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Monaldi Arch Chest Dis 2001; 56: 6, 527534

REVIEW

Community-acquired pneumonia: role of atypical organisms

R. Cosentini, P. Tarsia, F. Blasi*, E. Roma*, L. Allegra*
ABSTRACT: Community-acquired pneumonia: role of atypical organisms. R. Cosentini, P. Tarsia, F. Blasi, E. Roma, L. Allegra. M. pneumoniae infection occurs world-wide and is the most common cause of community-acquired pneumonia (CAP) in the 5 to 20 year-old age group. The most reliable diagnostic test is enzyme immunoassay that allows immunoglobulin (Ig)G and IgM titration and presents 92% sensitivity and 95% specificity on paired samples. Potentially active drugs are tetracyclines, macrolides, ketolides, lincosamides, streptogamines, chloramphenicol, and fluoroquinolones. The incidence of Legionella infection, in spite of its world-wide diffusion, is highly variable in different studies, ranging from 1% to 27% of CAP. The most likely mode of transmission is direct inhalation from Legionella-contaminated water-supply systems. Extrapulmonary manifestations are relatively common but nonspecific. However, some signs and symptoms may raise the suspicion of Legionella infection: a sputum Gram stain with a high number of neutrophils without any organism, hyponatremia, and diarrhea in a critically ill patient. Urinary radioimmunoassay (RIA) antigen detection is the method of choice for L. pneumophila serogroup 1. The best treatment regimen is a full three-week treatment with a macrolide (erythromycin, clarithromycin, azithromycin). An alternative treatment regimen may be the association of second generation fluoroquinolones with tetracyclines. A notable improvement in most of the new fluoroquinolones is their activity against Legionella, so that their use as single agent may be hypothesised even if clinical data are still insufficient for a definitive indication. Chlamydia pneumoniae account for 6-20% of CAP depending on several factors such as setting of the studied population, age group examined, and diagnostic methods used. The current gold standard for serological diagnosis of acute infection is microimmunofluorescence testing. Tetracyclines and erythromycin show good in vitro activity and so far have been the most commonly employed drugs in the treatment of C. pneumoniae infection. New macrolides, ketolides, and new fluoroquinolones are other potentially effective drugs. Monaldi Arch Chest Dis 2001; 56: 6, 527534.

Keywords: Community-acquired pneumonia, atypical micro-organisms, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella spp. Department of Emergency Medicine, IRCCS Ospedale Maggiore di Milano. *Institute of Respiratory Diseases, University of Milan, IRCCS Ospedale Maggiore di Milano, Italy. Correspondence: Dr Roberto Cosentini; IRCCS Ospedale Maggiore; Divisione Medicina dUrgenza; Via F. Sforza, 35; 20122 Milan, Italy; e-mail: medurg3@polic.cilea.it

Atypical pneumonia is a clinical syndrome without a precise definition, first described by Reimann in 1938 [1], who realised that in some patients with pneumonia the clinical picture and the natural history differed from that seen in patients with pneumococcal infection. The syndrome includes a subacute onset with low-moderate grade fever, dry cough, prominent constitutional symptoms, absent or moderate leukocytosis, with a more extensive radiographic involvement than physical examination would suggest. The term atypical pathogens indicates a number of micro-organisms that can cause so-called atypical pneumonia and other respiratory and probably non-respiratory diseases. For the past decade, the frequency of pneumonia due to atypical pathogens has varied considerably in different clinical series, but these pathogens as a group have become accepted as relatively common causes of pneumonia in both outpatient and inpatient settings (table 1) [2, 3]. The most important bacteria included in this group are Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella spp.

Mycoplasma pneumoniae M. pneumoniae is a slowly growing, pleiomorphic, nonmotile bacteria that lacks a cell wall. It was first identified by Eaton et al. and then cultured by Chanock et al. and eventually classified as Mycoplasma pneumoniae in 1963 [46]. M. pneumoniae is bound by a single triple-layered membrane, stains Gram negative, appears filamentous,
Table 1. Microbial causes of community-acquired pneumonia (CAP) in adults (%) Organism S. pneumoniae H. influenzae S. aureus L. pneumophila M. pneumoniae C. pneumoniae Amongst Amongst In intensive outpatients inpatients care 12-36 0-14 0-1 0-3 1-26 4-16 10-76 1-11 0-4 0-16 0-29 6-18 10-36 0-12 0-22 0-30 0-7 ?

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measures 10 x 200 nm in size, and displays a neuraminic acid receptor site for attachment to host cell membranes [7]. The absence of a cell wall has been associated with atypical biochemical, serological and cultural behaviour, marked pleiomorphism, and, from a clinical point of view, resistance to antibiotics that exert antibacterial activity by interfering with cell wall synthesis. Epidemiology M. pneumoniae infection occurs world-wide throughout the year without significant seasonal fluctuations and is both endemic and epidemic. Peaks of incidence occur every 5-7 years and epidemics of Mycoplasma infection last 6 to 8 months [8]. Children and young adults are the individuals most often involved in M. pneumoniae infections, and this agent is the most common cause of community-acquired pneumonia (CAP) in the 5 to 20 year-old age group (9). M. pneumoniae infection has however also been identified in 11 to 17% cases of pneumonia in patients over 40 years of age [10]. Epidemics have been described in enclosed populations such as college students, prisoners, military garrisons, and even hospital workers [11]. Simultaneous cases within single households are not uncommon. Infection is transmitted from person to person by inhalation of droplet nuclei after exposure to an acutely ill coughing individual. There is no prolonged carrier state, although a temporary carrier condition occurs following natural human infection. After attaching to epithelial cells by means of its neuraminic differentiated terminal unit, M. pneumoniae interrupts cell RNA and protein synthesis, resulting in ciliostasis, inflammatory cell recruitment, denudation of cilia and extensive epithelial cell injury [12]. Immunopathological damage is mediated by mimicry between M. pneumoniae and host antigens. Typical manifestations are the extrapulmonary manifestations of infection such as hemolytic anemia. The organism does not generally penetrate into the lung parenchyma or the bloodstream. Airway inflammation extends from the trachea and bronchi to the bronchioles. The most common pathological finding is an acute and chronic bronchiolitis and peribronchiolitis. Host defence to M. pneumoniae infection may be mediated by cellular rather than humoral mechanisms. Infection stimulates an initial specific immunoglobulin (Ig)-M antibody response present in up to 78% of patients within 2 weeks, followed by an IgG antibody response. Although the IgM response peaks at about one month, IgG antibodies persist for very long periods. Cold hemagglutinins and rheumatoid factor have been identified in patients with M. pneumoniae infection. Extrapulmonary complications Extrapulmonary involvement during M. pneumoniae infection may sometimes overshadow the respiratory picture (table 2). Presence of multiple extrapulmonary manifestations is an ominous
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Table 2. Extrapulmonary manifestations of M. pneumoniae infection Hematologic Hemolytic anemia, hemagglutination, paroxysmal cold hemoglobinuria, thrombocytopenic purpura, intravascular coagulation Gastrointestinal Anorexia, nausea, vomiting, diarrhea, pancreatitis, liver dysfunction Cardiovascular Myocarditis, pericarditis, endocarditis, congestive heart failure, pericardial effusion, complete heart block, Raynauds phenomenon Dermatological Skin rashes, Stevens Johnson syndrome Muscolo-skeletal Arthralgias, myalgias, migratory polyarthritis Neurological Aseptic meningitis, meningoencephalitis, cerebrovascular accident, ascending paralysis, hemiplegia, transverse myelitis, peripheral neuropathy, Guillain-Barr syndrome, cranial nerve palsies, cerebellar ataxia, polyradiculitis Miscellaneous Acute glomerulonephritis, immunoglobulin A (IgA) nephropathy, interstitial nephritis, renal failure, generalised lymphadenopathy, splenomegaly, biologic false-positive syphilis test, tubercolin anergy.

prognostic factor [13]. The exact mechanisms underlying the onset of extrapulmonary involvement are poorly understood. Immunopathogenetic factors are probably involved given the cross-reactivity between human and M. pneumoniae antigens. The principal hematologic manifestations associated with M. pneumoniae pneumonia are hemolytic anemia and cold hemagglutination. The latter has been found in 33-76% of patients with pneumonia and is determined by IgM antibodies that bind to red cell wall antigens and activate complement. Hemolytic anemia often appears during the second or third week following infection, is associated with high cold hemoagglutinin titres and may result in paroxysmal cold hemoglobinuria, thrombocytopenic purpura, intravascular coagulation, and renal failure (metahemolytic uremia). Maculopapular, measle-like, urticarial, bullous, and petecchial skin rashes have been reported in approximately 20% of M. pneumoniae infections and are sometimes interpreted as allergic drug reactions. Further important extrapulmonary manifestations are central nervous system symptoms that are however present in a limited number of cases. Legionella pneumophila Legionella is a small, pleiomorphic, Gramnegative bacillus. It is a strict aerobic bacterium rich in ramified fatty acids. Legionella is a fastidious organism that needs a specific growth medium. Water reservoirs are the micro-organisms natural habitat in which it may thrive.

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In 1976, an outbreak of pneumonia that caused 34 deaths in Philadelphia at an American Legion convention led to the clinical definition of Legionnaires disease [14]. A previously unknown bacterium was isolated and identified as the etiologic agent and named Legionella pneumophila. Retrospective analysis of stored sera of patients with previously unexplained pneumonia reveals that outbreaks may be traced back to at least the 1950s. Epidemiology The bacteria have been consistently isolated form a variety of man-made water reservoirs in nosocomial outbreaks and community-acquired cases [15]. Available data indicate that the most likely mode of transmission is direct inhalation from Legionella-contaminated water supply-systems. Patient isolation is not mandatory as no evidence of person-to-person transmission has been reported. The incidence of Legionella infection, in spite of its world-wide diffusion, is highly variable in different studies, ranging from 1 to 27% of community-acquired pneumonia [16]. The clinical severity of Legionella pneumonia ranges from mild respiratory disease to fulminating pneumonia. The incubation period ranges from 2 to 10 days. Most patients report dry cough, and high fever (>40C) is reported in about 20% of cases. Extrapulmonary manifestations such as neurologic complaints, abnormal liver enzymes, diarrhea, hypophosphatemia, hematuria and hematologic abnormalities are relatively common but non-specific [17]. However, some signs and symptoms may raise the suspicion of Legionella infection: a sputum Gram stain with a high number of neutrophils without any organism, hyponatremia, and diarrhea in a critically ill patient. Initial radiological involvement is usually unilateral with a frequent spread to multilobar consolidation. Pleural effusion is present in about 50% of cases. Coxiella burnetii Coxiella burnetii is the agent of Q fever, a zoonotic infection [18]. It is a strictly intracellular Gram negative, pleiomorphic, coccobacillary organism. Epidemiology The infection is widely present in animals including cattle, sheep, goat, pets such as cats and dogs, and arthropods, mainly ticks. Transmission occurs by aerosolised particles. Infection may occur from inhalation of contaminated aerosols from amniotic fluid or placenta of contaminated wool, making Q fever an occupational hazard. Person-toperson transmission is unusual but may occur via droplet nuclei, transplacental transmission, intradermal inoculation and blood transfusions. Incubation time is around 3 weeks and the disease begins as a flu-like syndrome with extrapulmonary symp-

toms including headache, rigor, myalgia and arthralgia. In most studies C. burnetii is identified in 1-3% of pneumonia cases. Fever may be high but the disease is usually self-limited. Radiographic resolution is slow and may take up to 70 days [19]. A common complication of pneumonia is granulomatous hepatitis. Other extrapulmonary complications include hemolytic anemia, thyroiditis, pericarditis and myocarditis, and glomerulonephritis. Chlamydia pneumoniae In 1989, the previously labeled Chlamydia strain TWAR was recognised as a third species of the Chlamydia genus on the basis of ultrastructural and DNA homology analysis and named Chlamydia pneumoniae [20]. Like other Chlamydia, this agent is an obligate intracellular, Gram negative bacterium present in two developmental forms: infective elementary bodies (EB) and reproductive reticulate bodies (RB). Chlamydia possess a specific replication cycle which differs from conventional bacteria. They multiply within membrane-bound vacuoles in eucaryotic host cells but are unable to generate adenosine triphosphate (ATP) and are therefore dependent on the host cell ATP deposits for all energy requirements. Moreover, they are incapable of de novo nucleotide biosynthesis and are dependent on host nucleotide pools. Epidemiology Chlamydia pneumoniae has been recognised as a cause of respiratory tract infections and is considered the most common non-viral intracellular human respiratory pathogen. C. pneumoniae is involved in a wide spectrum of respiratory infections of the upper respiratory tract (pharyngitis, sinusitis and otitis) and lower respiratory tract (acute bronchitis, exacerbations of chronic bronchitis and asthma, and community-acquired pneumonia) in both immunocompetent and immunocompromised hosts. C. pneumoniae accounts for 6-20% of community-acquired pneumonia (CAP) depending on several factors such as setting of the studied population, age group examined, and diagnostic methods used. The clinical course may vary from a mild, selflimiting illness to a severe form of pneumonia, particularly in elderly patients, and in patients with coexisting cardiopulmonary diseases. This agent is present as part of a coinfection involving other bacterial agents in approximately 30% of cases [21]. Presenting symptoms most frequently reported by patients with C. pneumoniae pneumonia are sore throat and hoarseness [22] (table 3). After a period of up to a week, dry persistent cough often sets in [23]. Body temperature is generally slightly increased, seldom going higher than 38-39C. Fever may be often missed if the patient is not seen early in the course of infection. Physical examination does not often show abnormalities and, if present, physical findings are
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Table 3. Common signs and symptoms of Chlamydia pneumoniae pneumonia and frequency of presentation Signs and symptoms Headache Hoarseness Sore throat Dry cough Fever (> 37.8C) Abnormal breath sounds Leukocytes > 10 000/mm3 Sedimentation rate > 15 mm/h Frequency of presentation (%) 60-70 65-75 70-80 75-90 25-45 65-78 15-25 50-70

generally not specific. Pulmonary rales, ronchi or signs of pulmonary consolidation are sometimes found. Chest X-ray generally reveals small pulmonary infiltrates, sublobar or segmental at presentation (table 4). Multiple infiltrates may sometimes be seen and are often bilateral. Extensive lobar involvement is uncommon, whereas pleural effusion may be present in up to 20% of cases. Diagnostic methods (table 5) Mycoplasma pneumoniae M. pneumoniae culture is time consuming and requires specialised media. M. pneumoniae antigen may be detected by several methods. Polyclonal antiserum in respiratory secretions has yielded very low specificity since many subjects are healthy carriers [24]. Antigen capture enzyme immunoassay in sputum has shown variable sensitivity (40-81%) and specificity (64-100%) depending on the reference method (culture/serology) [25]. Caution is mandatory if negative results are found. Monoclonal antibody immunoblot A has been used in research samples for M. pneumoniae antigen detection in respiratory specimens [26]. DNA and RNA probes have been developed and are commercially avail-

Table 4. Most commonly occurring radiographic presentations of Chlamydia pneumoniae pneumonia Radiographic involvement Normal Single sublobar lesion Lobar Bilateral involvement Frequency of presentation (%) 0-6 70-85 4-7 7-14

Table 5. Summary of clinical relevance of diagnostic techniques for identification of Mycoplasma pneumoniae, Legionella spp, Coxiella burnetii and Chlamydia pneumoniae Pathogen Mycoplasma pneumoniae Technique Sputum antigen detection DNA detection by PCR Culture Serology Comments Variable sensitivity and specificity Variable sensitivity and specificity Difficult and time consuming EIA test: sensitivity 92% and specificity 95% on paired serum samples. Cold agglutinin test: sensitivity 50-75% suitable as a rapid bedside test Difficult and variable sensitivity (11-80%) Variable sensitivity (18-80%) good specificity (94%). Better sensitivity on BALF than sputum Sub-optimal sensitivity (50-69%) optimal specificity (99%) Method of choice for sero-group 1 infection diagnosis IFA and ELISA tests show good sensitivity (80-85%) and specificity (95%). However, worse performance for strains other than sero-group 1 Need for cell cultures in high biosafety labs Reference test is MIF Limited data Difficult and time consuming Sub-optimal sensitivity (20-60%), good specificity (95%). Little clinical value MIF is still the gold standard for acute infection diagnosis. Paired serum samples are required Variable sensitivity and specificity. No commercial kits available. Still under evaluation

Legionella spp

Culture Antigen detection Sputum DNA probes Urine antigen detection Serology

Coxiella burnetii

Culture Serology PCR Culture Antigen detection Serology PCR

Chlamydia pneumoniae

Abbreviations: PCR = polymerase chain reaction; EIA = enzyme immunoassay; BALF = bronchalveolar lavage fluid; IFA = immunofluorescent antibody; ELISA = enzyme-linked immunosorbent assay; MIF = microimmunofluoresnence assay.

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able, and show high specificity but low sensitivity (22-100%) in pharyngeal specimens [27]. The polymerase chain reaction (PCR) has been applied to clinical specimens showing the suitability of this technique for the detection of M. pneumoniae [28, 29]. However, a serological test should always be performed in order to distinguish between acute and persistent infection. Serological cold agglutinin testing is seldom employed in clinical practice; however, approximately 50-75% of patients with pneumonia due to M. pneumoniae have a positive test. Even if the sensitivity is suboptimal, this bedside test is still attractive since it is simple and rapid. Complement fixation (CF) yields a variable sensitivity (5090%) and suboptimal specificity. The most reliable test is enzyme immunoassay (EIA) that allows IgG and IgM titration and presents 92% sensitivity and 95% specificity on paired samples. Seroconversion timing is from 3 to 8 weeks [30]. Legionella pneumophila This difficult-to-culture pathogen, with culture sensitivity ranging from 11 to 80% (31), has been studied extensively by antigen detection. Buffered charcoal yeast extract agar added with -ketoglutarate (BCYE) is the primary medium for the isolation of this organism. Specimens should always be cultured on selective and semi-selective media since some strains of L. pneumophila are inhibited by antibiotics present. The direct fluorescence antibody (DFA) stain is used on clinical samples with variable sensitivity (18-80%) and good specificity (94%). Sensitivity appears to be greater on bronchoalveolar lavage specimens than sputum samples [32]. Radiolabelled DNA probes may be used on sputum samples with a 50-69% sensitivity and 99% specificity. The test is rapid, not operatordependent, but still very expensive and experimental [33]. Serologic test, immunofluorescent antibody (IFA) detection, enzyme-linked immunosorbent assay (ELISA), and microagglutination are readily available techniques for the diagnosis of L. pneumophila infection [34]. Seroconversion commonly requires 4 to 8 weeks, but may take up to 14 weeks in elderly patients. In addition, as many as 30% of patients with acute L. pneumophila infection do not show an antibody rise. IFA has a high specificity (95%) and a sensitivity of about 85% (joint IgG and IgM determination), although cross-reactivity with other bacteria has been described. ELISA and microagglutination present an 80% sensitivity and 96% specificity, which however decreases for strains other than serogroup 1. L. pneumophila antigen may also be detected in urinary specimens by radioimmunoassay (RIA), ELISA, and latex agglutination [35]. These are simple, noninvasive, rapid, sensitive, and highly specific tests. Urinary RIA antigen detection is the method of choice for L. pneumophila serogroup 1.

Coxiella burnetii Culture of this organism must be performed in high biosafety laboratories only, due to its extreme infectivity. C. burnetii may be isolated by inoculation in conventional cell cultures, yolk sacs, or laboratory animals. The recent development of a commercially available cell microculture system allows better isolation of this bacterium. Serological tests include indirect immunofluorescence, complement fixation, ELISA, and microagglutination. The immunofluorescence assay (IgG, IgM, and IgA fractions) is currently the reference method for the diagnosis of Q fever (18). Seroconversion is usually detected 7-15 days after the onset of clinical symptoms. PCR has been successfully employed both on clinical specimens and cell cultures. Chlamydia pneumoniae Laboratory methods for the diagnosis of C. pneumoniae infection include culture, antigen detection, serology and PCR. The procedure for culturing C. pneumoniae has been adapted from that for C. trachomatis. Different cell lines have been evaluated and HL and Hep-2 have been found to yield best results. So far successful culture of C. pneumoniae has been obtained in a limited number of laboratories. The main problems encountered with culture are easy inactivation during transport, collection from anatomical sites devoid of active colonisation, low yield often requiring repeated blind passages. The sensitivity of antigen detection using direct fluorescent antibodies on respiratory specimen smears is estimated to be 20-60% compared to culture, and the specificity should approach 95% but is highly operator-dependent. This technique is of little clinical use and is mostly employed as culture confirmation. The development of PCR technology has brought major advantages to the diagnosis of C. pneumoniae infection. It has been successfully employed on respiratory specimens, lung and vascular bioptical specimens, and blood. A number of studies have found PCR to be a more sensitive technique than culture, and nested PCR is probably the best technology now available [36]. Furthermore, two recent studies suggest that C. pneumoniae DNA detection by PCR on peripheral blood mononuclear cells may provide useful information on the presence of chronic C. pneumoniae infection [37, 38]. However, the overall diagnostic utility of PCR techniques is currently hampered by the lack of standardisation of extraction procedures, primer definition, etc. Serology testing for C. pneumoniae currently includes only microimmunofluorescence assay (MIF) and enzyme immunoassay (EIA), given that complement fixation is genus-specific, has a 60% sensitivity in acute primary infection, but a sensitivity below 10% in re-infection. Several EIA kits are commercially available, all giving qualitative but not quantitative information on C. pneumoniae antibody levels. Experience with these kits is lim531

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ited and sensitivity and/or specificity are currently unsatisfactory. The current gold standard for serological diagnosis is MIF testing. MIF may be employed to detect IgG, IgM, IgA antibodies and, when performed by an experienced reader, possesses high sensitivity and specificity. On the basis of available techniques, the most convincing evidence of acute infection is given when IgM antibodies or a fourfold rise in IgG antibodies can be shown. However, the need for paired sera to show a fourfold rise in antibody titres is a limitation of the MIF technique. Moreover, positive findings on PCR, DFA or culture specimens from the upper respiratory tract in the presence of clinical symptoms of infection strongly support the presence of C. pneumoniae infection given that asymptomatic carriage has been shown in only 1-5% of healthy subjects. Treatment Considering the distinctive pathogenic characteristics of Mycoplasma, Legionella and Chlamydia infections the best therapy should combine high levels of drug intrinsic activity with the ability to reach high intracellular concentrations. The specific characteristics of Mycoplasma pneumoniae determine the complete inactivity of some antibiotics: betalactams, glycopeptides, sulphonamides, and rifampicin. Potentially active drugs are tetracyclines, macrolides, lincosamides, streptogamines, chloramphenicol, and fluoroquinolones. Exceptional cases of acquired resistance to the macrolide-lincosamide-streptogamine group have been reported [39]. Many antibiotics that present high in vitro activity against Legionella spp., including imipenem and amoxicillin/clavulanic acid, are not clinically useful in vivo due to their inability to reach the target intracellularly, accounting for the in vitro-in vivo dichotomy. The best treatment regimen is a full three-week treatment with a macrolide (erythromycin, clarithromycin) combined with rifampicin. Baker et al. reported the possible induction of resistant strains using rifampicin as sole therapy [40]. An alternative treatment regimen may be the association of second generation fluoroquinolones with tetracyclines. A notable improvement in most of the new fluoroquinolones (levofloxacin, moxifloxacin, gatifloxacin, and gemifloxacin) is their activity against Legionella, so that their use as a single agent may be hypothesised even if clinical data are still insufficient for a definitive indication. Data on the in vitro activity of antibiotics against Chlamydia pneumoniae are relatively limited, due to the difficulty in isolating the agent and in performing the susceptibility test (table 6). Tetracyclines and erythromycin show good in vitro activity and so far have been the most commonly employed drugs in the treatment of Chlamydia pneumoniae infection. Doxycycline and minocycline are apparently slightly more active than tetracycline. The most active macrolide seems to be clarithromycin [4144].
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Table 6. In vitro susceptibility of C. pneumoniae Drug Tetracycline Doxycycline Minocycline Erythromycin Clarithromycin 14-OH clarithromycin Azithromycin Roxythromicin Telithromycin Ketolide RU 64004 Ciprofloxacin Ofloxacin Levofloxacin Lomefloxacin Fleroxacin Moxifloxacin Gemifloxacin MIC (mg/ml) 0.05-1 0.01-0.5 0.016-0.06 0.01-0.5 0.004-0.25 0.03 0.01-2 0.05-2 0.01-2 0.01-0.5 0.25-4 0.25-2 0.125-0.5 0.25 2-8 0.06 0.06-0.25 MCC (mg/ml) 0.05-4 0.12-2 0.06-0.125 0.01-0.25 0.004-0.25 0.25 0.06-0.25 0.06-2 0.03-2 0.01-1 2-8 0.5-2 0.125-0.5 2-8 0.125 0.06-0.25

MIC, minimal inhibitory concentration; MCC, minimal chlamydicidal concentration: ranges of values reported in literature (values are given as range against clinical isolates or against type strains of Chlamydia pneumoniae).

Ketolides are a new class of macrolide antibiotics with a 3-keto function instead of the cladinose sugar, endowed with good activity against a broad range of respiratory pathogens [45]. Fluoroquinolones show good activity (table 3). Levofloxacin is more active than ofloxacin [46, 47]. Chlamydia pneumoniae susceptibility to ciprofloxacin and fleroxacin is lower than that to other tested derivatives. The most recent quinolone derivatives show good activity against Chlamydia pneumoniae. The minimal inhibitory concentration (MIC) of moxifloxacin against three strains of Chlamydia pneumoniae were 0.6 g/ml and the minimal chlamydicidal concentration (MCC) ranged from 0.06 to 0.125. Beta-lactams and aminoglycosides show poor or absent cell penetration. The beta-lactam target is the bacterial cell wall, a structure lacking in chlamydiae. However, Kuo and Grayston observed that penicillin and ampicillin, while showing no effect on Chlamydia viability, could inhibit infectivity (48). Rifampicin seems to have a high activity against Chlamydia pneumoniae showing MIC and MCC values ranging from 0.005 to 0.01. Clindamycin, chloramphenicol and co-trimoxazole, which show some in vitro activity against C. trachomatis and C. psittaci, might also be active against Chlamydia pneumoniae, but no data are yet available. It appears that the eradication of Chlamydia pneumoniae during first infection may be obtained by prolonged (up to 3-4 weeks) use of macrolides. The length of treatment may be associated with Chlamydias long life cycle, and with the possibility of a quiescence phase in the replication of the bacterium. Much more complex is the eradication of chronic infection. Prolonged macrolide treat-

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ment of 6 or more weeks has been suggested, but no definitive proof of its efficacy has been obtained to date. To overcome the problem of the quiescence phase the possibility of multiple shot therapy or multiple drug regimens including marcrolides or ketolides with fluorquinolones has been employed. Insufficient clinical and laboratory data has until now been gathered to allow precise indications for the treatment of chronic infection. References
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