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Nocardia species (Nocardiosis) Updated January 2011
Michael M. McNeil, M.D. , June M. Brown, M.D.
Nocardiosis is difficult to diagnose clinically, radiologically, and histopathologically. A definitive diagnosis depends on the isolation and the identification of Nocardia species. Making the diagnosis may often involve performing invasive techniques on the patient and may take up to 2 or 3 weeks. Recent data derived from modern taxonomic methods have changed the taxonomy of the actinomycetes, leaving the genus Nocardia a relatively homogeneous taxon (18, 70). Three major pathogenic Nocardia species, N. farcinica, N. nova, and N. pseudobrasiliensis, were recently characterized. N. farcinica and N. nova were separated from the N. asteroides complex and N. pseudobrasiliensis from N. brasiliensis, primarily on the basis of DNA-DNA hybridization, 16S rRNA sequence analysis, antimicrobial susceptibility and biochemical profiles, and, to a lesser degree, on high-performance liquid chromatography (18, 44, 56, 88, 102, 107, 108, 111, 112, 118). The use of molecular technology for species identification and epidemiologic subtyping of the Nocardia species has been limited by the lack of simple and rapid assays. Rapid molecular identification and typing methods that may be useful include random amplified polymorphic DNA and a combination polymerase chain reaction-restriction fragment length polymorphism analysis (29, 98). MICROBIOLOGY Guided Medline Search The genus Nocardia is currently composed of 22 validly described species (12, 43, 46, 49, 119, 120). However, despite recent taxonomic changes, there is evidence that this genus is still underspeciated, in particular, the Nocardia asteroides complex, N. brevicatena, N. carnea, N. nova, and N. pseudobrasiliensis (43). The distinguishing characteristics of the 13 medically relevant species are given in Table 1. Nocardia microorganisms are filamentous rods that show right-angled branching both in culture and in tissues. For culture they require aerobic conditions, but growth on blood agar may be slow, and incubation for periods longer than 48 h is usually necessary. As cultures enter the stationary phase, the filaments tend to fragment into coccobacillary forms. Although the organisms are gram positive, many strains give a faint beaded appearance with alternating positive and negative areas. Since the Nocardia are weakly acid fast, the most useful acid-fast stain is the modified Kinyoun method (7, 43). The Brown-Brenn modification of Gram stain and the Gomori methenamine stain are useful in demonstrating the organisms in histopathologic preparations from tissue (16). Gram stain, the presence of aerial filaments, decomposition of substrates, and acid production from or carbon utilization of carbohydrates, as previously described, are used to differentiate the members of the genus Nocardia (7, 43). Of importance, the N. asteroides complex that is responsible for the majority of invasive human infections has been separated into four new taxa (N. abscessus [formerly N. asteroides sensu stricto type I], N. farcinica, N. nova, and one unnamed taxon, N. asteroides sensu stricto type VI) (Table 1). N. farcinica is particularly important to distinguish since it has increased virulence and differs in its antimicrobial susceptibility test results and its epidemiology (106, 112). Additional tests used to separate N. asteroides complex isolates further as N. abscessus, N. asteroides sensu stricto type VI, N. farcinica, and N. nova include growth on tryptone glucose yeast agar at 45oC for 1 day, hydrolysis of acetamide, production of acid from L-rhamnose, arylsulfatase production, utilization of citrate, and disk-diffusion susceptibility tests using Mueller-Hinton agar and commercial disks of cefamandole (30 µg) and tobramycin (10 µg) (108, 112, 120). Additional tests used to separate N. pseudobrasiliensis from N. brasiliensis include mycolic acid patterns, decomposition of adenine, nitrate reduction, susceptibility to ciprofloxacin and/or clarithromycin, and resistance to minocycline (88,107). Since Nocardia species infections are very often sporadic, information from randomized clinical trials comparing the clinical efficacy of specific antimicrobial agents is lacking. Reports have been limited to antimicrobial susceptibility test results of clinical isolates, usually from reference laboratories, animal studies and case summaries. Interpretation of these data may be complicated by several factors. When data are from a reference laboratory that is likely to receive referral isolates from patients who are intolerant of therapy or for whom therapy has failed, there is a potential for bias in their interpretation. Also, often it is difficult to compare in vitro susceptibility results with data reported by other investigators because of differences in methodology, e.g., lack of interlaboratory standardization of inocula (104 versus 102 CFU/ml), use of a broth microdilution method versus agar dilution or disk diffusion methods. The introduction in 2000 by the National Committee for Clinical Laboratory Standards (NCCLS) of a tentative standard for susceptibility testing of Nocardia spp. and other actinomycetes using the broth microdilution method may alleviate some of these problems (M24-T2) (80). In addition to differences in methodology, the results of some reported studies may vary because no distinction was made between N. nova and N. asteroides sensu stricto strains (52, 73) or between N. brasiliensis and N. pseudobrasiliensis (73, 88,107). Baron EJ. Mold EPIDEMIOLOGY Guided Medline Search Nocardia species are widely geographically distributed soil bacteria that usually cause chronic, progressive infections. These infections may be localized or disseminated and are more common and generally more serious in severely immunocompromised and debilitated patients. Invasive Nocardia infections may be an important cause of death and infectious disease in immunocompromised solid organ transplant recipients (70). Severe infections with Nocardia species have also been reported to affect patients with human immunodeficiency virus (HIV) infection (53, 54, 57 66, 67, 99). Cases may go undiagnosed, either because there is a delay in performing necessary diagnostic tests (invasive biopsies) for seriously ill patients or because the infection partially or successfully responds when prophylactic broad-spectrum antimicrobial therapy is prescribed (70). Recent in vitro and in vivo studies, clinical observations, and taxonomic developments indicate that antimicrobial therapy must be adjusted to the particular species of Nocardia present, to individual strain antimicrobial susceptibility patterns, and to the site and type of infection (6). CLINICAL MANIFESTATIONS Guided Medline Search Pulmonary Nocardiosis: Pulmonary nocardiosis may be associated with nonspecific clinical findings; however, immunocompetent patients may have a chronic course, as opposed to the progressive, disseminated, and life-threatening infection seen in severely immunocompromised patients. The most frequent clinical presentation may be as a subacute or chronic, often necrotizing pneumonia, which is frequently associated with cavitation (32, 70). Local complications of invasive Nocardia spp. pulmonary infections include pleural effusion, empyema, pericarditis, mediastinitis, superior vena cava obstruction, and rarely, development of local chest wall and neck abscesses. Metastatic infective foci may be present but unrecognized at the time of the patient's initial presentation with pulmonary nocardiosis, and infection in these sites may not become clinically evident until after the patient has begun receiving antimicrobial therapy. Disseminated Nocardiosis: Disseminated nocardiosis is often a late-presenting and potentially life-threatening infection. It is most frequently endogenous (i.e., secondary to bloodstream spread) from a primary pulmonary infection (70, 115). However, very rarely, it may result from a primary nonpulmonary (cutaneous) infection site (95). In patients with primary pulmonary nocardiosis, the development of disseminated infection may result in brain and skin lesions and invariably has a significant adverse effect on the patient's prognosis. Disseminated nocardiosis has a mortality rate of 7% to 44% (70, 115). In severely immunocompromised patients the mortality may be greater than 85% (70). Disseminated infection in susceptible patients may be caused by any of the Nocardia spp. identified as causing invasive pulmonary and cutaneous infections. As seen with pulmonary nocardiosis, the patients at highest risk for developing disseminated infections are severely immunocompromised patients. The brain is the most frequent nonpulmonary site involved in disseminated nocardiosis, and cerebral nocardiosis is an important cause of cerebral space occupying lesions. However, the infection may also involve multiple other deep organs including the kidney, spleen, liver, and rarely, bone, skin, and joints (70). In the brain and other organs, abscess formation is a particularly common pathologic manifestation of disseminated infection (70). Patients with cerebral nocardiosis may acutely present signs of sepsis and intracranial mass effects (70). However, severely immunocompromised patients with nocardial cerebral abscess may frequently be asymptomatic, and a prolonged latency (up to three years) may occur before this type of clinical presentation in patients infected following the commencement of immunosuppression (70). There may be clinical evidence of pulmonary nocardial infection in about one third of the cases (11), and blood cultures may also be positive for Nocardia spp. in these patients (11). Computed tomographic (CT) scanning is an extremely useful technique for making the diagnosis and may also be used to monitor the patient's response to treatment (68). However, a definitive diagnosis may only be established in the patient following the performance of a brain biopsy that yields clinical specimens, which are positive for Nocardia spp. on microbiologic culture and/or show morphologically compatible microorganisms on histopathologic examination. Specific investigations to detect cerebral involvement are recommended in all cases of pulmonary and invasive nocardiosis since a brain abscess may be a common serious complication in these patients, and early lesions may be asymptomatic (11). Cutaneous Nocardiosis: Cutaneous nocardiosis may be subdivided into four clinical types: mycetoma, lymphocutaneous infection, superficial skin infection (abscess or cellulitis), and secondary cutaneous involvement with disseminated disease. In North and South America, Mexico, and Australia, N. brasiliensis is the chief cause of actinomycetoma; whereas Actinomadura madurae, A. pelletieri, and Streptomyces somaliensis predominate in India and the African continent (70). These infections most commonly affect patients in rural areas in developing countries. Patients with these chronic infections may give a history of specific minor localized traumatic injury. The foot is the commonest site of involvement; however, the hand, face, and neck may also be affected (70). N. brasiliensis has been associated particularly with subcutaneous infections and is predominant in tropical countries (95). Frequently, there maybe spread beyond the initial cutaneous focus to involve the regional lymphatics and, in one-third of cases, the disease may progress to form lymphatic abscesses (70). When regional lymph node involvement occurs, this form of the disease is referred to as the lymphocutaneous syndrome or the sporotrichoid form of cutaneous nocardiosis because of its striking resemblance to the disease due to the fungus Sporothrix schenckii (70, 95). N. farcinica: N. farcinica may cause a variety of clinical presentations, including cerebral abscess, keratitis, bacteremia, and pulmonary, kidney, and cutaneous infections (76, 93, 112). There is a clear importance in differentiating between N. farcinica and other members of N. asteroides complex. N. farcinica has a high degree of resistance to various antibiotics, especially to third-generation cephalosporins, which may make treatment of the infection difficult (91, 112), and mouse pathogenicity studies have demonstrated that this may be a more virulent species than the other N. asteroides complex species (70). N. farcinica occurs more frequently than was previously recognized (91, 112). This can be attributed to recent developments in diagnostic methods and possibly also to a change in spectrum of human nocardiosis in countries such as Germany where N. farcinica is the prevailing species (91). Other reports from France, Germany, and the United States have implicated N. farcinica as the cause of postoperative wound infections in patients undergoing cardiac and other vascular surgeries (9, 29, 114). N. nova: The clinical diseases associated with N. nova isolates are similar to those previously described for diseases due to N. farcinica and N. asteroides complex microorganisms. The reasons for identifying these microorganisms include their susceptibility to erythromycin and third-generation cephalosporins and resistance to amoxicillin-clavulanate (108). Also, as suggested for N. farcinica infections, infection with N. nova may be more common than is currently suspected; however, the successful detection of these newly recognized species is dependent upon the performance of appropriate isolation and characterization techniques as well as increased clinical and microbiological awareness (108). N. transvalensis: Infections with N. transvalensis have been reviewed by McNeil et al. (71). Initially recognized as a cause of mycetoma, N. transvalensis infections have also been reported to cause life-threatening invasive pulmonary and disseminated infections in severely immunocompromised patients (70, 71). Importantly, clinical isolates of this unusual species may demonstrate a high level of inherent resistance to amikacin and aminoglycosides in general. In addition, therapy with trimethoprim-sulfamethoxazole (TMP-SMX) may not always be effective for this infection (70). In the recent study by Wilson et al. (116), N. transvalensis complex isolates showed a difference in geographic distribution of the designated subgroups. No isolates of the former N. asteroides complex type IV (now considered a member of the N. transvalensis complex) were identified among the clinical isolates identified in Queensland, Australia. However, the majority (75%) of N. transvalensis isolates of the new taxon I were from that location (116). The four most recently identified Nocardia species, N. abscessus, N. africana, N. paucivorans, and N. veterana, have only rarely been encountered as agents of disease (46, 49, 119, 120). N. abscessus has been isolated from patients with abscesses of knee joint, fibula, and leg (120); N. africana has been isolated from patients with pulmonary infections (49); N. paucivorans has been isolated from the sputa and bronchial secretions of a patient with chronic lung disease (119); and N. veterana has been isolated from bronchial lavage of a patient with upper lobe lesions (the strain was thought not to be of medical importance) (46). LABORATORY DIAGNOSIS Guided Medline Search In patients with suspected nocardial infection and a compatible clinical picture, a definitive diagnosis usually depends on the demonstration of the organisms in smears or sections examined microscopically together with isolation and identification by microbiologic culture. The importance of direct microscopic examination of stained preparations of clinical specimens in the diagnosis of aerobic actinomycotic infections cannot be overemphasized. The specimens most frequently received in the clinical microbiology laboratory for evaluation include sputum, bronchial lavage fluid, exudate, or CSF. If possible, the material should be spread out in a petri dish and observed for clumps of the microorganisms, which may resemble granules. If clumps or granules are present, they should be selectively removed and crushed between two glass microscope slides for microscopic examination. In addition, duplicate direct smears of the clinical material should be always be prepared for staining, and one smear stained with Gram's and the other with the modified Kinyoun acid-fast method. On Gram-stained smears, gram-positive branched filamentous hyphae are seen that are similar to the appearance of nocardiae in cultures: they measure from 0.5 to 1 µm in diameter and as much as 20 µm in length. To be of diagnostic value the hyphae must branch at right angles. Although the hyphae of nocardiae may resemble those of Actinomyces species in width, they are usually much greater in length and more widely scattered throughout purulent material and in the walls of the abscesses. In mycetoma, compact granules are formed, similar to those observed for the anaerobic actinomycetes. Very rarely, clubbing has been seen with N. asteroides, but often granules with clubbing are seen with N. brasiliensis and N. otitidiscaviarum (70). The hematoxylin and eosin stain is very useful for staining the tissue reaction and the granules but does not stain the individual filaments (16). A tissue Gram stain such as the modified Brown and Brenn procedure is recommended for demonstration of the gram-positive filaments of nocardiae (16). The Gomori methenamine silver stain may also be useful. However, in both of these procedures, the filaments may not stain uniformly. Acid-fast stains are also of value in the histopathologic diagnosis of infections caused by N. asteroides, N. brasiliensis, and N. otitidiscaviarum. These species are frequently, but not always, acid fast in tissue sections stained with both the modified Kinyoun or the Fite-Faraco staining methods (70). Actinomyces and related species are usually not acid-fast. These examinations provide a rapid presumptive diagnosis of the patient's infection and the information they yield may critically influence the clinician's choice of initial antimicrobial therapy. PATHOGENESIS Guided Medline Search Nocardia species have been shown to act as facultative intracellular organisms within macrophages (4, 21), where they inhibit the fusion of phagosomes with the lysosomes. In addition, human neutrophils and monocytes have been shown not to kill these organisms (30). Therefore, for optimal therapy for these intracellular microorganisms, it may be important to choose antimicrobial agents that are able to penetrate the cell. However, a demonstrated ability of a drug to enter cells does not guarantee activity. The microenvironment and intracellular distribution of the organisms and antimicrobial agent, and interactions between antimicrobial agent, pathogenic organism, and host cell all contribute to the determination of the therapeutic result (24).
SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo Six major classes of antimicrobial compounds are currently in clinical use: the sulfonamides, the aminoglycosides, the β-lactams (penicillins, carbapenems, and cephalosporins) and the b-lactam/b-lactamase inhibitors, the quinolones, the macrolides, and the tetracyclines (Table 2). Single Drug General Drug of Choice: Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid. Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the essential enzyme, dihydrofolate reductase. Thus, trimethoprim-sulfamethoxazole (TMP-SMX) blocks two consecutive steps in the biosynthesis of nucleic acids and proteins (Table 2). Sulfamethoxazole and trimethoprim have intermediate and high intracellular penetration of human polymorphonuclear leukocytes (PMNs), respectively (34, 50) (Table 2). For trimethoprim, in particular, this may be connected to its efficacy in combination with sufamethoxazole in treating intracellular pathogens (50). Sulfonamides (or the combination TMP-SMX) are the therapy of choice for nocardiosis (37, 65, 96, 110). Certain N. asteroides complex isolates may be susceptible to sulfonamides or TMP-SMX, and response to treatment may be attained in 90% or more of cases if the infection is confined to pleuropneumonia (96). However, in patients with disseminated disease to the central nervous system, or with depressed cell-mediated immunity such as occurs with renal transplant recipients and HIV-infected patients, several factors may complicate therapy (3, 6, 35, 41, 45, 53, 57, 59, 66, 77, 91, 97, 99, 125). One factor is the frequent occurrence of patient intolerance or side effects with the most commonly used drug combination, TMP-SMX; this occurs in HIV-infected patients with either Pneumocystis carinii (45, 57) or Nocardia species infections (99), and in renal transplant recipients with nocardiosis (2, 125). In these patient populations, adverse reactions such as skin rash, fever, and neutropenia have been reported in 44% to 80% of cases (45, 57). Hepatic toxicity, reported rarely with TMP-SMX, has occurred in 20% of patients with acquired immunodeficiency syndrome (AIDS) and the probability of toxicity is further increased by its prolonged use as a prophylactic therapy (45). Another factor is resistance of the infecting microorganism to drug therapy (TMP-SMX, and alternative agents or drug therapy combinations) (19, 35, 41, 59, 92, 97). In a recent review of nocardiosis in AIDS, TMP-SMX was used as therapy for 50% of patients; however, 90% of these patients were nonresponsive and died (66). The need for prolonged antimicrobial therapy (6-12 months routinely) to prevent recurrences of the infection and lifetime prophylactic therapy in AIDS patients further increases the possibility of the development of drug resistance (53). In a review of 19 patients on TMP-SMX for P. carinii prophylaxis, two patients developed Nocardia infections (53). Also, an infection caused by a TMP-SMX-resistant N. nova strain has been reported in a leukemic child placed on TMP-SMX prophylaxis for P. carinii infection (77). A third factor is the lack of information on newer oral alternative antimicrobial agents or combinations that might improve the outcome of patients with Nocardia species infection. Tables 3 and 4 contain the results of our susceptibility study using a microdilutional technique to test 98 patient isolates of N. asteroides complex that included 10 reference strains and include the current taxonomy. All N. asteroides sensu stricto isolates were susceptible to sulfamethoxazole and to TMP-SMX. These isolates were usually susceptible to dapsone (8% resistant). N. farcinica isolates were usually susceptible to TMP-SMX (7% resistant), sulfamethoxazole (11%), and dapsone (14%). N. nova isolates were usually susceptible to TMP-SMX (11% resistant), sulfamethoxazole (11%), and dapsone (6%). In addition, the results of minimum inhibitory concentration (MIC) ranges -- the MIC50, and the MIC90 of four experimental folate pathway antagonists that were provided by Jacobus Pharmaceutical, Princeton, N.J.-- were consistent for each of these experimental drugs with most strains of N. farcinica, N. nova, and N. asteroides sensu stricto. WR99210 was the most active, with a MIC90 for N. farcinica strains of 0.5 μg/ml, a MIC90 for N. nova strains of 0.125 μg/ml, and a MIC90 for N. asteroides sensu stricto strains of 2 μg/ml. The prodrug of WR99210, PS-15, was slightly less active: the MIC90 for all three Nocardia species strains was 4 μg/ml. Cycloguanil and its prodrug, proguanil showed much less activity for the three Nocardia species. The MIC90 for both N. farcinica and N. asteroides sensu stricto strains was 512 μg/ml or greater. Cycloguanil and proguanil were more active with MIC90 for N. nova strains of 128 μg/ml and 64 μg/ml, respectively. Studies by Boiron and Provost (10) and Schaal et al. (92) found a high degree of resistance to TMP-SMX in N. farcinica strains and a lesser degree of susceptibility in N. asteroides sensu stricto strains than our study results. These discrepancies with our data may reflect differences in methodology or differences in the geographic origin of strains. Nevertheless, in general, our study results agreed with those of Wallace and colleagues in their evaluations of antimicrobial susceptibilities of N. farcinica, N. nova, and N. asteroides sensu stricto (109, 111, 112). However, an important exception was the increase in resistance detected in our study of N. farcinica and N. nova to sulfamethoxazole and TMP-SMX (Table 3). In a study by McNeil et al., all isolates of N. brasiliensis were susceptible to sulfamethoxazole and TMP-SMX (73). These results are in good agreement with the data of other investigators (6, 10, 92). In contrast to N. brasiliensis, all N. otitidiscaviarum isolates in this study and in a study by Boiron and Provost were resistant to sulfamethoxazole and TMP-SMX (6, 10, 73, 92). Alternative Antimicrobial Agents Aminoglycosides: Amikacin and the most recent aminoglycosides are semisynthetic compounds designed to have potent antibacterial activity and minimal potential aminoglycoside-associated nephro- and ototoxicity (Table 2). They are bactericidal agents that inhibit bacterial protein synthesis by binding irreversibly to the bacterial 30S ribosomal subunit (Table 2). With the exception of N. transvalensis (71) (Table 1), all Nocardia species have low MIC values to amikacin in vitro (20, 36, 111) (Tables 3 and 4). Two new aminoglycosides, SCH 21420 and SCH 22591 (Schering Corp. Kenilworth, N.J.), had low MIC values to all Nocardia species (MIC90 for N. asteroides complex was 2 to 4 μg/ml and MIC50 for both N. brasiliensis and N. otitidiscaviarum was 1 to 2 μg/ml), but their minimal bactericidal concentration values were high (59). Despite low MIC values, this class of antimicrobial agents has been reported to have poor penetration into macrophages and neutrophils (105) (Table 2). However, most of these reports were short-term (1-6 h) experiments; the duration of incubation may have been insufficient to obtain detectable intracellular levels (103). Furthermore, the intracellular/extracellular (I/E) ratio was increased from <1 to 2 to 4 after 72 h incubation (103) (Table 2). In a mouse model study using a biochemically-typical N. asteroides sensu stricto strain and a N. farcinica strain, amikacin, amoxicillin-clavulanic acid, and minocycline proved to be therapeutically more effective than sulfadiazine (92). β-Lactams: The vast majority of Nocardia strains in our study were intermediately to highly resistant to the β-lactam antimicrobial agents currently in use (Tables 3 and 4). This may be predominantly due to the production of potent β-lactamases that have been identified in pathogenic nocardiae (62). These enzymes appear to be especially active in members of the species N. farcinica, N. asteroides sensu stricto type VI (unnamed taxon), N. brasiliensis, and N. otitidiscaviarum (92, 109). Only 44% of N. nova isolates were susceptible to ampicillin (Tables 3 and 4). All N. farcinica isolates were resistant to cefixime. The majority of isolates were resistant to cefamandole (70%), cefuroxime (64%), cefotaxime (82%), and ceftriaxone (86%) (Table 3). Although all isolates of N. nova were resistant to cefixime, the isolates were usually susceptible to cefamandole (17% resistant), cefotaxime (6%) and ceftriaxone (11%). All isolates of N. nova were susceptible to the oral cephalosporin cefuroxime. The majority of N. asteroides sensu stricto isolates were resistant to cefixime (87%); isolates were less frequently resistant to cefamandole (29%). These isolates were usually susceptible to cefuroxime (6% resistant), cefotaxime (2%), and ceftriaxone (2%). In another study of 12 clinical isolates of N. asteroides, Gutmann et al. (47) found that the oral cephalosporin cefuroxime had the best activity of the cephalosporins tested, followed by cefotaxime. Carbapenems are a unique class of β-lactam agents with the widest spectrum of antimicrobial activity of the currently available antimicrobial agents. Structurally, they differ from other β-lactams in the unique stereochemistry of the hydroxyethyl side chain that confers stability against β-lactamases. Imipenem (N-formimidoyl thienamycin), a semisynthetic derivative of thienamycin, was the first carbapenem antimicrobial agent developed for clinical use. The drug is metabolized and inactivated in the kidneys by a dehydropeptidase-I (DHP-I) enzyme found in the brush borders of proximal renal tubular cells. To achieve adequate concentrations in serum and urine, a DPH-I inhibitor, cilastatin, was developed and is combined with imipenem in a 1:1 dosage ratio for clinical use (Table 2). Other members of this class currently undergoing preclinical evaluation or clinical trials include meropenem and biapenem. These agents are thought to be resistant to the action of DPH-I without the need of a DHP-I inhibitor. With the carbapenem imipenem, most isolates in our study were susceptible, in particular, N. nova (100%) (Table 3). The resistance of N. farcinica isolates was high (36%), followed by N. asteroides sensu stricto resistance (23%) (Table 4). Our MIC results for N. nova correlated with those of a study of 22 isolates of this species, but that study found less resistance for N. asteroides and N. farcinica than in our study (122). Most isolates of N. brasiliensis and N. otitidiscaviarum have been reported to be resistant to imipenem (85, 122). However, N. brasiliensis isolates were less frequently resistant to one of the new carbapenems, meropenem, and this drug has also been shown to have intermediate activity against N. otitidiscaviarum isolates (122). As with other β-lactams, the in vivo activity of imipenem may be effected by poor penetration into macrophages (Table 2). Macrolides: The macrolides are a class of antimicrobial agents that demonstrate bactericidal activity through inhibiting bacterial protein synthesis by binding to the 50S ribosomal subunit (Table 2). However, in general, poor results were seen with these agents in our study (Tables 3 and 4), despite the advantage they possess of good penetration into phagocytes (Table 2). The isolates of N. nova are an exception: these isolates are always susceptible to erythromycin (108) (Table 3). The inconsistency in results (40% resistance) between our study given in Tables 3 and 4 and the results (> 90% resistance) given in Table 1 for N. asteroides sensu stricto isolates reported in the literature may reflect different methodology (broth microdilutions versus disk diffusion) or a different species distribution. Quinolones: Quinolones, also called fluoroquinolones, are a group of synthetic agents related to an older synthetic agent, nalidixic acid. Norfloxacin was the first of the fluorinated compounds to be introduced and, in contrast to nalidixic acid, was bactericidal and had less ocular toxicity. Currently, in addition to norfloxacin, there are four new quinolones approved by the Food and Drug Administration for use in the United States -- ciprofloxacin, ofloxacin, lomefloxacin, and enoxacin. These agents have proved effective against most N. asteroides complex; however, the MICs of each quinolone varied greatly depending on the species (59). This variability may reflect the different permeabilities of each species to the antimicrobial agent. Most isolates of N. nova, N. otitidiscaviarum, and N. brasiliensis were resistant to ciprofloxacin and to experimental quinolones (8, 88, 107). However, the recently described taxon N. pseudobrasiliensis is susceptible to ciprofloxacin (88, 107). One experimental carboxyquinolone PD 117558 (Warner Lambert Pharmaceutical Research, Ann Arbor, Mich.) was exceptional: all isolates tested including the N. asteroides complex, N. otitidiscaviarum, and N. brasiliensis were susceptible (8). These agents can be taken orally and achieve high concentrations in the bloodstream. Another advantage is that there is little or no associated toxicity even when prolonged therapy is required. More and more quinolone derivatives are becoming available; each derivative has a different serum half-life. Quinolones inhibit bacterial DNA gyrase and are not subject to alteration or degradation by plasmid-mediated mechanisms (Table 2). Quinolones can be given orally, and ciprofloxacin and the newer experimental fluoroquinolones -- tosufloxacin (T-3262) (123), grepafloxacin (121), PD 117596 and PD 127391 (59), and PD 117558 (8) -- may be parenterally administered. The marked intracellular penetration of ciprofloxacin, ofloxacin, and pefloxacin (IE ratio, >8, >7, and 6.9, respectively), into the alveolar macrophages should allow for the effective therapy for pathogens in respiratory infections (15, 82) (Table 2). Tetracyclines: Tetracyclines are bacteriostatic agents that act by inhibiting bacterial protein synthesis (Table 2). These antibiotics have high PMN penetration (IE =7.1) (34). All isolates of N. nova in our study were susceptible to minocycline, and the majority of N. asteroides sensu stricto and N. farcinica were susceptible (6 and 4% resistance, respectively) (Table 3). Our results obtained for minocycline correlated well with the data of other investigators (3, 44, 92). Minocycline resistance of the recently separated N. pseudobrasiliensis may have contributed to the reports in the literature of N. brasiliensis’s resistance to this agent (107). In one study, 25% of N. brasiliensis isolates were resistant (73). In the 1995 Wallace study, 60% of the invasive disease isolates of N. brasiliensis that were resistant to minocycline were identified as N. pseudobrasiliensis, the new taxon (107). All isolates of N. otitidiscaviarum were susceptible to minocycline in studies by Schaal et al. (92) and Boiron and Provost (10). Linezolid: Linezolid is a synthetic antibacterial agent of a new class of antibiotics, the oxazolidinones, which has activity against most species of gram-positive bacteria, including multiresistant pathogens such as N. farcinica and N. transvalensis (13). Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other bacterial agents; therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely. Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process (69). Brown-Elliott et al. (13) recently reported the in vitro activities of linezolid by broth microdilution against eight species of Nocardia including N. abscessus, N. asteroides sensu stricto type VI, N. brasiliensis, N. farcinica, N. nova, N. otitidiscaviarum, N, pseudobrasiliensis, and N. transvalensis. Linezolid is the first antimicrobial agent to be active against all clinically significant species of the genus Nocardia. Its clinical activity remains to be determined, although its use as a compassionate agent is ongoing. Because of its activity and availability as an oral agent, linezolid has the potential to be the primary treatment for nocardiosis (13). Combination Drugs The β-lactam-β-lactamase inhibitor combination amoxicillin-clavulanic acid presents an approach to the problem of β-lactamase-induced resistance to antibiotics. Clavulanic acid is a β-lactam that is structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active site of the enzyme (Table 2). In our study, N. nova was usually resistant to amoxicillin-clavulanic acid (94%); N. asteroides sensu stricto and N. farcinica isolates were less frequently resistant at 33% and 29%, respectively (Table 3). Another species of Nocardia, N. otitidiscaviarum, has been reported to be resistant to amoxicillin-clavulanic acid (6, 10, 92). In vitro studies assessing potential synergy with β-lactam-β-lactamase inhibitor combinations showed that 11 ampicillin resistant strains of N. asteroides became susceptible to these drugs in the presence of clavulanic acid (62). Furthermore, Wallace et al. (109) showed that amoxicillin resistance in N. brasiliensis could be reduced in the presence of clavulanic acid. The triple combination of amoxicillin plus clavulanic acid plus amikacin has been reported in vivo in a murine model to be superior to each agent alone in reducing the infective burden of microorganisms in tissue (92). However, the organisms studied were other members of the N. asteroides complex and did not include N. nova or N. otitidiscaviarum.
Tripodi MF et al.
In vitro activity of multiple antibiotic combinations
against Nocardia: relationship with a short-term treatment strategy in heart
transplant recipients with pulmonary nocardiosis.
Animal Models Although the results derived from animal studies are thought to be more relevant clinically than in vitro data, it is difficult to compare data between animal studies because of differences in dosage and route of inoculation (6, 41, 92). Beaman et al. recently reported on the development of an experimental model of murine nocardiosis that has provided data for evaluating various antimicrobial agents as treatments for this infection (6). Colony counts of N. asteroides in various target organs, assessed over time, have provided quantitative endpoints for assessing both the comparative bactericidal efficacy of these agents and the timing of bactericidal activity. Evidence from this animal model has shown that imipenem and amikacin are superior to other antimicrobial agents, including TMP-SMX (38, 39, 40, 92); this finding has also been supported by clinical observations of infected persons (92). Of note in our study, minocycline showed in vitro activity comparable to those of the folate pathway antagonists. Also, this antibiotic has been shown to be as effective as sulfonamides in eliminating a large inoculum of N. asteroides from mice after intraperitoneal injection of a suspension in mucin (3). On the other hand, in a mouse model of cerebral nocardiosis, minocycline did not eradicate intracerebral microorganisms and its effects were no different from saline control (41). Despite these in vivo results, there has been adequate support in the literature for using minocycline to treat cerebral infection effectively based on the drug’s excellent in vitro activity (60, 61, 117).
ANTIMICROBIAL THERAPY Drug of Choice Guided Medline Search Sulfonamides (with or without trimethoprim) have been the mainstay of antimicrobial therapy for human nocardiosis. TMP-SMX has become a frequently used drug combination for this infection; however, this usage may not be as much related to properties of synergism or improved efficacy compared with that of sulfonamide treatment alone as to favorable pharmacokinetics (effective penetration of the cerebrospinal fluid [CSF]) and general familiarity among clinicians. For most patients with nocardiosis, clinical improvement is expected within 7 to 10 days after the initiation of empiric therapy with sulfonamides (with or without trimethoprim). For infected patients, the exact route of drug administration may be influenced by the assessment of their overall clinical status. In addition, a serum level estimation at least once following institution of antimicrobial therapy may be useful to establish that adequate drug absorption is occurring and to provide a basis for any necessary adjustment of the patient’s drug dosage to achieve recommended levels in blood of 100 to 150 Fg/mL approximately 2 h after an oral dose. It is recommended that therapy with sulfonamides be given at a high dose (3 to 6 g/day) for extended periods (6 to 12 months). While primary cutaneous nocardiosis may be cured by a 1- to 3-month course of antimicrobial therapy and uncomplicated pulmonary nocardiosis may respond to therapy for 6 months or less, therapy for 12 months or more is usually required for disseminated infection or when the patient is immunocompromised. In addition, it is advisable that HIV-infected patients receive long-term maintenance suppressive therapy. Also, in organ transplant patients treated with the commonly used antirejection medication cyclosporine, TMP-SMX may cause reversible cyclosporine-induced nephrotoxicity (Table 2). Special Infections Pulmonary Nocardiosis: Guided Medline Search Trimethoprim/sulfamethoxazole (TMP/SMX) is the preferred agent in treating pulmonary nocardiosis. TMP-SMX has the additional benefits of excellent penetration into most tissue compartments including lungs, pericardium, mediastinum, and high serum concentrations after oral administration. The recommended treatment doses for pulmonary infection is 10 to 20 mg/kg of TMP and 50 to 100mg/kg of SMX should be given daily in two to four divided doses (160mg/800mg TMP/SMX IV every 6 hours, or 2 tab DS PO BID. Sulfonamides alone are also effective in the treatment of pulmonary nocardiosis when used in high doses (1.5– 2g PO QID). Endocarditis: Guided Medline Search There is a dismal prognosis associated with endocarditis due to Nocardia species; four of eight patients reported with this condition died of this disease before specific therapy could be instituted. Six cases of prosthetic valve endocarditis due to Nocardia species have been reported (23, 26, 28); but only two cases of native valve endocarditis (23, 113). Nocardia-like organisms were demonstrated only on histopathologic examination of one of the native valve endocarditis patients (23). In the other patient, cultures of valve specimens were positive for N. asteroides (113). Lack of appropriate therapy in the four patients that died was likely because of the indolent onset or low level of suspicion for this disease. Nocardial endocarditis should be suspected when there is no pulmonary or CNS involvement, which was the case in the four cases that survived, and when there is prosthetic valve replacement or recurrent skin and soft tissue infections due to these organisms, particularly if blood cultures are negative for these organisms (23). Improved outcome was demonstrated in patients who received a cell wall active agent, imipenem/cilastin or meropenem, and/or a bactericidal agent, aminoglycoside, in combination with TMP-SMX for 1 month to produce a synergistic bactericidal effect against susceptible strains of nocardiae due to the enhanced intracellular penetration of the aminoglycoside in the presence of the cell wall-active agent (23). This initial therapy was followed by TMP-SMX for 9 months. In one patient, the successful outcome was attributed to the combination of the following factors: the causative agent N. farcinica was identified early; abscesses did not occur in vital organs; an effective bactericidal antibiotic regimen was instituted; and the patient had surgical replacement of the infected aortic valve prosthesis (28). A summary of this case is provided. After receipt of a prosthetic heart valve, the patient was slow to recover and developed intermittent fever that did not respond to treatment with cefadroxil, amoxicillin, mezlocillin, or tobramycin. After the isolate was identified as N. farcinica, the treatment was changed to oral sulfadiazine (12 g/day); this produced unacceptable gastrointestinal side-effects. Intravenous treatment was started with amikacin (250 mg, 2 to 4 times /day) and a combination of 5 g of amoxicillin plus 5 g of clavulanic acid every 8 h. This combination only temporarily reduced the patient’s fever and leukocyte counts. Therapy was then changed to intravenous imipenem (1.5 g) and amikacin (500 mg) every 6 h to maintain serum bactericidal concentrations, which were monitored during therapy. With this treatment, the patient recovered quickly and was discharged without further antibiotic therapy. Three months later, the patient was readmitted, and blood cultures were again positive for N. farcinica that was still susceptible to imipenem and amikacin. These antimicrobial agents were reinstituted, and the patient’s aortic valve was surgically replaced. Postoperatively, the patient recovered quickly without fever or an elevated erythrocyte sedimentation rate (28). The results derived from in vitro and in vivo experiments as well as the results in this case suggest that treatment of human nocardial endocarditis can be improved by the combination of a β-lactam compound, such as imipenem, and amikacin (70). CNS Infections: Guided Medline Search
Nocardiae have a specific predilection
for invading the CNS (6). Dissemination to the CNS is
noted in 25% of reported cases of nocardial infections (5).
Brain abscess is the most common clinical manifestation of CNS infection,
and although CSF culture has been positive in up to 20% of these cases,
meningitis itself is considered uncommon (11). Mortality
associated with Nocardia brain abscess is more than three times that
of brain abscess from other bacterial etiologies (101).
In 1991, Bross and Gordon reviewed 28 cases that fulfilled at least one of
the following criteria for meningitis: isolation of Nocardia species
from CSF or meningeal cultures; concurrent culture-positive extrameningeal
nocardial infection with histopathologic evidence of meningitis at autopsy
and no evidence of another infectious etiology; and concurrent
culture-positive extrameningeal nocardial infection with two of the
following signs suggestive of meningitis: head/neck pain,
lethargy/confusion, and stiff neck (11). The typical
findings in CSF studies were increased leukocytes (83% of cases, >500
leukocytes/mm3) with a predominance of neutrophils; hypoglycorrhachia (64%,
<40 mg of glucose/dL); and elevated protein level (61%, >100 mg/dL). In this
review the authors cited the following difficulties in establishing the
etiologic agent as a Nocardia species:
Gram stains
of CSF are often
negative and cultures are discarded prematurely or may demonstrate growth
too late to be clinically useful (11). Eighteen of 21
(86%) of the culture-positive nocardial meningitis cases in this series were
caused by N. asteroides complex, two cases were due to N.
brasiliensis, and one was due to N. otitidiscaviarum; all
survivors, were treated with some form of
sulfonamide except one patient who
received
minocycline Underlying Diseases Despite the characteristic severe degree of cellular immunodeficiency found in patients infected with HIV, recent reviews have emphasized that reports of opportunistic Nocardia sp. infections in HIV-infected patients have been relatively rare in the United States and Europe (53, 60, 61). The major factors postulated for the relatively low reported incidence of nocardiosis compared with other opportunistic infections in patients with AIDS include difficulty in making the clinical diagnosis of nocardiosis and especially difficulty in distinguishing nocardiosis from pulmonary tuberculosis, difficulty in identifying Nocardia spp., and the frequent use in HIV-infected patients of prophylactic and therapeutic drug regimens that also have activity against Nocardia spp. (70). Two studies designed to assess the frequency of nocardiosis in AIDS patients in an endemic tuberculosis area in the Ivory Coast found a prevalence of 4% nocardial infections in the autopsy study and a prevalence of 4.2% pulmonary nocardiosis (63, 67). In 2000, Jones et al. studied the occurrence, clinical, and microbiologic features of nocardial infection complicating HIV in South Africa (54). The clinical presentation in the 10 identified patients included pulmonary (five patients), pulmonary and cerebral (one patient), cerebral (one patient) and skin and soft tissue infection of the lower limb (three patients) (54). These investigators estimated a ratio of one case of pulmonary nocardiosis to 90 cases of pulmonary tuberculosis. HIV-infected patients with documented disseminated nocardiosis were treated initially with TMP-SMX; however, therapy was stopped in 50% of patients because of adverse reactions. In addition, these patient reactions may be aggravated by prolonged use of this drug as prophylaxis and the organism may develop resistance with prolonged therapy (45). Transplant Recipients: Guided Medline Search Reviews of invasive nocardial infection in high-risk, severely immunocompromised patients have included renal transplant patients (70, 115), cardiac (94), heart and/or lung transplant recipients (87), liver transplant recipients (70), and bone marrow transplant recipients (104). In spite of advances in renal transplantation, infection remains a leading cause of morbidity and mortality in renal transplant recipients. Depending on the transplant center, the reported incidence of nocardiosis varies from 0 to 20% (115). A review of renal transplant centers estimated that nocardial cases accounted for about 4% of infections in these centers (65). In renal transplants, nocardiosis has an overall mortality of 25%, and with CNS involvement mortality increases to 42% (68, 115). Special risk factors that have been identified for the development of nocardiosis include early rejection episodes, the epidemiological exposure to pathogens, and intensive immunosuppressive therapy (high-dose prednisolone and azathioprine) (2, 70, 115). The introduction of cyclosporine as an antirejection agent in both renal and cardiac transplant patients has been reported to have effectively decreased the incidence of nocardial infections in these patients (52). In the renal transplant patient, nocardial full dosage treatment is recommended for one year then a maintenance dose of oral TMP-SMX for as long as graft survival (115). The concomitant use of TMP-SMX and cyclosporine has been reported to cause nephrotoxicity (2) and intravenous TMP-SMX was found to cause reduction in cyclosporine trough levels leading to graft loss (89). After stereotactic aspiration of a nocardial brain abscess in a renal transplant patient, Sabeel et al. reported successful treatment with triple antimicrobial agents (TMP-SMX, ceftriaxone, and amikacin) while monitoring the trough levels of cyclosporine that had been lowered by 40% to improve the immune status of the patient (89).
Nocardial infections are uncommon in heart, lung, or heart-lung transplant
recipients. In a retrospective review of 540 recipients, 10 (1.5%) patients
developed nocardial pulmonary infection after transplantation with no
evidence of extrapulmonary disease (87). In this series,
two of six (33%) patients treated with TMP-SMX had adverse reactions that
were considered serious enough to warrant change of therapy. Six patients in
this series were initially treated with a carbapenem (i Alternative Therapy Guided Medline Search There is scant information concerning the effectiveness of newer oral alternative antimicrobial agents or combinations of antimicrobial agents that might improve the outcome of Nocardia species-infected patients. Alternative oral drug therapy for Nocardia infections may include the cephalosporins, cefixime and cefuroxime, these may potentially avoid some of the problems incurred by TMP-SMX. Beta-lactam parenteral antibiotics are usually effective including cefotaxime (1g IV q12h), ceftriaxone (2g IV q6h), imipenem (500mg IV q 6h) and meropenem (1h IV q8h). Although dapsone, a long-acting oral sulfone, is known as a therapeutic agent for human Mycobacterium leprae infections, more recently there have been reports of its effectiveness in the treatment and prophylaxis of P. carinii pneumonia (74). In addition, there are reports of the efficacy of dapsone in treating chronic nocardial mycetoma infections (51). Therefore, dapsone may be potentially useful in the therapy of other Nocardia species infections. Its mechanism of action is identical to that of the sulfonamides. Although there is considerable clinical trial experience with this drug in the treatment of human leprosy with respect to the occurrence and severity of clinical side effects, to our knowledge, ours are the only in vitro antimicrobial susceptibility data that may assist in predicting its potential effectiveness for the therapy of Nocardia species infections (Tables 3 and 4). Four promising folate pathway antagonists that have been evaluated for the therapy of other infections are cycloguanil chloride, WR99210 (a triazine inhibitor of dihydrofolate reductase) and their respective prodrugs, proguanil, and PS-15 (14, 42). To circumvent the adverse gastrointestinal symptoms and poor absorption found in clinical pharmacologic trials of WR99210 in humans, PS-15, the biguanide precursor of WR99210, was designed and synthesized. Analysis of plasma drug concentrations by high-performance liquid chromatography showed that monkeys converted PS-15 into its active metabolite WR99210 (25). Should these drugs with suggested in vitro activity demonstrate in vivo activity against Nocardia species isolates, they could represent new alternative therapy for patients with these infections. Clinical experience shows that aminoglycosides are both efficacious and safe when used and monitored conventionally. The conventional amikacin dosage regimen (7.5 mg/kg every 12 h) should be adjusted so that the peak serum levels (drawn 60 min after the start of a 30- to 60-min infusion) are sufficiently high to be bactericidal, and trough levels (drawn within 30 min of the next dose) are sufficiently low to avoid toxicity. The safety and efficacy of conventional aminoglycoside dosing regimens have been proven in clinical trials. The newer approach of a single, daily dosage has many theoretical benefits including improved efficacy, decreased toxicity, and pharmacoeconomic advantages. However, there is limited experience with a single daily dosage of aminoglycosides in patients with normal renal function and even less experience in those with impaired function. Issues regarding dosing, combination therapy, and proper monitoring for efficacy and toxicity need to be evaluated in clinical trials (22). Monitoring of serum aminoglycoside levels in patients with impaired renal function is essential for providing adequate therapy and reducing toxicity. Specifically, the status of the patient’s renal function should be estimated by measuring the serum creatinine concentration or calculating endogenous creatinine clearance rate (33). The first successful use of surgical debridement followed by amikacin in the treatment of nocardiosis was in 1980 in a renal transplant recipient (125). Other favorable treatment outcomes have been reported with amikacin and surgical drainage or debridement in a patient with a pancreatic N. asteroides abscess and in a patient with primary cutaneous N. farcinica infection (75, 93). Only rarely have nocardial infections been treated with macrolides, possibly because of the lack of availability of antimicrobial susceptibility studies and species identification in the past. The value of antimicrobial susceptibility studies and species identification was recently illustrated in a cardiac transplant recipient with pneumonia caused by N. nova. When TMP-SMX was not tolerated, the patient was treated successfully with the macrolide clarithromycin (78). Rarely have the quinolones been used for therapy for nocardiosis. Only two cases of N. asteroides sternotomy infection have reportedly been treated successfully with ofloxacin (124). In addition, ciprofloxacin (to which the patient’s isolate was only intermediately susceptible in vitro) was administered late and unsuccessfully to a renal transplant patient with disseminated N. farcinica infection to the brain; amikacin had been avoided for this patient because of the risk of associated nephrotoxicity (76).
Minocycline is a well-established oral alternative and can give in doses of
100 to 200 mg twice a day. An illustrative case summary follows. Although the diagnosis in a case of
cerebral Nocardia asteroides infection in an AIDS patient was
presumptive, the CT scan of the brain showed a right frontal lobe abscess
that progressed to involve the right parietal lobe. With this progression,
the previous treatment consisting of sulfadiazine (1.5 g every 6 h) and
intravenous i Since all reported isolates of N. otitidiscaviarum have been susceptible to minocycline, some authors recommend that optimal therapy for these infections should include the combination of minocycline with an aminoglycoside to which the isolate been demonstrated to have low MIC values, such as amikacin and kanamycin (6). However, as demonstrated for the folate pathway antagonists, minocycline is bacteriostatic and prolonged therapy may be associated with toxicity. Linezolid (600mg PO/IV BID) could be used as another alternative agent in the treatment of pulmonary nocardiosis. Clinical cure occurred in 6 patients with Nocardia pulmonary infections (Moylett et al, CID 2003;36:313-8). However, the high cost and adverse effects may limit the use of linezolid. The manufacturer explicitly cautions against the use of linezolid for greater than 28 days because of the risk of bone marrow suppression and peripheral and optic neuropathy. Jodlowski TZ, Melnychuk I, Conry J. Linezolid for the treatment of Nocardia spp. infections (October). Ann Pharmacother 2007;41:1694-9. Combination Therapy: Generally, a combination of two or more antimicrobial agents is selected to achieve one or more of the following goals: to attain the broadest spectrum possible of activity for empirical therapy of potentially infected persons; to minimize drug toxicity by using relatively low doses of two or more agents with additive efficacies but independent toxicities; to minimize the emergence of strains resistant to a single agent; and to exploit the possibility of synergistic inhibitory or bactericidal activities (27). Combination therapy is recommended for disseminated pulmonary nocardiosis and in patients who are immunocompromised. TMP/SMX plus amikacin or TMP/SMX plus cefotaxime /ceftriaxone is suggested. In transplant patients, imipenem (500mg IV q6h) plus amikacin (10-15mg mg/kg/day) or TMP/SMX (160mg/800mg TMP/SMX IV every 6 hours or 2 tab DS PO BID) is recommended (Am J Transplant 2004; 4 (Suppl. 10): 47-50). In vitro studies have demonstrated the selected combinations can be synergistic (Table 5).
Different combinations of
amikacin with
ceftriaxone,
erythromycin,
sulfisoxazole,
imipenem, In other experimental studies that used antimicrobial combinations that demonstrated synergy in vitro, the combinations of amikacin and either imipenem or amoxicillin-clavulanic acid, or cefotaxime and either amikacin or imipenem, were found to be efficacious (6, 38, 41, 92). In a study of CNS nocardiosis in a murine model, these combinations were also shown to be statistically superior to single-agent therapy (40). However, despite their efficacy in vitro and in vivo, the above combinations of antimicrobial agents require parenteral administration. Other limitations are the effects of long-term toxicity with amikacin (110). However, an advantage of amikacin and imipenem is their bactericidal activity, in contrast with the bacteriostatic activity of the sulfonamides. In addition, the weak in vivo activity of sulfonamides may be one of the reasons for treatment failures with these drugs and for the recommendation for long-term, high-dosage therapy.
(Printable Version of
Antimicrobial Therapy for
ADJUNCTIVE THERAPY Guided Medline Search Mamelak et al. recommended an aggressive surgical mode of therapy for nocardial brain abscess (68). For immunocompromised patients with multiple abscesses, craniotomy with excision of cerebral abscesses may be indicated. Other authors also recommended this approach (31, 101). The recommendation for early stereotactic or open biopsy may facilitate an early and accurate diagnosis including identification of the etiologic agent and its specific susceptibility profile so that therapy can be optimized for the particular infecting organism (31). However, for the immunocompetent patient with a single abscess (less than 2 cm in diameter), Mamelak et al. recommended a trial of empiric sulfonamide therapy followed by stereotactic aspiration if the patient’s condition deteriorated or the abscess did not decrease in size after 4 weeks (68).
ENDPOINTS FOR MONITORING THERAPY Guided Medline Search Clinical Clinical improvement is the best and most comprehensive guide to the adequacy of therapy; however, this is often difficult to monitor objectively. For infections requiring long-term therapy, such as endocarditis, clinical improvement may also be prolonged. If a patient remains febrile during antimicrobial therapy, it is important to consider various factors, such as treatment failure, drug fever, a sequestered abscess (which may require surgical drainage), and a coexistent or secondary opportunistic infection with another pathogen. Mounting evidence from recent in vitro and in vivo studies, clinical observations, and taxonomic developments has suggested that therapeutic decisions for patients with nocardiosis concerning the most appropriate drug treatment and the duration of therapy may be complicated. Such decisions may have to be individualized on the basis of knowledge, not only of the site and type of infection involved and the nature and degree of any underlying immunocompromise in the patient, but also of the particular Nocardia species causing the infection and the antimicrobial susceptibility test results for significant clinical isolates. Antimicrobial susceptibility testing should be performed on all important clinical isolates, preferably at a specialized reference laboratory (65). The results of such testing not only alert clinicians to the presence of primary or acquired resistance, which may complicate a patient’s drug therapy, but also provide a rational basis for the selection of alternative antimicrobial agents. Close monitoring of serum antibiotic levels may be extremely useful clinically. In addition, it is vitally important to maintain the antibiotic level at the site of the infection above the in vitro MIC of the organism, in particular in settings where host defenses are reduced or absent. The primary reason for serum drug level monitoring is to attain therapeutic levels quickly but not excessively. Nephrotoxicity may be associated with prolonged treatment with amikacin, whereas ototoxicity is associated with total cumulative dose as well as prolonged treatment (81). The evaluation of possible drug toxicity makes it necessary for frequent patient contact, which also facilitates evaluation of disease symptoms. Imaging Studies In pulmonary nocardiosis, the chest radiograph typically shows some degree of consolidation, multiple nodular lesions and cavitation or abscesses over both lung fields. A CT scan of the lungs may show abscess formation and other important features earlier than the plain chest radiograph. In most cases of cerebral nocardiosis, the antimicrobial agents given initially intravenously for 5 to 7 days were then continued orally for a total of 8 to 10 weeks or longer until abscesses were resolved, as monitored by CT scan (83). In a series of three patients with brain abscesses who were receiving immunosuppressive therapy at the time of diagnosis of nocardial infection, accurate localization of the abscess was obtained from CT scans, but CT-guided stereotactic aspiration was required for diagnosis and treatment (48). In two of these patients, the authors attributed their clinical success to early abscess evacuation and prolonged antibiotic therapy. The patients’ response to the therapy was satisfactorily monitored by CT scan. In a series of 131 cases, Mamelak et al. found that the overall mortality of brain abscess due to Nocardia had dropped from 61% before the use of CT scans to 37% after use of CT scans. These investigators attributed part of the overall drop in mortality to an earlier diagnosis using CT and magnetic resonance imaging (MRI) scans (68). Laboratory Studies Studies for routine monitoring of CSF infections should include CSF leukocyte count, glucose and protein levels, and results of smears and culture (11). Philpott-Howard found that patients who received appropriate antimicrobial agents and improved clinically may yield Nocardia in their sputum for the first 2 to 3 weeks of therapy (83). This finding suggests that sputum cultures may not be useful for monitoring the early response to therapy in these patients. Salinas-Carmona et al. obtained specific 24- and 61-kDa antigen fractions of N. brasiliensis and proposed their use in an enzyme-linked immunosorbent assay (ELISA), not only for laboratory diagnosis of N. brasiliensis infections in mycetoma, but also for use as an assay to monitor a patient’s therapeutic response (90).
VACCINES Guided Medline Search There are no commercially available vaccines for use in the prevention of nocardiosis.
PREVENTION OR INFECTION CONTROL MEASURES Guided Medline Search There are no specific measures for preventing nocardiosis; however, the concurrent administration of TMP-SMX prophylactically while receiving high dose immunosuppressants for rejection has been shown to reduce the occurrence of P. carinii pneumonia and/or toxoplasmosis after heart transplantation and was thought to have contributed to the reduction of nocardial infections in some series (1, 58). In one series of heart-lung transplants, 3 of 10 patients contracted nocardiosis while receiving TMP-SMX (160 mg of TMP and 800 mg of SMX 3 times weekly) prophylaxis (87). In another case series of nocardiosis, van Burik et al. evaluated 25 invasive allogeneic marrow transplant recipients. Ten of these marrow recipients with invasive nocardiosis were also receiving twice weekly, double-strength oral TMP-SMX as prophylaxis for P. carinii pneumonia (104). In these studies, acquired resistance to TMP-SMX may have been a factor or there may have been inherent resistance of the infecting Nocardia species. Sabeel et al. were successful in treating a brain abscess in a renal transplant patient with medical therapy alone. These authors were able to improve the patient’s immune status by decreasing cyclosporine trough levels by 40% for the first 6 weeks of treatment after transplant (89). Nosocomial nocardial infections are rare. Recently, three nosocomial endemic or epidemic outbreaks of N. farcinica surgical-site infections occurred (9, 29, 114). In one outbreak, the transmission of the infection was via an asymptomatic, colonized health care worker and the infectious source was confirmed epidemiologically by genetic methods to be the environment of the health care worker’s home (114). Although definitive sources of the infectious agents could not be identified in the other two outbreaks, it appeared that aerogenic transmission of N. farcinica occurred during operative or postoperative treatment in the endemic in Germany (9). The increase in the number of patients with N. farcinica of the same genotype (18 of 20) as identified by pulsed-field gel electrophoresis correlated with increased construction work during a specific time frame (9). These authors recommended that because of this correlation, precautions against nocardial infections should be taken in hospitals where renovation work is planned (9). In the other outbreak involving three heart transplant recipients in France, randomly amplified polymorphic DNA analysis showed one pattern for the epidemiologically related isolates (29). These outbreaks illustrate the importance of using epidemiologic and laboratory data as the basis for formulating effective control interventions for terminating nosocomial transmission of pathogenic organisms.
COMMENTS Our study found that, despite interspecies differences in antimicrobial susceptibility, the folate pathway antagonists, sulfamethoxazole, TMP-SMX, dapsone, amikacin, minocycline and amoxicillin-clavulanic acid, may all be effective therapy for patients with Nocardia species infections. The experimental folate pathway antagonist WR99210 has excellent in vitro activity against all strains of N. farcinica, N. nova, and N. asteroides sensu stricto. Thus, this agent, via its prodrug PS-15, may offer a desirable option for the therapy of multidrug-resistant N. farcinica infections. Moreover, in vitro studies with the experimental carboxyquinolone PD 117558 suggest that this drug may be effective against N. asteroides complex, N. brasiliensis, and N. otitidiscaviarum (8). Furthermore, meropenem, because of its in vitro activity against N. brasiliensis and N. otitidiscaviarum, may also be an effective carbapenem for therapy of these infections (122). Although in vitro activity does not always correlate with clinical response, these data may aid in formulating new recommendations for the therapy of clinical infections. Because of good in vitro and in vivo responses and the confirmation of clinical usefulness in patients, a combination of either imipenem or amoxicillin-clavulanic acid together with amikacin has great potential for becoming the antibiotic choice for the management of human nocardiosis (39, 40, 92). However, before alternative drugs -- such as dapsone and WR99210 via PS-15, and the carboxyquinolone PD 117558 -- and combination therapy of either imipenem or amoxicillin-clavulanic acid with amikacin can be recommended as therapy for Nocardia spp. infections (e.g., in HIV-infected patients who are unable to tolerate sulfonamides), their efficacy and potential toxicity will ideally have to be evaluated in controlled clinical trials.
TABLES TABLE 1 Characteristics differentiating the medically important species of the genus Nocardia
Table 2
Characteristics of some antimicrobial agents used clinically Table 3 Antimicrobial susceptibility of N. farcinica, N. nova, and N. asteroides sensu stricto isolates Table 4 Antimicrobial susceptibility of Nocardia abscessus and Nocardia asteroides sensu stricto type VI TABLE 5 Treatment for Pulmonary Nocardiosis
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