tissue culture model (promyelocytic leukaemic macrolides against C. pneumoniae; the lowest MIC (0.05
cell line, ATCC), roxithromycin demonstrated significant mg/L) was obtained with roxithromycin and the highest (1
activity against Legionella spp. at 8 3 MIC (Table VI). mg/L) with erythromycin A. In J-774 macrophage cells,
the accumulation of erythromycin A and roxithromycin in
Chlamydia spp. The genus Chlamydia encompasses three C. trachomatis-infected cells was similar to that in unin-
species—Chlamydia trachomatis, Chlamydia psittaci and fected cells. Roxithromycin showed greater activity than
Chlamydia pneumoniae. Chlamydiae are obligate intra- erythromycin A against C. trachomatis and was as
cellular parasites which accumulate in cytoplasmic effective against C. pneumoniae in the J-774 macrophage
vacuoles, where they undergo a complex transformation model. Fewer than 1% of the cells were infected after
from elementary bodies to reticular bodies.98 MIC exposure to 5 mg/L of the macrolides for 60 h (C.
determinations are carried out in tissue culture and trachomatis) or 74 h (C. pneumoniae).106
numerous cell lines have been used, including non-phago- Fenelon et al.,107 using McCoy cells, found an MIC of
cytic cells (HeLa, McCoy, HEp-2) and macrophages (J- roxithromycin of 0.25 mg/L against C. pneumoniae strain
774). However, it is difficult to compare results obtained TW183. Bowie et al. 108 determined the in-vitro activity of
with the macrolides because of the different methodologies roxithromycin against ten clinical isolates of C. tracho -
used by investigators. matis using cycloheximide-treated McCoy cell mono-
Table VI. Activity of roxithromycin against Legionella spp.90
Species Serogroup 104 cfu/spot 106 cfu/spot
L. pneumophila 1 ATCC 33152 0.0625 0.25

1 ATCC 33153 0.0625 0.25
2 ATCC 33154 0.0625 0.25
3 ATCC 33155 0.0625 0.25
4 ATCC 33156 0.0625 0.25
5 ATCC 33216 0.125 0.25
6 ATCC 33125 0.125 0.50
L. micdadei ATCC 33218 0.0625 0.50
L. dumoffii ATCC 33219 0.25 0.25
L. longbeachae 1 ATCC 33462 <0.03 0.25
2 ATCC 33484 <0.03 0.125
L. gormanii ATCC 33297 <0.03 0.0625
L. jordanis ATCC 33623 <0.03 0.25
L. wadsworthii ATCC 33877 <0.03 0.25
8
layers. The MIC50 and MIC90 of roxithromycin were 0.5 In this in-vitro test, roxithromycin and clarithromycin
and 1.0 mg/L, respectively. Several other studies have were each more potent than erythromycin A or azithro-
confirmed these results.109–114 mycin, and exhibited greatest activity in increasing the rate
Three studies have investigated the activity of roxi- of ATP decay and reducing rates of palmitate oxidation.
thromycin against C. psittaci (reference 115; S. Richmond Roxithromycin and other macrolides were administered in
(two studies), data on file, Roussel Uclaf). S. Richmond the diet of Balb/c mice at 0.01% (w/w). Neither erythro-
(data on file, Roussel Uclaf) determined the MIC and mycin A nor roxithromycin inhibited growth of M. leprae
minimum lethal concentration (MLC) of roxithromycin in mouse footpads. In contrast, Gelber119 found that
and erythromycin A against a duck strain of C. psittaci in aroxithromycin and clarithromycin were bactericidal in the
cycloheximide-treated McCoy cell line. The MICs and murine footpad model.
MLCs were 0.1/.32 mg/L and 0.025/1.6 mg/L for Several studies have been performed to test the activity
erythromycin A and roxithromycin, respectively. Orfila of roxithromycin against MAC.120,121–130 Casal et al.,124
et al.115 compared the in-vitro activity of roxithromycin, using Middlebrook 7H10 agar, studied the in-vitro activity
erythromycin A, josamycin and other antibacterials of roxithromycin alone or in combination with rifampicin
against a test strain of C. psittaci using a McCoy cell lineagainst 20 isolates of M. avium. MICs ranged from 2 to 16
supplemented with fetal calf serum; they found that mg/L. Rifampicin and roxithromycin acted synergically:
roxithromycin and erythromycin A were similarly when 2 mg/L rifampicin was added, the MIC of roxi-
effective (Table VII). thromycin fell to 0.25 mg/L. Naik & Ruck130 tested the in-
vitro activity of 12 macrolide compounds against 28
Mycobacterium spp. Mycobacteria may be divided into M. avium strains isolated from AIDS patients. In-vitro
three categories: Mycobacterium tuberculosis, Myco - activity was determined by the conventional proportion
bacterium leprae and atypical mycobacteria such as method and the radiometric method (BACTEC) method.
Mycobacterium avium complex (MAC). The MIC50 and MIC90 of roxithromycin were 8 and 16
None of the currently available 14- and 15-membered mg/L, respectively, while those of azithromycin, erythro-
ring macrolides show activity against M. tuberculosis, with mycin A and clarithromycin were 16/32 mg/L, 32/64 mg/L
MICs being .64 mg/L.116 The MICs of roxithromycin and 2/4 mg/L, respectively. Maugein et al.125 also studied
against Mycobacterium bovis BCG were 0.5–4 mg/L at pH the in-vitro activity of roxithromycin and erythromycin A
6.8 and 0.25–2 mg/L at pH 7.4. MICs for all isolates (M. against 20 isolates of M. avium using a conventional
tuberculosis, Mycobacterium africanum, M. bovis) were in method; the MIC 50 and MIC90 of roxithromycin were 8/16
the range 32–.64 mg/L at pH 6.8 and 16–32 mg/L at pH mg/L and 16/32 mg/L using 7H9 and Löwenstein agar
7.4.116 medium, respectively, while those of erythromycin A were
Franzblau and colleague117,118 determined the anti- 16/64 mg/L and 32/>64 mg/L. Gévaudan et al. 120 recorded
bacterial activity of roxithromycin, clarithromycin, mean MICs of 4 mg/L (range 4–16 mg/L) of roxithromycin
azithromycin and erythromycin A against M. leprae by and 8 mg/L (range 8–32 mg/L) of azithromycin. They also
measuring intracellular ATP, a radiospirometric assay of observed that roxithromycin and amikacin acted synergic-
palmitate oxidation, and the rate of phenolic glycolipid I ally. Bermudez & Young122 found that this synergy
synthesis. increased tumour necrosis factor (TNF) concentrations.
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 0.03–0.125

C. trachomatis (10)100 – – 0.03–0.125
C. trachomatis (10)108 – – 0.5–2.0
C. pneumoniae (RS)115 – – 0.05–0.125
C. psittaci (RS)115 – – 0.025–2.0
M. pneumoniae (20)148 0.03 0.03 0.008–0.03
M. hominis (ND)110 8 16 8–16
Mycoplasma genitalium (7)187 – – <0.01
U. urealyticum (ND)110 0.25 0.25 0.125–0.25
U. urealyticum (100)146 0.25 0.5 0.125–2
Mycobacterium avium complex (ND)120 – – 4–16
ND, not determined; RS, reference strains.
9
A. Bryskier
Rastogi et al.131 determined roxithromycin MICs against isolates of Mycobacterium marinum.134 Maugein et al.125
MAC clinical isolates using the BACTEC method at two showed that roxithromycin was slightly more active than
pH values. MICs obtained at pH 7.4 (0.5–2.0 mg/L) were erythromycin A against Mycobacterium xenopi. Roxithro-
one or two dilutions lower or higher than those obtained at mycin MIC 50s and MIC90s on 7H9 and Löwenstein media
pH 6.8 (1–8 mg/L) and may indicate that the measured were 0.12/0.25 mg/L and 0.25/0.5 mg/L, respectively.
MIC is influenced by pH. Rastogi et al.126 also examined
combinations of roxithromycin with other antibacterial Rickettsiae. Recent reviews have dealt with Rickettsia and
agents. They found that the antibacterial activity of Coxiella spp.135,136 In vitro, MICs of roxithromycin for
roxithromycin was enhanced against all ten strains tested Rickettsia rickettsii and Rickettsia conorii were 1.0 mg/L,
when the drug was combined with ethambutol, in three whereas those of erythromycin A and spiramycin were 8.0
strains with rifampicin or clofazimine, in two strains with and 32.0 mg/L, respectively. Roxithromycin and erythro-
amikacin, and in one strain with ofloxacin. Casal et al.123 mycin A also have good activity against Rickettsia pro -
found that addition of rifabutin reduced the MIC of wazekii and Rickettsia tsutsugamuchi (B. Hanson & D. J.
roxithromycin to 0.01–0.5 mg/L. Silverman, data on file, Roussel Uclaf).
Roxithromycin was tested against 25 MAC strains Bartonella (Rochalimaea) henselae is a newly identified
isolated from patients with AIDS and disseminated MAC rickettsial pathogen that causes bacillary angiomatosis and
disease.129 A broth radiometric macrodilution method was visceral peliosis. In-vitro reports indicate that macrolides
used to measure the in-vitro activity of roxithromycin and are active against this organism (MIC 5 0.25 mg/L),137 and
other agents (pH approximately 6.8). The range of activity these data have been validated clinically for roxithromycin
was ,2–32 mg/L and the combination of roxithromycin against Bartonella quintana and Bartonella elizabethae,
and ethambutol was additive or synergic. In the macro- with MICs of 0.125 and 0.06 mg/L, respectively.82,134
phage test system, the intracellular activity of roxithro-
mycin was strain-dependent. Against MAC 100, roxi- Brucella spp. Garcia-Rodriguez et al.138 tested the in-vitro
thromycin was bactericidal at concentrations of 1–64 activity of five macrolide antibiotics, including roxithro-
mg/L. Against MAC 101 and MAC 109, roxithromycin mycin, against reference strains of Brucella melitensis,
was bacteriostatic at concentrations of <8 mg/L (MAC Brucella abortus, Brucella neotomae, Brucella suis, Brucella
101) and 32 mg/L (MAC 109). canis and Brucella ovis, and 46 clinical isolates. The MIC50
Rastogi et al.127 screened the intracellular activity of and MIC90 of roxithromycin were 8 and 16 mg/L,
roxithromycin in human macrophages and its further respectively, with MICs ranging from 0.1 to 32 mg/L. In a
potentiation by other antibacterial agents. Roxithromycin murine brucellosis infection, roxithromycin was given orally
used alone was bactericidal against the five MAC isolates. (50 mg/kg) alone or in combination with streptomycin
The bactericidal effect of roxithromycin in combination (75 mg/kg) for 14 days. A significant reduction in B.
with rifampicin against all five strains tested was greater melitensis (MIC 5 3.31 mg/L) numbers in the spleen was
than that of any of the drugs alone. In another study the recorded with both regimens. The mean log10 cfu/g of
combination of roxithromycin with ethambutol and levo- spleen was 3.64 in the roxithromycin-treated mice and 2.6 in
floxacin was also found to be synergic.128 These data the mice treated with the combination regimen. In the
correlate well with the therapeutic efficacy of roxithromycin untreated control animals the value was 5.7.139
observed in animal models of MAC infections.132
Sexually transmitted pathogens
Other atypical mycobacteria. Potentially useful roxithro-
mycin MICs were obtained at pH 7.4 and 6.8 for Myco - Sanson-Le Pors et al.140 tested the in-vitro activity of
bacterium scrofulaceum (1.0 and 0.5 mg/L, respectively), roxithromycin against Haemophilus ducreyi and recorded
Mycobacterium sulzgai (4.0 and 1.0 mg/L), Mycobacterium MICs of 0.016–0.06 mg/L. Miller et al. 141 reported MIC 50s/
malmoenese (2 and 0.5 mg/L), Mycobacterium xenopi MIC90s of 0.001/0.004 mg/L, 0.004/0.005 mg/L and 0.004/
(0.5 and 0.25 mg/L) and Mycobacterium kansasii (1 and 0.015 mg/L for roxithromycin, erythromycin A and clari-
0.5 mg/L), but not for Mycobacterium simiae (32 and thromycin, respectively. Lukehart & Baker-Zander142
8.0 mg/L). Roxithromycin was more active at pH 7.4 found that roxithromycin and erythromycin A had
than at pH 6.8.131 Brown et al.133 evaluated the in-vitro significant activity against Treponema pallidum.
efficacy of roxithromycin against reference isolates of Comparative studies of the in-vitro activity of roxi-
rapidly growing mycobacteria. Roxithromycin inhibited thromycin and erythromycin A against clinical isolates of
.90% of isolates of Mycobacterium abscessus, Myco - Gardnerella vaginalis showed MICs of 0.008–0.016
bacterium chelonae, M. chelonae-like organisms and mg/L.51,143,144 MIC90s were identical for roxithromycin,
Mycobacterium peregrinum at a concentration of 2 mg/L. erythromycin A and clarithromycin (0.12 mg/L).143 MICs
Mycobacterium fortuitum was less susceptible, with of roxithromycin rose as the bacterial inoculum size
only 29% of isolates being susceptible to roxithromycin increased (10 3 cfu/mL, 0.003 mg/L; 10 5 cfu/mL, 0.01 mg/L;
(2 mg/L). Roxithromycin had minimal activity against 20 107 cfu/mL, 0.04 mg/L).51
10
Both roxithromycin and erythromycin A show good tested the antibacterial activity of roxithromycin, erythro-
activity against Ureaplasma urealyticum.99,145–147 However, mycin A, clarithromycin and azithromycin against B.
differences in methodology make comparisons between burgdorferi in vitro and in vivo. In vitro, all macrolides
studies difficult. Ridgway 145 found MICs of roxithromycin displayed excellent activity (roxithromycin MIC50 5 0.015,
and erythromycin A of 0.125–0.5 mg/L, whereas other MIC90 = 0.03 mg/L). However, roxithromycin was not
investigators have reported MICs of 0.1–4.0 mg/L overall effective in the gerbil model.
for both compounds. Bébéar et al.146 reported values of 0.2 Early investigations revealed relative homogeneity of
and 1.0 mg/L for roxithromycin and erythromycin A, protein profiles and antigenic reactions among American
respectively, and roxithromycin MIC50 and MIC90 of isolates of B. burgdorferi and heterogeneity among
0.25/1.0 mg/L. European isolates.154 B. burgdorferi sensu lato has been
Like all 14- and 15-membered ring macrolides, roxi- subdivided into three genospecies:155 B. burgdorferi sensu
thromycin is not active against Mycoplasma hominis (MIC stricto, Borrelia garinii and Borrelia afzelii. Recent
. 32 mg/L). findings suggest that the genospecies are associated with
The in-vitro activity of roxithromycin against Neisseria different clinical manifestations (arthritis, neurological
gonorrhoeae has been determined in a number of symptoms and acrodermatitis chronica atrophicans,
studies.32,34,37 MICs range between 0.25 and 4 mg/L, with respectively).156 Péter & Bretz152 investigated the in-vitro
an MIC50 and MIC90 of 0.7 and 3 mg/L, respectively. activity of seven antibacterial agents, including roxithro-
N. gonorrhoeae isolates resistant to penicillin G were two mycin, against these three subspecies. MICs of roxithro-
to four times less susceptible than the penicillin-susceptible mycin were 0.062 mg/L, 0.015 mg/L and 0.125–0.062 mg/L,
strains, with MIC 50s and MIC 90s of 0.12–1 mg/L compared respectively, and roxithromycin was bacteriostatic for
with 0.12–0.25 mg/L.37,145 most isolates. Roxithromycin was more effective against
B. burgdorferi sensu stricto and B. garinii than B. afzelii. In
another study the combination of roxithromycin and
Other pathogens minocycline was synergic against all three B. burgdorferi
genospecies.157
Mycoplasma pneumoniae. The in-vitro activity of roxi-
thromycin, erythromycin A, and josamycin was assessed Helicobacter pylori. Eradication of H. pylori cures gastritis
against 100 strains of M. pneumoniae. The geometric mean and prevents duodenal ulcer relapse. However, there are
MICs were 0.27, 1.97 and 0.12 mg/L, respectively; the several drawbacks to the 2 week triple-drug therapy used
MIC50 and MIC90 were 0.03 mg/L.146,148 Hara et al.90 in- to eradicate H. pylori, and macrolide antibiotics may be an
vestigated the in-vitro activity of roxithromycin and alternative. Czinn et al. 158 compared the in-vitro activities
erythromycin A against 18 clinical isolates of M. pneu - of roxithromycin, erythromycin A and azithromycin
moniae and reported geometric mean MICs of 0.01 mg/L against ten strains of H. pylori. Overall MICs ranged from
and 0.0039 mg/L, respectively. Palu et al.147 compared 0.06 to 0.5 mg/L. The MIC50 and MIC 90 of roxithromycin
eight macrolides against ten strains of M. pneumoniae and against H. pylori were 0.12 and 0.25 mg/L, respectively
reported MICs of <0.01 mg/L for roxithromycin, erythro- (MIC range 0.12–0.25 mg/L).30,159 Mégraud et al.160
mycin A and miokamycin and 0.05 mg/L for oleando- determined the killing curves of roxithromycin alone or in
mycin. combination with amoxycillin and/or lansoprazole. Roxi-
thromycin at >1 mg/L had a bactericidal effect (reduction
Borrelia spp. Lyme disease is the most commonly reported of 3 log10 cfu/mL) after 24 h. When a subinhibitory
tick-borne disease in Europe and the USA. In-vitro and concentration of amoxycillin (0.001 mg/L) was added, an
in-vivo studies have been carried out to assess the efficacy additive effect was observed. Combination of the proton-
of roxithromycin in the treatment of the disease and have pump inhibitor lansoprazole, amoxycillin and roxithro-
shown that isolates of Borrelia burgdorferi are highly mycin was also found to be additive or synergic but never
susceptible to the new macrolides (MIC ' 0.03 antagonistic. Cross-resistance between all macrolides was
mg/L).149–153 Sambri et al.149 tested roxithromycin and observed for clarithromycin-resistant isolates.
other antibacterial agents against six clinical isolates of B.
burgdorferi and one of Borrelia hermsii. MBCs of roxi- Campylobacter spp. Microorganisms of the genus Campy -
thromycin for all isolates were 0.125 mg/L. Gasser et al. 153 lobacter are increasingly common in enteric disease,
found a roxithromycin MIC of 0.031 mg/L for B. usually causing non-invasive diarrhoea which occasionally
burgdorferi ATCC 35210. Hansen et al. 151 showed that all requires antibacterial therapy. Goosens et al. 161 compared
strains of B. burgdorferi were highly susceptible to roxi- the in-vitro activity of roxithromycin and erythromycin A
thromycin in vitro, with a median MBC of 0.12 mg/L. In an against Campylobacter jejuni. The MIC50 and MIC90 of
animal (gerbil) model systemic B. burgdorferi infection roxithromycin were 1 and 4 mg/L, respectively (range
was eradicated within 10 days’ treatment with roxithro- 0.25–8 mg/L). These results are similar to those obtained
mycin at doses of .25 mg/kg/day. Preac-Mursic et al.150 by Barlam & Neu31 MICs of azithromycin, clarithromycin,
11
A. Bryskier
roxithromycin and erythromycin A were determined for on both the concentration of the drug and the duration of
36 quinolone-susceptible and 106 quinolone-resistant exposure. Similar results were obtained with erythromycin
strains of C. jejuni. MIC90s were 0.5, 4, 16 and 4 mg/L, A and clindamycin after exposure for 1 h; concentrations
respectively. No difference in activity was found between similar to the MIC resulted in PAEs of 1–2 h. In contrast, 1
macrolides against quinolone-susceptible and quinolone- and 2 h exposure to 5–10 3 MIC were followed by PAEs
resistant strains. 162 Resistance to roxithromycin remained of 3.2 and 5.3 h (erythromycin A), 2.5 and 4.9 h
stable between 1988 and 1992 (MIC50 5 2 mg/L) and (clindamycin) and 2.6 h and 4.4 h (roxithromycin).
comprises approximately 10% of strains for a breakpoint Corresponding PAEs for a 6 h exposure were 6.3 h for
MIC of >8 mg/L.163 The MIC50s of roxithromycin for erythromycin A and roxithromycin, and 6.9 h for
Campylobacter upsaliensis and Campylobacter fetus sub- clindamycin. Roxithromycin concentrations of 50–100 3
species fetus were 3.12 and 1.56 mg/L, respectively.164 MIC produced a maximal PAE of 7.9 h following exposure
for 6 h. Similar PAEs of up to 1.5 h were observed when S.
Vibrio cholerae. Macrolides can be used in the treatment pyogenes Abs 86-29 was exposed to 0.5–1.0 3 MICs of the
of cholera in children.165 The MIC50 and MIC90 for 50 three drugs for 1 and 6 h. In contrast, 6 h exposure to 5–10
clinical isolates of V. cholerae serovar Ogawa of African 3 MIC of roxithromycin resulted in PAEs of 6–7 h. PAEs
origin were 6.2 and 15.5 mg/L, respectively (Table VIII). of 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 produced
PAEs of 2.5–5.2 h depending on exposure time.
Faecal flora Exposure of H. influenzaeto the MIC for 2 h produced no
significant PAE. However, a maximal PAE of 2–4 h was
The ecological impact on the intestinal flora of obtained after 1–2 h exposure to 10 3 MIC of
roxithromycin given orally at a dose of 300 mg was studied roxithromycin and erythromycin A. Exposure to 10 3 MIC
in six volunteers.166 The faecal concentrations of roxi- of clindamycin for 1–2 h produced a PAE of only 1–2 h.
thromycin were in the range of 100–200 mg/kg of faeces. Castillo et al. 169 determined the duration of the PAE of
Changes in the faecal flora were limited to a decrease in clarithromycin, erythromycin A, and roxithromycin in
overall counts of Enterobacteriaceae. Other intestinal vitro against 12 clinical isolates of S. aureus and S.
flora, including anaerobes, were not significantly affected epidermidis, and found that roxithromycin PAEs lasted
and no overgrowth of P. aeruginosa , staphylococci, fungi 0.9–2.6 h.
or highly erythromycin-resistant strains of Enterobac- Hamilton-Miller & Shah170 showed that the PAE of
teriaceae was observed. In six volunteers receiving roxithromycin against Lancefield group A streptococci
repeated doses of roxithromycin (150 mg every 12 h for 29 was similar to that of erythromycin A and miokamycin,
doses), no abnormal growth of C. difficile was observed.167 but inferior to that of miokamycin against group B
streptococci and erythromycin A-sensitive enterococcal
Post-antibiotic effect isolates.
Post-exposure, sub-MIC concentrations may enhance
Kuenzi et al.168 performed a study involving H. influenzae, the duration of macrolide PAEs. Exposure of S. pyogenesto
S. aureus, S. pyogenes and S. pneumoniae. Like erythro- sub-MIC concentrations (0.1, 0.2 and 0.3 3 MIC) of roxi-
mycin A, roxithromycin showed a time-dependent post- thromycin during the PAE phase increased the PAE
antibiotic effect (PAE). S. pneumoniae ATCC 27336 duration from 5 h to 5.6, 9.8 and 10.4 h respectively.171 It has
(MIC , 0.06–0.125 mg/L) was exposed for 2 h to 7 mg/L of been suggested that subinhibitory concentrations of anti-
roxithromycin. Subcultures were taken into fresh drug- bacterial agents reduce the virulence of some bacterial
free broth. Analysis of regrowth revealed a PAE of 5.2 h. species. In vitro, roxithromycin completely inhibited
Further experiments showed that the PAE was dependent coagulase and b-haemolysin production by S. aureus and
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 0.39–25

Campylobacter coli (50)164 3.12 12.5 0.39–50
C. upsaliensis (20)164 3.12 12.5 0.19–12.5
C. fetus (20)164 1.56 3.12 0.39–3.12
V. cholerae (30)165 6.2 15.5
Helicobacter pylori (33)161 – – 0.25
12
lecithinase and deoxyribonuclease were partially in- Experimental pneumonia. Tsuboi et al.54 compared the
hibited.172 cure rate provided by roxithromycin and erythromycin A
in mice infected with S. pneumoniae (HL-438) by intra-
nasal inoculation. The number of microorganisms found in
In-vivo activities the lungs of mice 48 h after treatment with roxithromycin
was very low. In mice treated with erythromycin A the
Non-discriminative infections number fell initially and rose after 72 h. Concentrations in
Systemic infections. Numerous studies on the effectiveness serum and tissue (lung, liver) were determined by
of roxithromycin in systemic infections have been microbiological assay after a single oral administration of 2
performed (references 3, 7, 54 and 90; N. Klesel & G. mg/mouse (100 mg/kg). The tissue distribution and plasma
Seibert, data on file, Roussel Uclaf). Chantot et al. 7 com- levels of roxithromycin in mice were five to ten times
pared the efficacy of roxithromycin and erythromycin A higher than those of erythromycin A.
following intraperitoneal or oral administration to Charles Muraoka et al. 53 also tested the in-vivo efficacy of roxi-
River CD1 mice. The overall in-vivo activity of roxithro- thromycin and erythromycin A in ICR mice with experi-
mycin was three to six times higher than that of erythro- mental S. pneumoniae infection. Antibiotic treatment was
mycin A, irrespective of in-vitro activity (e.g. for infections started 6 h following intranasal challenge and two further
with S. aureus Giorgio, PD50s were 23 and 60 mg/kg for doses were given 30 and 54 h after the challenge. In the
roxithromycin and erythromycin A, respectively). roxithromycin group there was a marked decrease in the
The antibacterial activity of roxithromycin was also number of viable organisms in the lungs when first
compared with that of erythromycin A in mice inoculated measured at 24 h and later at 48 h compared with the
intraperitoneally with S. aureus, S. pyogenes, S. agalactiae, erythromycin A group. All the animals in the erythro-
L. monocytogenes, Erysipelothrix rhusopathiae (MIC 5 mycin A group died of septicaemia.
0.125 mg/L) or Pasteurella multocida. The in-vitro MICs of
roxithromycin and erythromycin A were equivalent over- Subcutaneous infections. Roxithromycin was more active
all but animals treated with roxithromycin had improved than erythromycin A in preventing subcutaneous infec-
survival, as shown by the lower ED50s compared with tions caused by S. aureus 265 and S. aureus BB.3
those treated with the comparators. The therapeutic ratio
of the ED50 of erythromycin A and roxithromycin suggests
Specific experimental infections
that identical effects are obtained in susceptible bacteria
with doses of roxithromycin six to 14 times lower than Legionella pneumophila. The in-vivo activity of oral
those of erythromycin A (N. Klesel & G. Seibert, data on roxithromycin was compared with that of erythromycin A,
file, Roussel Uclaf). rifampicin, josamycin and rokitamycin against experi-
The in-vivo efficacy of oral roxithromycin, erythro- mental Legionella pneumophila infections in guinea pigs.92
mycin A, josamycin and rokitamycin were compared in Five male guinea pigs (body weight 280–320 g) were
experimental staphylococcal infections (S. aureus Smith) infected with L. pneumophila serogroup 1 by intratracheal
in Std/ddy mice (inoculum of 1.86 3 108 cells/mouse inoculation of 1.9 3 102–1.9 3 108 cfu/animal. The LD50
without mucin).54 ED50s were 0.76, 4.0, 6.63 and 6.94 was calculated by the Behrens–Kärber method.173 Each
mg/mouse for roxithromycin, erythromycin A, josamycin animal was given ten times the LD50 in 0.5 mL. After 24 h,
and rokitamycin, respectively. Nishino et al.3 recorded treatment was started with two daily doses for 7 days (all
similar results when they compared the efficacy of roxi- compounds). None of the animals in the roxithromycin (10
thromycin, erythromycin A, josamycin and rokitamycin mg/kg/day) or rifampicin groups (7.5 mg/kg/day) had died
against other bacterial species (S. aureus, S. pneumoniae by day 10. In the erythromycin A group (20 mg/kg/day)
III and S. pyogenes C-203). the survival rate at day 5 was 60%. All animals in the
Muraoka et al.53 compared the in-vitro and in-vivo josamycin group (20 mg/kg/day) and the rokitamycin
activity of roxithromycin, erythromycin A, josamycin group (10 mg/kg/day) died by day 9 and day 6, res-
and rokitamycin against Gram-positive cocci. ICR mice pectively.
were challenged intraperitoneally with a 5% mucin
suspension of various isolates of S. aureus (Smith, TMS 27, Mycoplasma pneumoniae. Hara et al.90 reported the in-
TMS 298, TMS 299), S. pyogenes (TMS 1, TMS 22) and vitro and in-vivo activities of oral roxithromycin and
S. pneumoniae (TMS 43, TMS 51). ED50s (Van der erythromycin A against M. pneumoniae. Young golden
Waerden method) were determined from the number hamsters (ten in each group) were challenged by the
of mice surviving 7 days after inoculation. Roxithromycin intranasal route with 30 mL of a suspension of 9.2 3 107
was highly effective, two to 50 times more so than other cfu/mL M. pneumoniae. Antibiotic treatment was begun 7
macrolides. Even when other macrolides showed higher days after challenge (5 mg/hamster once daily for 14 days).
in-vitro efficacy, roxithromycin was more effective in The results demonstrated similar, good activity in both
vivo. treatment groups and the number of viable bacterial
13
A. Bryskier
colonies in the lungs was reduced after 3 days in both <100, roxithromycin was effective in cryptosporidium
groups. diarrhoea.184,185
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Roxithromycin Review of Its Antimicrobial Activity

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Journal of Antimicrobial Chemotherapy (1998) 41, Suppl.

Hoechst Marion Roussel, Direction des Recherches Anti-Infectieux, Pharmacologie Clinique,

Roxithromycin is a semi-synthetic 14-membered-ring macrolide antibiotic in which the

Introduction (Bacteroides fragilis group, Prevotella melaninogenica,

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

clarithromycin (MIC50 5 4–8 mg/L).6,20–22 According to

Determination of in-vitro susceptibility

Table I. Activity of roxithromycin against Gram-positive cocci

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

Table II. Activity of roxithromycin against Gram-positive bacilli

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

L. monocytogenes (20)55 0.5 0.5 0.25–1

Table III. Activity of roxithromycin against Gram-negative bacilli

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

N. meningitidis (26)6 0.12 0.5 –

β–, β-lactamase negative; β1, β-lactamase-positive; PPNG, penicillinase-producing N. gonorrhoeae.

Table IV. Activity of roxithromycin against species of Haemophilus68

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

H. influenzae biotype I (3) 0.19 0.78 0.19–0.78

Table V. Activity of roxithromycin against anaerobic bacilli74

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

B. fragilis (148) 4 >64 0.25–>64

Table VI. Activity of roxithromycin against Legionella spp.90

Species Serogroup 104 cfu/spot 106 cfu/spot

L. pneumophila 1 ATCC 33152 0.0625 0.25

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 0.03–0.125

ND, not determined; RS, reference strains.

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 0.39–25

Chlamydia trachomatis salpingitis. Zana et al.174 used a References

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