Nocardia species (Nocardiosis)

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. Data derived from modern taxonomic methods have changed the taxonomy of the genus Nocardia (27). Major pathogenic Nocardia species, Nocardia farcinica, N. nova,  N. cyriacigeorgica , and N. pseudobrasiliensis, have been characterized. Nocardia cyriacigeorgica, N. farcinica, and N. nova were separated from  the Nocardia asteroides complex and Nocardia pseudobrasiliensis from Nocardia brasiliensis. These species were validated primarily on the basis of DNA-DNA hybridization, 16S rRNA gene sequence analysis, antimicrobial susceptibility and biochemical profiles, and, to a lesser degree, on high-performance liquid chromatography (22, 54, 55, 69).   The use of molecular technology for 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 16S rRNA gene sequencing, random amplified polymorphic DNA and a combination polymerase chain reaction-restriction fragment length polymorphism analysis (39, 116).

MICROBIOLOGY

The genus Nocardia is currently composed of 87 validly described species: 46 of these species are medically relevant (16, 27, 53). However, despite recent taxonomic changes, there is evidence that this genus is still underspeciated. The distinguishing phenotypic characteristics of the five major clinically 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 Nocardia are weakly acid fast, the most useful acid-fast stain is the modified Kinyoun method (33, 55). The Brown-Brenn modification of Gram stain and the Gomori methenamine stain are useful in demonstrating the organisms in histopathologic preparations from tissue (20). 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 (8, 27, 55).  

Of importance, the former N. asteroides complex, responsible for the majority of invasive human infections, has been separated into six susceptibility patterns: N. abscessus (formerly N. asteroides type I), N. brevicatena/paucivorans complex (type II), N. cyriacigeorgica (type VI), N. farcinica (type V), N. nova complex that includes N. africana, N. kruczakiae, N. nova, and N. veterana (type III), and N. wallacei (type IV) (16).  N. farcinica is particularly important to distinguish since it has increased virulence and differs in its antimicrobial susceptibility test results and its epidemiology (16, 126). In addition to susceptibility studies, tests used to separate the four most commonly isolated N. asteroides complex and N. brasiliensisisolates further as N. abscessus, N. cyriacigeorgica, N. farcinica, and N. nova include growth on tryptone glucose yeast agar at 45oC for 1 day, production of: 14-day arylsulfatase, nitrate reductase, and urease; hydrolysis of adenine, casein, esculin, hypoxanthine, tyrosine, and xanthine; and utilization of acetamide, citrate, L-rhamnose and D-sorbitol (16); these same tests are used to separate N. pseudobrasiliensis from N. brasiliensis (16). 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 (19, 78). 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 (e.g.,104 versus102 CFU/ml), and 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 alleviated some of these problems (M24-T2) (96); these standards were updated in 2011 as document M24-A2 (29). In addition to differences in methodology, the results of some reported studies may vary because no distinction was made between N. nova and the former N. nova complex strains drug pattern type III (now includes N. africana, N, kruczakiae, and N. veterana) (88) or between N. brasiliensis and N. pseudobrasiliensis (27, 88, 105, 127). The typical in vitro susceptibility profiles of the clinical important Nocardia are given in Table 2.

16S rRNA gene sequencing

Currently, accurate identification of aerobic actinomycetes requires the use of molecular methods, specifically, gene sequencing and analysis. 16S rRNA gene sequence analysis can provide genus-level, and for most genera species-level, identification of clinically relevant aerobic actinomycetes (27, 28). Based on recommendations from Tindall et al. (120), nearly complete high quality gene sequences are necessary to maintain accurate genus/species assignment based on sequence similarity values as defined by Clinical and Laboratory Standards Institute (120). Speciation of isolates suspected of being an aerobic actinomycete requires a 16S rRNA gene sequence with a minimum length of 1440 bp. A BLAST analysis of a high quality gene sequence against a DNA sequence database such as GenBank [www.ncbi.nlm.nih.gov/Genbank] will allow for genus or species assignment based on sequence similarity results compared to a reference strain. Limitations to identifying aerobic actinomycetes by molecular methods include: lack of availability of technology and expertise; difficulty in generating high quality sequence data of sufficient length; inherent limitations of large public databases (25).

Many clinical laboratories rely on pyrosequencing to generate short (~500 bp) 16S rRNA gene sequences for identification of clinical isolates; however, it has been shown that some pathogenic aerobic actinomycetes cannot be accurately differentiated by short 16S sequences (26). It is recommended to send clinical isolates to a reference laboratory for confirmation of identification when adequate sequencing technology and analysis are unavailable.

EPIDEMIOLOGY

Nocardia species are widely geographically distributed soil bacteria that usually cause chronic, progressive infections (108). 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 (23, 79, 85). Severe infections with Nocardia species have also been reported to affect patients with human immunodeficiency virus (HIV) infection (65, 66, 70, 81, 82, 117). 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 (85).  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,  23, 135).

CLINICAL MANIFESTATIONS

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 (42, 85, 92). 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 (85, 92, 137). However, very rarely, it may result from a primary nonpulmonary (cutaneous) infection site (114). 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% (85, 138). In severely immunocompromised patients the mortality may be greater than 85% (85). 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 (85). In the brain and other organs, abscess formation is a particularly common pathologic manifestation of disseminated infection (85). Patients with cerebral nocardiosis may present acutely with signs of sepsis and intracranial mass effects (85). However, severely immunocompromised patients with nocardial cerebral abscess may frequently be asymptomatic initially, and demonstate a prolonged latency (up to 3 years) before this type of clinical presentation in infected patients following the commencement of immunosuppression (85). There may be clinical evidence of pulmonary nocardial infection in about one third of the cases (12), and blood cultures may also be positive for Nocardia spp. in these patients (12). 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 (83). 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 (12).

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 (85). 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 (85). Nocardia brasiliensis has been associated particularly with subcutaneous infections and is predominant in tropical countries (113,  114, 134). Frequently, there may be 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 (85). 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 (85,  113,  114).

N. cyriacigeorgica (formerly Nocardia asteroides type VI susceptibility pattern and N. asteroides sensu stricto)

Of the previously established N. asteroides drug patterns, type VI is the most commonly isolated drug pattern type in areas where actinomycotic mycetoma is not endemic (16, 27). In 2012, in a study on sulfonamide resistance in clinical Nocardiaisolates, Brown-Elliott et al. reported testing 552 total isolates from six major U.S. medical or referral centers received from 2005-2011. Of these, 136 (25%) were identified as N. cyriacigeorgica making this group the most numerous among all species reported in the study (15). The Centers for Disease Control and Prevention have reported N. cyriacigeorgica as the third most prevalent species identified among clinical Nocardia isolates referred to the Special Bacteriology Reference Laboratory for identification over the last 10 years (unpublished data). In addition, Kageyama et al., in 2005, reported N. cyriacigeorgica as a significant pathogen in Japan and Thailand (68). There are also reports of N. cyriacigeorgica as the causative agent of disseminated nocardiosis in Canada, France, Greece, The Netherlands, and Turkey (27).  Molecular methodologies including 16S rRNA, heat shock protein, and secA1 gene sequencing have allowed more accurate assignment of clinical isolates to this group.  In 2001, Yassin et al. described N. cyriacigeorgica from bronchial secretions of a patient with chronic bronchitis and with this publication successfully validated the establishment of the species (144). Nocardiacyriacigeorgica is often a cause of pulmonary nocardiosis but there are also several reports of brain abscess, and disseminated disease. A 2014 case report from Brazil described disseminated disease in an immunocompetent patient who required a total of 28 months treatment before resolution (97). Nocardia cyriacigeorgica was isolated from this patient’s ulcerative cutaneous lesions and pleural fluid; symptoms included high fever, respiratory distress, arthritis, peripheric neuropathy, and reoccurrence of new nodules. Evolution of antimicrobial therapy was as follows: initial treatment was with ceftizoxime and clindamycin then switched to TMP-SMX and imipenem. Due to intolerance of TMP-SMX, the combination therapy was changed to imipenem, amikacin, and doxycycline. Imipenem was removed and amikacin and doxycycline continued which resulted in reoccurrence. Imipenem, amikacin, and vancomycin were then given for two months with doxycycline monotherapy given as maintenance. After six months, there was a second reoccurrence and ceftriaxone, amikacin, and doxycycline were given for two months. With no change in disease progression, linezolid with doxycycline were given and clinical cure achieved. Linezolid had to be stopped after 3 months due to adverse effects without complete eradication of the organism. Final resolution and cure was attained only after treatment of relapsing episodes of acute cutaneous lesions with TMP-SMX for 10 months. This case is an example the persistence of nocardiosis and challenges in finding effective therapy, even when the identity of the species is known.

N. farcinica

Nocardia farcinica may cause a variety of clinical presentations, including cerebral abscess, keratitis, bacteremia, and pulmonary, kidney, and cutaneous infections (91, 111, 132). There is a clear importance in differentiating between N. farcinica and other Nocardia species. Nocardia farcinica has a high degree of resistance to various antibiotics, especially to third-generation cephalosporins, which may make treatment of the infection difficult (109, 132). Mouse pathogenicity studies have demonstrated that this may be a more virulent species than the others (85). Nocardia farcinica occurs more frequently than was previously recognized (109, 132). 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 (109). 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 (10, 39, 136).

N. nova

The clinical diseases associated with N. nova isolates are similar to those previously described for diseases due to N. farcinica and other former N. asteroides complex microorganisms. The reasons for identifying these microorganisms include their susceptibility to erythromycin and third-generation cephalosporins and resistance to amoxicillin-clavulanate (128). 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 (128, 141).

N. transvalensis

Infections with N. transvalensis have been reviewed by McNeil et al. (86). 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 (85, 86). 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 (85). In a study by Wilson et al. (139), 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 were from that location (139).

Four Nocardia species, N. abscessus, N. africana, N. paucivorans, and N. veterana, have only rarely been encountered as agents of disease (57, 60, 142, 143). N. abscessus has been isolated from patients with abscesses of knee joint, fibula, and leg (143); N. africana has been isolated from patients with pulmonary infections (61); N. paucivorans has been isolated from the sputa and bronchial secretions of a patient with chronic lung disease (142); 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) (57).

LABORATORY DIAGNOSIS

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 (134). Very rarely, clubbing has been seen with N. asteroides, but often granules with clubbing are seen with N. brasiliensis and N. otitidiscaviarum (85). The hematoxylin and eosin stain is very useful for staining the tissue reaction and the granules but does not stain the individual filaments (20). A tissue Gram stain such as the modified Brown and Brenn procedure is recommended for demonstration of the gram-positive filaments of nocardiae (20). 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 all Nocardia species. These species are frequently, but not always, acid fast in tissue sections stained with both the modified Kinyoun or the Fite-Faraco staining methods (85). 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

Nocardia species have been shown to act as facultative intracellular organisms within macrophages (4, 31), where they inhibit the fusion of phagosomes with the lysosomes. In addition, human neutrophils and monocytes have been shown not to kill these organisms (40). 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 (34).

SUSCEPTIBILITY 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 3).

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 3). Sulfamethoxazole and trimethoprim have intermediate and high intracellular penetration of human polymorphonuclear leukocytes (PMNs), respectively (44, 61) (Table 3). For trimethoprim, in particular, this may be connected to its efficacy in combination with sulfamethoxazole in treating intracellular pathogens (61). Sulfonamides (or the combination TMP-SMX) are the therapy of choice for nocardiosis (47,80, 114, 130). Certain Nocardia 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 (114). 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 (6, 45, 51, 66, 70, 81, 93, 109, 115, 148).  

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 (now Pneumocystis jiroveci) (56, 70) orNocardia species infections (117), and in renal transplant recipients with nocardiosis (2). In these patient populations, adverse reactions such as skin rash, fever, and neutropenia have been reported in 44% to 80% of cases (56, 70). 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 (56).  

Another factor is resistance of the infecting microorganism to drug therapy (TMP-SMX, and alternative agents or drug therapy combinations) (24, 45, 51, 72, 110, 115). In a review of nocardiosis in AIDS, TMP-SMX was used as therapy for 50% of patients; however, 90% of these patients were nonresponsive and died (81). 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 (P. jiroveci) prophylaxis, two patients developed Nocardia infections (66). 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 (P. jiroveci) infection (93).  

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. Table 4 contains 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. cyriacigeorgica 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 and  N. nova, and N. cyriacigeorgica. 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. cyriacigeorgica 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. cyriacigeorgica 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 (11) and Schaal et al. (110) found a high degree of resistance to TMP-SMX in N. farcinica strains and a lesser degree of susceptibility in N. cyriacigeorgica 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. cyriacigeorgica (15,129, 131, 132). 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 4). In a study by Mc Neil et al., all isolates of N. brasiliensis were susceptible to sulfamethoxazole and TMP-SMX (88). These results are in good agreement with the data of other investigators (6, 11, 110). 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, 11, 88, 110).

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 (86) (Table 1), all Nocardia species have low MIC values to amikacin in vitro (30, 36, 131) (Table 3 and Table 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 (72). Despite low MIC values, this class of antimicrobial agents has been reported to have poor penetration into macrophages and neutrophils (125) (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 (122). Furthermore, the intracellular/extracellular (I/E) ratio was increased from <1 to 2 to 4 after 72 h incubation (122) (Table 3). In a mouse model study using a biochemically-typical N. cyriacigeorgica (then called N. asteroides sensu stricto) strain and a N. farcinica strain, amikacin, amoxicillin-clavulanic acid, and minocycline proved to be therapeutically more effective than sulfadiazine (110).

β-Lactams

The vast majority of Nocardia strains in our study were intermediate to resistant to the β-lactam antimicrobial agents currently in use (Table 3 and Table 4, actually, we do not use to direct therapy only for profiling ). This may be predominantly due to the production of potent β-lactamases that have been identified in pathogenic nocardiae (75). These enzymes appear to be especially active in members of the species N. farcinica, N. cyriacigeorgica, (previously N. asteroides sensu stricto type VI), N. brasiliensis, and N. otitidiscaviarum (110, 129). Only 44% of N. nova isolates were susceptible to ampicillin (Table 3 and Table 4).  

All N. farcinica isolates were resistant to cefixime. The majority of isolates were resistant to cefuroxime (64%), cefotaxime (82%), and ceftriaxone (86%) (Table 4). Although all isolates of N. nova were resistant to cefixime, the isolates were usually susceptible to cefotaxime (6%) and ceftriaxone (11%). All isolates of N. nova were susceptible to the oral cephalosporin cefuroxime. The majority of N. cyriacigeorgica isolates were resistant to cefixime (61%). These isolates were usually susceptible to cefuroxime (11% resistant), cefotaxime (6%), and ceftriaxone (6 %). In another study of 12 clinical isolates of N. asteroides, Gutmann et al. (58) 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 3). 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 4). The resistance of N. farcinica isolates was high (36%), followed by N. cyriacigeorgica (previously 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 (145). Most isolates of N. brasiliensis and N. otitidiscaviarum have been reported to be resistant to imipenem (102, 145, 146). 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 (145, 146). As with other β-lactams, the in vivo activity of imipenem may be affected 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 3). However, in general, poor results were seen with these agents in our study (Table 4), despite the advantage they possess of good penetration into phagocytes (Table 3). The isolates of N. nova are an exception: these isolates are always susceptible to erythromycin (128) (Table 4). The inconsistency in results (40% resistance) between our study given in Table 4 and the results (> 90% resistance) given in Table 2 for N. cyriacigeorgica (formerly N. asteroides sensu stricto) isolates reported in the literature (27, 29) 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 several new quinolones approved by the Food and Drug Administration for use in the United States -- ciprofloxacin, ofloxacin, lomefloxacin, and enoxacin, and moxifloxacin which was approved in 2009  (64). In a retrospective comparative evaluation of ciprofloxacin and moxifloxacin of 181 clinical strains of Nocardia species (n=181) in our laboratory, moxifloxacin demonstrated higher activity than with ciprofloxacin towards all nocardial strains tested (Melissa Bell and June Brown, personal communication). The MICs of each quinolone varied greatly depending on the species (72). 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 (9, 105, 127).   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 3). 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 (18, 99) (Table 3).

Tetracyclines

Tetracyclines are bacteriostatic agents that act by inhibiting bacterial protein synthesis (Table 3). These antibiotics have high PMN penetration (IE =7.1) (44). All isolates of N. nova in our study were susceptible to minocycline, and the majority of N. abscessus, N. cyriacigeorgica, and N. farcinica were susceptible (14, 6, and 4%, resistance, respectively) (Table 4). Our results obtained for minocycline correlated well with the data of other investigators (110). Previous reports in the literature of N. brasiliensis resistance to minocycline may have been a result of the heterogeneity of the species and has changed with the separation out of N. pseudobrasiliensis (127). In one study, 25% of N. brasiliensis isolates were resistant (88). 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 (127). All isolates of N. otitidiscaviarum were susceptible to minocycline in studies by Schaal et al. (110) and Boiron and Provost (11).

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 (14). 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 (84). Brown-Elliott et al. (14) reported the in vitro activities of linezolid by broth microdilution against eight species of Nocardia including N. abscessus, N. cyriacigeorgica, 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. Until its approval April 18, 2000, linezolid was used as compassionate alternative agent. Because of its activity and availability as an oral agent, linezolid has the potential to be the primary treatment for nocardiosis (14).

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 3). In our study, N. nova was usually resistant to amoxicillin-clavulanic acid (94%); N. cyriacigeorgica and N. farcinica isolates were less frequently resistant at 61% and 29%, respectively (Table 4). Another species of Nocardia, N. otitidiscaviarum, has been reported to be resistant to amoxicillin-clavulanic acid (6, 11, 110). In vitro studies assessing potential synergy with β-lactam-β-lactamase inhibitor combinations showed that 11 ampicillin resistant strains of the former N. asteroides complex became susceptible to these drugs in the presence of clavulanic acid (75). Furthermore, Wallace et al. (129) 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 (110). However, the organisms studied were other members of the N. asteroides complex and did not include N. nova or N. otitidiscaviarum.

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, 51, 110). Beaman et al. 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 (48, 49, 50, 110); this finding has also been supported by clinical observations of infected persons (110).  

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 (51). 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 (73,  140).

ANTIMICROBIAL THERAPY

Drug of Choice

Sulfonamides (with or without trimethoprim) have been the mainstay of antimicrobial therapy for human nocardiosis.   TMP-SMXhas 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 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 mg/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 3).

Special Infections

Pulmonary Nocardiosis

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 (160 mg/800 mg 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

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 (33, 36, 38) but only two cases of native valve endocarditis (33, 133). Nocardia-like organisms were demonstrated only on histopathologic examination of one of the native valve endocarditis patients (33). In the other patient, cultures of valve specimens were positive for N. asteroides (133). 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 (33). Improved outcome was demonstrated in patients who received a cell wall active agent,  imipenem 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 (33). 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 (38). 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 (38). 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 (87).

CNS Infections

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 (12). Mortality associated with Nocardia brain abscess is more than three times that of brain abscess from other bacterial etiologies (119). 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 (12). 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 (12). 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. Further, as noted by these authors, the utility of using large volumes of CSF or concentration techniques to enhance the yield of Nocardia species from CNS has not been well studied (12). Most in vitro susceptibility studies have suggested that sulfonamides, minocycline,  amikacin,  imipenem, and the quinolones are the most active agents. Combination testing has revealed synergy of TMP and SMX, and this combination appears to penetrate the blood-CSF barrier and achieve high CSF concentrations (118). Another study suggested that antimicrobial combinations should include at least one of the cephalosporins or  ciprofloxacin (100). Several cephalosporins reach the CSF in concentrations adequate to inhibit Nocardia in vitro, but cefuroxime appears to be the most active (118). Although amikacin may be active in vitro against most Nocardia species, this agent penetrates the blood-CSF barrier poorly; therefore, it is sometimes necessary to administer this agent directly into CSF (120). Other authors have suggested that the use of a combination of a cell wall-active agent plus amikacin may yield a bactericidal synergism that will enhance intracellular uptake of amikacin (37). Mamelak et al. suggested that regardless of the antibiotic regimen selected, the antimicrobial agent should be administered intravenously for at least 6 weeks and longer if necessary (83). In immunocompromised patients, intravenous antibiotic therapy should be followed by 1 year of oral antibiotics (83). The recommended antibiotic of choice for nocardial brain abscess is the synergistic combination of TMP-SMX and the recommended daily intravenous doses of SMX and TMP are 75 to 100 mg/kg and 15 to 20 mg/kg, respectively (83). In a series of 11 cases of nocardial brain abscess treated at their institution and a retrospective review of 120 cases reported since 1950 studied by Mamelak et al., 90% of individuals received a sulfonamide alone or in combination with TMP or other agents such as a beta-lactam or an aminoglycoside; therefore, no meaningful analysis of comparative efficacies was possible (83). In 16 patients in this series, sulfa drugs were discontinued because of patient intolerance or allergic reactions; these patients then received either minocycline (14 patients) or imipenem (two patients) (83).

Underlying Diseases

AIDS

Despite the characteristic severe degree of cellular immunodeficiency found in patients infected with HIV, literature reviews have emphasized that reports of opportunistic Nocardia sp. infections in HIV-infected patients have been relatively rare in the United States and Europe (66, 73). 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. (85). 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 (76, 82). In 2000, Jones et al. studied the occurrence, clinical, and microbiologic features of nocardial infection complicating HIV in South Africa (66).  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) (67). 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 (56).

Transplant Recipients

Reviews of invasive nocardial infection in high-risk, severely immunocompromised patients have included renal transplant patients (85, 137), heart and/or lung transplant recipients (104), liver transplant recipients (85), and bone marrow transplant recipients (124). 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% (137). A review of renal transplant centers estimated that nocardial cases accounted for about 4% of infections in these centers (80). In renal transplants, nocardiosis has an overall mortality of 25%, and with CNS involvement mortality increases to 42% (83, 137). 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, 85,137). 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 (63). 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 (137). 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 (106). 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 (106).  

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 (104). 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 (imipenem or meropenem) without adverse reactions. Of interest, when these nocardial strains were speciated, N. nova was the predominant species, accounting for 6 of 10 (60%) isolates (104). In a case series of cardiac transplant recipients with nocardial infections, Simpson et al. identified patients with a history of high-dose prednisolone therapy, uremia, prolonged respiratory support, and frequent rejection episodes as having an increased risk for an adverse outcome (112). In a 2001 review of treatment of three heart transplant patients with pulmonary nocardiosis, Tripoli et al. suggested that a synergistic combination of a beta-lactam/beta-lactamase inhibitor with ciprofloxacin or amikacin followed by a short course of TMP-SMX may be effective in eradicating nocardial disease and may reduce the need for long-term treatment (121).  Opportunistic infection with nocardiosis affects 0.04 to 3.5% of patients with solid organ and hematopoietic stem cell transplants, depending on the type of organ transplanted, presence of cytomegalovirus Infection, immunosuppressant corticosteroid dose, and calcineurin inhibitor levels. Extensive clinical, radiological, and microbiological evaluations are mandatory, including brain imaging, even in the absence of neurological symptoms.  In transplanted patients differential diagnosis is challenging, with co-infections reported in 20 to 64% of the cases. As the antimicrobial susceptibility pattern varies among species, the regimen before species identification should rely on the use of antimicrobial agents active against all species of Nocardia. Bactericidal agents are required in cases of severe or disseminated disease. Further, in transplant recipients, combination therapy is difficult to manage because of cumulative toxicity and interactions with immunosuppressive agents. Because of the high recurrence rate, antibiotic therapy should be prescribed for 6 to 12 months (79).

Alternative Therapy

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 (1g IV q8h).

Although dapsone, a long-acting oral sulfone, is known as a therapeutic agent for human Mycobacterium leprae infections, there have been reports of its effectiveness in the treatment and prophylaxis of P. jiroveci (P. carinii) pneumonia (89). In addition, there are reports of the efficacy of dapsone in treating chronic nocardial mycetoma infections (62). 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 (Table 2 and Table 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 (17, 52). 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 (35). 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 (32). 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 (43).  

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 (90, 111).  

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 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 (94).  

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 (147). 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 (91).  

Minocycline is a well-established oral alternative and can be given 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 imipenem (500 mg every 6 h) was discontinued, and oral minocycline (200 mg every 12 h) was increased to 300 mg in combination with intravenous ceftriaxone (2 g every 12 h), an antimicrobial agent that is likely to achieve adequate CSF concentrations (73,74) After 5 weeks of therapy with minocycline and ceftriaxone, the patient’s brain lesions almost completely resolved, as evidenced by CT scan (74). This case suggests that in a patient with AIDS and a presumptive nocardial cerebral infection antibiotic treatment alone was successful without surgical intervention.  

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 (600 mg PO/IV BID) could be used as another alternative agent in the treatment of pulmonary nocardiosis. Clinical cure occurred in six patients with Nocardia pulmonary infections (95). 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. Linezolid is gaining more attention as a primary therapy for nocardial infections as antimicrobial susceptibility testing results have shown that it has excellent activity against all species of Nocardia including N. farcinica. A review in 2008 summarized 16 patients with nocardiosis treated with linezolid as monotherapy or in combination with other agents reported a high success rate with 12 of16 cured and 3 improvements (including cerebral and disseminated disease), although anemia and myelosuppression were common. In vitro studies have shown an antagonistic effect against Nocardia isolates for combinations of linezolid with amikacin and imipenem but linezolid is bactericidal when used in combination with moxifloxacin. Linezolid is given 600 mg twice a day either intravenously or orally with few significant drug interactions. Serious toxicities include thrombocytopenia, aplastic anemia, peripheral neuropathy, lactic acidosis and serotonin syndrome in the setting of concomitant serotonin reuptake inhibitor use. Myelosuppression, in particular, as well as the high cost of the drug may limit its widespread use for nocardiosis (7, 23).

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 (37).  

Different combinations of amikacin with ceftriaxone, erythromycin, sulfisoxazole, imipenem, cefotaxime, and clarithromycin were clinically efficacious in three bone marrow recipients. Two of these patients’ isolates were identified as N. nova; the third, as N. cyriacigeorgica (formerly N. asteroides sensu stricto) (21). A favorable clinical outcome with the combination of imipenem and amikacin was reported for a patient with nocardial endocarditis of an aortic valve prosthesis caused by N. farcinica (38) and for a patient with primary cutaneous N. farcinica infection following heart transplantation (103). In addition, the combination of amikacin with imipenem and surgical excision has resulted in a successful clinical outcome in a patient with cerebral nocardiosis (77). In another study, seven of eight patients with disseminated nocardiosis were treated with amikacin in combination with other effective antimicrobial agents for a duration of 2 to 12 months (45). These patients received drug combinations that included cefuroxime (two patients), cefuroxime and TMP-SMX (two patients), cefuroxime plus the amoxicillin-clavulanic acid combination (two patients), and TMP-SMX plus minocycline (one patient). These patients were all considered cured at follow-up after 2 years. Because of good in vitro and in vivo responses, and the confirmation of the clinical usefulness of imipenem, amoxicillin-clavulanic acid, and amikacin in patients, the 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 (6, 49, 50).  

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, 48, 51, 110). In a study of CNS nocardiosis in a murine model, these combinations were also shown to be statistically superior to single-agent therapy (50). 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 (130). 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.

ADJUNCTIVE THERAPY

Mamelak et al. recommended an aggressive surgical approach to therapy for nocardial brain abscess (83). For immunocompromised patients with multiple abscesses, craniotomy with excision of cerebral abscesses may be indicated. Other authors also recommended this approach (41, 119). 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 (41). 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 (83).

ENDPOINTS FOR MONITORING THERAPY

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 immunocompromised 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 (80). The results of such testing not only alert clinicians to the presence of inherent 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 (98). 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 (100). 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 (59). 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 (83).

Laboratory Studies

Studies for routine monitoring of CSF infections should include CSF leukocyte count, glucose and protein levels, and results of smears and culture (12). 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 (100). 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 (107).

VACCINES

There are no commercially available vaccines for use in the prevention of nocardiosis.

PREVENTION OR INFECTION CONTROL MEASURES

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(P. jiroveci) pneumonia and/or toxoplasmosis after heart transplantation and was thought to have contributed to the reduction of nocardial infections in some series (1, 71). 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 (104). In another case series of nocardiosis, van Burik et al. evaluated 25 invasive infections in 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 (P. jiroveci) pneumonia (124). 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 (106).  

Nosocomial nocardial infections are rare. Three nosocomial endemic or epidemic outbreaks of N. farcinica surgical-site infections have been reported (10, 39, 136). 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 (136). 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 report from Germany (11). 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 (10). These authors recommended that because of this correlation, precautions against nocardial infections should be taken in hospitals where renovation work is planned (10). In the other outbreak involving three heart transplant recipients in France, randomly amplified polymorphic DNA analysis showed one pattern for the epidemiologically related isolates (39). 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 (9). 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 (148).  

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 (49, 50, 110).

During the last 10 years, there have been dramatic changes in taxonomy: both new molecular and traditional phenotypic methodologies remain important.  However, modern molecular technical advances have made possible the characterization of an organism as accurately and rapidly as possible which in turn has made possible earlier performance of susceptibility studies.  By reducing the time from 5-6 weeks to 1 week, one is able to optimize earlier therapeutic options (123, 135).

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Tables

TABLE 1.  Major phenotypic characteristics and occurrence of the five most commonly isolated Nocardia species associated with human disease^{a, b}

^aSymbols and abbreviations: -, negative; +, positive.
^b Adapted from reference (16). Occurrence based on in-house evaluation of 1745 clinical isolates from 2002-2012 (unpublished data from Special Bacteriology Reference Laboratory records).
^cUtilization as sole source of carbon and nitrogen.
^dUtilization as sole source of carbon.

TABLE 2. Typical in vitro antimicrobial susceptibility patterns of    “ Nocardia asteroides complex”,  Nocardia brasiliensis, and Nocardia pseudobrasiliensis^a

Agent	N. abscessus Type I	N. brevicatena and N. aucivorans Type II	N. cyriacigeorgica Type VI	N. farcinica Type V	N. nova complexb Type III	N. wallaceic Type IV	N. brasiliensis	N. pseudobrasiliensis
Amikacin	S	S	S	S	S	R	S	S
Amox-clav	S	S	R	NC	R	NC	S	S
Ceftriaxone	S	S	S	R	S	S	S	NC
Ciprofloxacin	R	S	R	S	NC	S	S (R)	S (S)
Clarithromycin	R	R	R	R	S	R	R	S
Imipenem	NC	R	S	S	S	S	S	S
Linezolid	S	S	S	S	S	S	S	S
Minocycline	NC	NC	NC	NC	NC	NC	NC (S)	NC (R)
TMP-SMX	NC	NC	NC	NC	NC	NC	NC	NC

Amox-clav, amoxicillin-clavulanate;  TMP-SMX, trimethoprim-sulfamethoxazole; S, susceptible; R, resistant; NC, no consistent result

^aResults adapted from Conville and Witebsky (27 and 29)  and based on MICs using CLSI  breakpoints. Results of N. brasiliensis and N. pseudobrasiliensis with ciprofloxacin and minocycline in parentheses are adapted from references 127 and 29.

^bN. nova complex includes N. africana,  N. kruczakiae, and N. veterana.

^c N. wallacei was formerly N. asteroides type IV.

TABLE 3. Characteristics of some antimicrobial agents used clinically^a

Class and microbial agent (s)	Route of administration	Drug concentration intracellular/extracellular ratio	Mechanism of action	Drug interactions	Side effects
Aminoglycoside    Amikacin Tobramycin	Parenteral	<1 (125)  2 to 4 after 72 h of incubation (122)	Bactericidal activity results from action on 30S ribosomal subunit to produce faulty protein synthesis	Calcium, sodium bicarbonates, $β-lactams, and heparin	Nephro- and ototoxicity
β-Lactams Ampicillin PenicillinsAmpicillin	Oral/ Parenteral	<1 in PMNs and macrophages after prolonged  incubation (125)	Bactericidal activity results from interference with construction of bacterial cell wall by inhibition of transpeptidases responsible for catalysis of peptidoglycan cross-linking	Allopurinol, bacteriostatic antibiotics (chloramphenicol,  sulfonamides, or tetracyclines) may interfere with bactericidal effect of ampicillin and probenecid Aminoglycosides	Nephro-and ototoxicity
Carbapenem        Imipenem	Parenteral
Cephalosporins
Cefotaxime	Parenteral
Ceftriaxone	Parenteral
Cefixime	Oral
Cefuroxime	Oral/Parenteral
β-Lactam-β-lactamase inhibitor      Amoxicillin-clavulanic acid	Oral		Bactericidal activity  results from the ability of clavulanic acid to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes and thus protects amoxicillin from degradation	Probenecid, allopurinol, antabuse, and ampicillin	Gastrointestinal and hypersensitivity reactions
Macrolides      Erythromycin Clarythromycin	Oral/Parenteral	16 to 32 in alveolar macrophages (68) 2 to 10 in PMNs (18)	Bactericidal activity results from inhibition of protein synthesis by binding 50S ribosomal subunit	Theophylline, digoxin, oral anticoagulants, ergotamine	Gastrointestinal irritation, transient CNS reactions,and cardiac arrhymias
Oxazolidinone Linezolid	Oral/Parenteral	N/A	Oxazolidinone antibacterial; inhibits bacterial protein synthesis. 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	Use of MAOIs A or B (eg, phenelzine, isocarboxazid) either concomitantly or within 2 weeks of taking such drugs.	Diarrhea, nausea, thrombocytopenia, abnormal Hgb/WBC/neutrophils, serum AST/ALT/alkaline phosphatase/lipase/total bilirubin elevations.
Quinolones      Ciprofloxacin Moxifloxicin	Oral/Parenteral Parenteral	2 to 8 in macrophages and fibroblasts (15) >8 (65)	Bactericidal activity results from gyrase inhibition required to fold DNA stra	Theophylline, magnesium -aluminum antacids, and other cations (calcium, zinc, and iron)	Gastrointestinal, CNS,  and skin/allergic reactions
Sulfonamides Sulfamethoxazole Trimethoprim TMP/SMX	Oral Oral Oral/Parenteral	1.7 in PMNs (44) 4.1 in PMNs (44) and 9 at 37°C and 13 at 25°C (62)	Bacteriostatic results from the inhibition of folate pathway	Thiazides, warfarin, phenytoin, cyclosporine,and cyclosporin	Hepatotoxicity, myelosuppression, and gastrointestinal, allergic skin, hematologic, neurologic, and psychiatric reactions
Tetracyclines Doxycycline Minocycline	Oral/Parenteral Oral/Parenteral	7.1 in PMNs (44)	Antacids and anticoagulant therapy  Bacteriostatic drugs may interfere with bactericidal action of penicillin	Antacids and anticoagulant therapy  Bacteriostatic drugs may interfere with bactericidal action of penicillin	Gastrointestinal reactions and renal toxicity  Hypersensitivity reactions and IV minocycline may cause thrombophlebitis

PMN, polymorphonuclear leukocytes; CNS, central nervous system; N/A, not available;  IV, intravenous.

^aAdapted from Physicians’ Desk Reference (101) except where referenced.

TABLE 4. Extended antimicrobial susceptibilities of  Nocardia farcinica, Nocardia nova,  Nocardia abscessus, and Nocardia cyriacigeorgica^a

	MIC (ug/ml)
Antimicrobial Agent (Breakpoint for resistance in ug/ml) b	50%				90%				Geometric meanc
	Nf	Nn	Na	Nc	Nf	Nn	Na	Nc	Nf	Nn	Na	Nc
	(n=28)	(n=18)	(n=7)	(n=18)	(n=28)	(n=18)	(n=7)	(n=18)	(n=28)	(n=18)	(n=7)	(n=18)
Amox-clav  (MIC, ≥32/16)	16/8	64/32	2-Apr	32/16	32/16	64/32	16/8	64/32	6-Dec	48/24	3.2/1.6	20/10
Cefuroxime (MIC, ≥32)	32	1	2	1	64	4	4	16	30	1	2	2
Cefotaxime (MIC, ≥64)	64	4	2	2	>64	16	4	8	66	4	2	3
Ceftriaxone (MIC, ≥64)	>64	4	<1	2	>64	16	4	8	45	5	3	3
Cefixime (MIC, ≥4)	>64	64	64	>64	>64	>64	>64	>64	111	49	32	45
Imipenem (MIC, ≥16)	8	<0.25	1	4	>32	0.5	4	16	7	0.3	1	5
Amikacin (MIC, ≥64)	1	<0.25	0.5	0.5	1	>0.25	2	1	1	0.25	1	0.5
Erythromycin (MIC, ≥8)	16	0.25	>16	16	>16	0.5	> 16	>16	14	0.3	24	12
Minocycline (MIC, ≥16)	2	1	1	2	8	4	8	8	2	1.6	3	2
Doxycycline (MIC, ≥16)	4	4	8	2	8	8	16	8	4	4	7	2
Ciprofloxacin (MIC, ≥4)	1	8	8	8	8	>8	8	>8	1	8	4	2
Rifampin (MIC, ≥4)	>32	2	>32	32	>32	>32	>32	>32	42	8	24	24
Sulfamethoxazole (MIC, ≥32)	8	32	8	4	32	8	32	16	7	2.3	32	5
Dapsone (MIC, ≥32)	8	4	4	4	>32	8	8	32	8	3.5	4	4
PS-15 (MIC, ≥32)	4	2	2	2	4	4	2	4	2	1.8	2	2
WR99210 (MIC, ≥32)	≤0.063	≤0.063	0.125	0.125	0.5	0.125	2	2	0.2	0.08	0.26	0.35
Cycloguanil (MIC, ≥32)	512	64	128	512	>512	128	>512	>512	512	60	388	338
Proguanil (MIC, ≥32)	128	32	64	64	512	64	128	>512	132	37	97	97
Trimethoprim (MIC, ≥16)	4	8	8	4	>32	32	16	32	5	7	9.7	6.5
TMP-SMX (MIC, ≥32)	0.5/ 9.55	0.06/ 1.19	0.5/9.5	0.25/4.80	Feb-38	0.5/ 9.5	0.5/9.5	0.5/9.5	0.5/ 9.5	0.17/ 3.2	0.15/ 2.80	0.2/ 4.4

 

	MIC (ug/ml)
Antimicrobial Agent (Breakpoint for resistance in ug/ml) b	Range				% Resistant isolates
	Nf	Nn	Na	Nc	Nf	Nn	Na	Nc
	(n=28)	(n=18)	(n=7)	(n=18)	(n=28)	(n=18)	(n=7)	(n=18)
Amox-clav  (MIC, ≥32/16)	2/1-64/32	2/1-64/32	<0.5/0.25-16/8	1/0.5->64/32	29	94	0	61
Cefuroxime (MIC, ≥32)	4->64	≤1-16	<1-4	<1-32	64	0	0	11
Cefotaxime (MIC, ≥64)	32->64	≤0.5-64	0.5-16	Jan-64	82	6	0	6
Ceftriaxone (MIC, ≥64)	8->64	≤1-64	<1-16	<1-64	86	11	0	6
Cefixime (MIC, ≥4)	64->64	8->64	0.5->64	0.5->64	100	100	71	61
Imipenem (MIC, ≥16)	0.5-32	≤0.25-2	<0.25->32	<0.25>32	36	0	14	11
Amikacin (MIC, ≥64)	≤0.25-2	≤0.25	<0.25-4	<0.25-1	0	0	0	0
Erythromycin (MIC, ≥8)	1->16	≤0.13-0.3	8->16	2->16	86	0	100	72
Minocycline (MIC, ≥16)	0.5-16	0.25-8	16-Jan	<0.13->16	4	0	14	6
Doxycycline (MIC, ≥16)	16-Jan	1->16	0.25->8	0.13->16	14	6	43	6
Ciprofloxacin (MIC, ≥4)	0.25->8	4->8	0.25->8	0.13->8	32	100	71	83
Rifampin (MIC, ≥4)	≤0.25->32	≤0.5->32	4->32	0.5->32	93	50	100	94
Sulfamethoxazole (MIC, ≥32)	≤1-128	≤1->128	2->32	<1-16	11	11	0	0
Dapsone (MIC, ≥32)	1->32	≤0.5->32	16-Feb	1->32	14	6	0	17
PS-15 (MIC, ≥32)	≤0.063->4	0.5-4	4-Jan	1->4
WR99210 (MIC, ≥32)	≤0.063-2	≤0.063-0.5	<0.063-2	<0.063-4
Cycloguanil (MIC, ≥32)	128->512	16-256	128->512	8->512
Proguanil (MIC, ≥32)	32->512	16-128	32->512	8->512
Trimethoprim (MIC, ≥16)	≤0.5->32	1->32	2->32	2->32	82	39	43	33
TMP-SMX (MIC, ≥32)	≤0.06/ 1.19-4/76	≤0.06/1.19->8/152	<0.06/1.19-1/19	<0.06/1.19-1/19	7	11	0	0

 

Abbeviations: Nf,  Nocardia .farcinia;  Nn, Nocardia nova; Na, Nocardia abscessus; Nc , Nocardia cyriacigeorgica; amox-clav, amoxicillin-clavulanic;TMP-SMX, trimethoprim-sulfamethoxazole.

^a Modified from reference 87.

^b Breakpoint point for resistance from National Committee for Laboratory Standards (96).

^c Estimated value (next highest twofold value used when calculating geometric mean that were greater than the highest concentration tested).

What's New

Pea, F. Successful long-term treatment of cerebral nocardiosis with unexpectedly low doses of linezolid in an immunocompromised patient receiving complex polytherapy.  Antimicrob Agents Chemother. 2012 Jun;56(6):3438-40.

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.  Transpl Infect Dis. 2010 [Epub ahead of print]

Uhde KB, Antimicrobial-resistant nocardia isolates, United States, 1995-2004. Clin Infect Dis. 2010 Dec 15;51(12):1445-8

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Baron EJ. Mold

Hosseini-Moghaddam SM, Husain S. Nocardiosis after Solid Organ Transplantation.

Parvu M, et al.  Skin Infections Caused by Nocardia Species. A Case Report and Review of the Literature of Primary Cutaneous Nocardiosis Reported in the United States.  Infect Dis Clin Prac 2012;20:237-241.

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Haas L.  Edmond Isidore Etienne Nocard (1850-1903).  J Neurol Neurosurg Psychiatry 2000;69(1):130.

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Nocardia species (Nocardiosis)