Disseminated Gonococcal Infection in an Immunocompetent Patient Caused
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《微生物临床杂志》
STI Clinic, Department of Infectious Diseases, Amedeo di Savoia Hospital, University of Turin, Turin, Italy
Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanita, Rome, Italy
ABSTRACT
We herein report the microbiological features of a Neisseria gonorrhoeae strain isolated from an immunocompetent patient with disseminated gonococcal infection (DGI). The strain expressed the IA/IB serovar; was resistant to penicillin, tetracycline, and ciprofloxacin; and had presumably been acquired in Southeast Asia. To date, this is the first case reported in our country of DGI due to an imported multidrug-resistant strain.
CASE REPORT
A 48-year-old man reported to the emergency department of Turin General Hospital with generalized malaise, pyrexia, nausea, and vomiting. His past medical history revealed hypertension and a recent trip to Thailand where he had engaged several times in sexual intercourse with local sex workers. Physical examination revealed a temperature of 39.8°C, a blood pressure of 190/100 mm Hg, a faint mitral holosystolic murmur, and diffuse hemorrhagic skin rash. There were no signs of meningeal involvement. The patient was admitted to the general medicine ward with suspected bacterial endocarditis. Upon admission, biochemistry was normal, and the white blood cell count was 14,100 (83.9% polymorphonuclear leukocytes, 7.3% lymphocytes, and 8.5% monocytes). The erythrocyte sedimentation rate was 78 mm/h, and the C-reactive protein level was 5.9 mg/dl. Chest X rays and transthoracic echocardiography were normal. Gram-negative diplococci were identified by API-NH (bioMerieux, France) as Neisseria gonorrhoeae in blood culture. Urethral specimens were negative; no throat or rectum specimens were collected. Serology for human immunodeficiency virus and syphilis was negative, and the patient was not immunocompromised. Treatment with 2 g oxacillin four times daily intravenously and 80 mg gentamicin twice daily was commenced. Three days later, the patient was afebrile. Following blood culture results, the patient was treated with 2 g ceftriaxone intramuscularly daily for 10 days. At discharge and follow-up, no clinically relevant problems were observed. The gonococcal strain was sent to the laboratory of the Istituto Superiore di Sanita for complete phenotypic and genotypic characterization. After growth on GC agar plates supplemented with 2% Isovitalex (Oxoid) and incubated at 37°C in 5% CO2 for 18 to 20 h, a serological assay by coagglutination reaction was performed using two monoclonal antibodies (Phadebact GC serovar test; Boule Diagnostic AB, Sweden) directed against epitopes of the IA and IB porin proteins. The isolate showed a reactivity against both porin proteins, thus resulting in a hybrid serovar (IA/IB).
Antimicrobial susceptibility testing was carried out using a panel of five antibiotics (penicillin, tetracycline, spectinomycin, ciprofloxacin [Cip], and ceftriaxone) by the E test method (ABbiodisk, Sweden) according to the manufacturer's instructions. The antimicrobial susceptibility breakpoints were those defined by the CLSI (3). A nitrocefin chromogenic test (Oxoid) was used to detect the presence of -lactamase production. The strain was resistant to three of the five antibiotics tested. In particular, the MICs were >32 μg/ml for penicillin, 24 μg/ml for tetracycline, and 4 μg/ml for Cip. MICs for ceftriaxone and spectinomycin were 0.002 and 6 μg/ml, respectively.
Molecular analysis of the target genes involved in each antibiotic resistance mechanism was performed. In particular, after total bacterial DNA extraction with a QIAGEN DNA extraction kit, a multiplex PCR assay was used to differentiate -lactamase plasmids using the following primers: BL1 (5'-TACTCAATCGGTAATTGGCT), BL2 (5'-CACCTATAAATCTCGCAAGC), BL3 (5'-CCATAGTGTTGAGTATTGCGAA), and BL4 (5'-TCATTCGTGCGTTCTAGGA) (10, 11, 16). Detection of a plasmid named "Toronto/Rio" confirmed the presence of a penicillinase-producing N. gonorrhoeae isolate, a common feature of most gonococci responsible for disseminated gonococcal infection (DGI) (8, 9).
The tetracycline resistance mobile elements were detected by PCR using three primers, UF (5'-CTCGAACAAGAGGAAAGC), AR (5'-GCATTCCACTTCCCAAC), and DR (5'-TGCAGCAGAGGGAGG), as previously described (10, 11, 16). The high level of tetracycline resistance (MIC of 24 μg/ml) was due to a plasmid defined as an "American type plasmid," the most frequently detected plasmid in tetracycline-resistant N. gonorrhoeae isolates (16).
To investigate the presence of amino acid substitutions on the two target genes (gyrA and parC) known to be involved in resistance to ciprofloxacin (2), sequence analyses of the quinolone resistance determinant regions were performed after amplification with primers gyrA1 (5'-CGGCGCGTACTGTACGCGATGCA), gyrA2 (5'-ATGTCTGCCAGCATTTCATGTGAGA), parC1 (5'-ATGGCGATATGGGTTTGAC), and parC2 (5'-GGACAACAGCAATTCCGCAA) (15). The analysis of sequences revealed the presence of amino acid substitutions Asp86Asn in the parC gene and Ser91Phe and Asp95Gly in the gyrA gene. These changes have already been described in the literature as being correlated to the Cip-resistant phenotype (1).
N. gonorrhoeae, the causative agent of the homonymous sexually transmitted disease, has the human genital tract as its reservoir. However, it has also numerous other presentations both inside and outside the genitourinary tract (14). In recent years, despite the worldwide increase in genital gonococcal infections, complicated cases such as DGI have rarely been reported (6, 9, 14). The clinical manifestations of DGI include skin disorders, arthritis, endocarditis (rarely occurring in 1 or 2% of cases), or other localized infections (1, 7-9, 13, 14). The pathogenesis of DGI has been associated with both microbial and host factors. The patient's complement deficiency is considered one of the most important causes favoring the course of disease (12). In this report, we investigated a case of DGI in an immunocompetent patient with suspected bacterial endocarditis. The N. gonorrhoeae isolate was completely characterized for its microbiological features.
Considering the history of the patient, infection very likely occurred in Southeast Asia; the isolated strain showed multiple-antibiotic resistance, and this is particularly significant, since N. gonorrhoeae isolates with these properties have not been frequently described in cases of DGI. Moreover, the American type plasmid, responsible for tetracycline resistance, although frequent in Africa, has rarely been described in Thailand.
Two main comments arise from the case described. First, despite a widespread increase in the rates of reproductive tract infections, this case is evidence of a low attention to sexually transmitted infections, since a sexually transmitted pathogen was not initially suspected despite the history of travel and sexual exposure in a country with a high prevalence of sexually transmitted infections. Travel to such areas must be regarded as a risk factor for acquiring gonorrhea.
Second, since the last series of DGI described (7-9), many changes have occurred in the laboratory diagnosis of gonococcal infection. Now, molecular epidemiology can efficiently clarify transmission dynamics and geographic patterns; it may also be helpful in exploring bacterial virulence factors and drug resistance. The infection had probably been contracted in an area where drug resistance is a well-recognized issue. However, besides sharing common features with the majority of gonococci responsible for DGI, identified as penicillinase-producing N. gonorrhoeae (10, 11), and the presence of the most commonly identified plasmid in tetracycline-resistant N. gonorrhoeae strains (16), the imported strain is characterized by the presence of an IA/IB serotype. Hybrid N. gonorrhoeae strains expressing both IA and IB porin proteins are quite uncommon among clinical isolates (4, 5). However, the most characterized hybrid strains are those described previously by Gill et al. (5). Those authors hypothesized two possible reasons for the rare occurrence of a hybrid form of porin: first, there might be a reduced fitness of such strains since they could be more easily recognized and killed by bactericidal antibodies in patients with a previous gonococcal infection; second, a hybrid form of this porin could be responsible for its altered function on the surface of the gonococcus. A possible selective antibiotic pressure, for instance, penicillin and tetracycline, could also contribute to the appearance and survival of such hybrid gonococcal strains (5). To date, this is the first case of DGI due to a multidrug-resistant strain reported in Italy. The spread of gonococci with multiple-antibiotic resistance could partially explain the occurrence of DGI without any particularly altered host factor. The characterization of molecular changes associated with gonococcal resistance in DGI is essential to provide rapid advice for clinical management of cases. In fact, multidrug-resistant DGI can be fatal if not recognized and treated correctly. Moreover, the sporadic occurrence of DGI highlights the need for a reconsideration of diagnostic and epidemiologic criteria to include the search for N. gonorrhoeae in clinical samples in order to avoid misidentification and thus a delay in appropriate treatment.
ACKNOWLEDGMENTS
We are grateful to Rosangela Milano and Barbara Fianchino for technical assistance. We also thank Tonino Sofia and Marta Boffito for editing the manuscript and Paola Mastrantonio for helpful comments.
This work was supported by Ministero della Salute grant Quinto Programma Nazionale di Ricerca sull'AIDS (20F/F-Art529).
FOOTNOTES
Corresponding author. Mailing address: Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanita, Viale Regina Elena 299, Rome, Italy. Phone: 390649902126. Fax: 390649387112. E-mail: paolaste@iss.it.
REFERENCES
Abe, H., T. Nishimura, Y. Norose, T. Aoto, H. Ohzuka, and H. Ohkuni. 2003. Frequency of alterations in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV in 19 clinical isolates of Neisseria gonorrhoeae in Tokyo in 2002. J. Infect. Chemother. 9:310-313.
Arreaza, L., C. Salcedo, B. Alcala, S. Berron, E. Martin, and J. A. Vazquez. 2003. Antibiotic resistance of Neisseria gonorrhoeae in Spain: trends over the last two decades. J. Antimicrob. Chemother. 51:153-156.
CLSI. 2005. Performance standards for antimicrobial susceptibility testing. 15th informational supplement, vol. 5. CLSI, Wayne, Pa.
Cooke, S. J., K. Jolley, C. A. Ison, H. Young, and J. E. Heckels. 1998. Naturally occurring isolates of Neisseria gonorrhoeae, which display anomalous serovar properties, express PIA/PIB hybrid porins, deletions in PIB or novel PIA molecules. FEMS Microbiol. Lett. 162:75-82.
Gill, M. J., J. Jayamohan, M. P. Lessing, and C. A. Ison. 1994. Naturally occurring PIA/PIB hybrids of Neisseria gonorrhoeae. FEMS Microbiol. Lett. 119:161-166.
Holmes, K. K., P. J. Weisner, and A. H. Pedersen. 1971. The gonococcal arthritis-dermatitis syndrome. Ann. Intern. Med. 75:470-471.
Mehrany, K., J. M. Kist, W. J. O'Connor, and D. J. DiCaudo. 2003. Disseminated gonococcemia. Int. J. Dermatol. 42:208-209.
Mirmiran, R., J. L. Hembree III, W. P. Reed, and D. Jessup. 2000. Disseminated gonococcal infection: a case of beta-lactamase-producing Neisseria gonorrhoeae. J. Am. Podiatr. Med. Assoc. 90:273-275.
O'Brien, J. P., D. L. Goldenberg, and P. A. Rice. 1983. Disseminated gonococcal infection: a prospective analysis of 49 patients and a review of pathophysiology and immune mechanisms. Medicine (Baltimore) 62:395-406.
Pagotto, F., A. T. Aman, L. K. Ng, K. H. Yeung, M. Brett, and J. A. Dillon. 2000. Sequence analysis of the family of penicillinase-producing plasmids of Neisseria gonorrhoeae. Plasmid 43:24-34.
Palmer, H. M., J. P. Leeming, and A. Turner. 2000. A multiplex polymerase chain reaction to differentiate beta-lactamase plasmids of Neisseria gonorrhoeae. J. Antimicrob. Chemother. 45:777-782.
Petersen, B. H., T. J. Lee, R. Snyderman, and G. F. Brooks. 1979. Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency. Ann. Intern. Med. 90:917-920.
Shetty, A., D. Ribeiro, A. Evans, and S. Linnane. 2004. Gonococcal endocarditis: a rare complication of a common disease. J. Clin. Pathol. 57:780-781.
Spencer, S. E., and M. C. Bash. 2006. Extragenital manifestations of Neisseria gonorrhoeae. Curr. Infect. Dis. Rep. 8:132-138.
Tanaka, M., H. Nakayama, M. Haraoka, T. Saika, I. Kobayashi, and S. Naito. 2000. Susceptibilities of Neisseria gonorrhoeae isolates containing amino acid substitutions in GyrA, with or without substitutions in ParC, to newer fluoroquinolones and other antibiotics. Antimicrob. Agents Chemother. 44:192-195.
Turner, A., K. R. Gough, and J. P. Leeming. 1999. Molecular epidemiology of tetM genes in Neisseria gonorrhoeae. Sex. Transm. Infect. 75:60-66.(Ivano Dal Conte, Stefania Starnino, Giov)
Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanita, Rome, Italy
ABSTRACT
We herein report the microbiological features of a Neisseria gonorrhoeae strain isolated from an immunocompetent patient with disseminated gonococcal infection (DGI). The strain expressed the IA/IB serovar; was resistant to penicillin, tetracycline, and ciprofloxacin; and had presumably been acquired in Southeast Asia. To date, this is the first case reported in our country of DGI due to an imported multidrug-resistant strain.
CASE REPORT
A 48-year-old man reported to the emergency department of Turin General Hospital with generalized malaise, pyrexia, nausea, and vomiting. His past medical history revealed hypertension and a recent trip to Thailand where he had engaged several times in sexual intercourse with local sex workers. Physical examination revealed a temperature of 39.8°C, a blood pressure of 190/100 mm Hg, a faint mitral holosystolic murmur, and diffuse hemorrhagic skin rash. There were no signs of meningeal involvement. The patient was admitted to the general medicine ward with suspected bacterial endocarditis. Upon admission, biochemistry was normal, and the white blood cell count was 14,100 (83.9% polymorphonuclear leukocytes, 7.3% lymphocytes, and 8.5% monocytes). The erythrocyte sedimentation rate was 78 mm/h, and the C-reactive protein level was 5.9 mg/dl. Chest X rays and transthoracic echocardiography were normal. Gram-negative diplococci were identified by API-NH (bioMerieux, France) as Neisseria gonorrhoeae in blood culture. Urethral specimens were negative; no throat or rectum specimens were collected. Serology for human immunodeficiency virus and syphilis was negative, and the patient was not immunocompromised. Treatment with 2 g oxacillin four times daily intravenously and 80 mg gentamicin twice daily was commenced. Three days later, the patient was afebrile. Following blood culture results, the patient was treated with 2 g ceftriaxone intramuscularly daily for 10 days. At discharge and follow-up, no clinically relevant problems were observed. The gonococcal strain was sent to the laboratory of the Istituto Superiore di Sanita for complete phenotypic and genotypic characterization. After growth on GC agar plates supplemented with 2% Isovitalex (Oxoid) and incubated at 37°C in 5% CO2 for 18 to 20 h, a serological assay by coagglutination reaction was performed using two monoclonal antibodies (Phadebact GC serovar test; Boule Diagnostic AB, Sweden) directed against epitopes of the IA and IB porin proteins. The isolate showed a reactivity against both porin proteins, thus resulting in a hybrid serovar (IA/IB).
Antimicrobial susceptibility testing was carried out using a panel of five antibiotics (penicillin, tetracycline, spectinomycin, ciprofloxacin [Cip], and ceftriaxone) by the E test method (ABbiodisk, Sweden) according to the manufacturer's instructions. The antimicrobial susceptibility breakpoints were those defined by the CLSI (3). A nitrocefin chromogenic test (Oxoid) was used to detect the presence of -lactamase production. The strain was resistant to three of the five antibiotics tested. In particular, the MICs were >32 μg/ml for penicillin, 24 μg/ml for tetracycline, and 4 μg/ml for Cip. MICs for ceftriaxone and spectinomycin were 0.002 and 6 μg/ml, respectively.
Molecular analysis of the target genes involved in each antibiotic resistance mechanism was performed. In particular, after total bacterial DNA extraction with a QIAGEN DNA extraction kit, a multiplex PCR assay was used to differentiate -lactamase plasmids using the following primers: BL1 (5'-TACTCAATCGGTAATTGGCT), BL2 (5'-CACCTATAAATCTCGCAAGC), BL3 (5'-CCATAGTGTTGAGTATTGCGAA), and BL4 (5'-TCATTCGTGCGTTCTAGGA) (10, 11, 16). Detection of a plasmid named "Toronto/Rio" confirmed the presence of a penicillinase-producing N. gonorrhoeae isolate, a common feature of most gonococci responsible for disseminated gonococcal infection (DGI) (8, 9).
The tetracycline resistance mobile elements were detected by PCR using three primers, UF (5'-CTCGAACAAGAGGAAAGC), AR (5'-GCATTCCACTTCCCAAC), and DR (5'-TGCAGCAGAGGGAGG), as previously described (10, 11, 16). The high level of tetracycline resistance (MIC of 24 μg/ml) was due to a plasmid defined as an "American type plasmid," the most frequently detected plasmid in tetracycline-resistant N. gonorrhoeae isolates (16).
To investigate the presence of amino acid substitutions on the two target genes (gyrA and parC) known to be involved in resistance to ciprofloxacin (2), sequence analyses of the quinolone resistance determinant regions were performed after amplification with primers gyrA1 (5'-CGGCGCGTACTGTACGCGATGCA), gyrA2 (5'-ATGTCTGCCAGCATTTCATGTGAGA), parC1 (5'-ATGGCGATATGGGTTTGAC), and parC2 (5'-GGACAACAGCAATTCCGCAA) (15). The analysis of sequences revealed the presence of amino acid substitutions Asp86Asn in the parC gene and Ser91Phe and Asp95Gly in the gyrA gene. These changes have already been described in the literature as being correlated to the Cip-resistant phenotype (1).
N. gonorrhoeae, the causative agent of the homonymous sexually transmitted disease, has the human genital tract as its reservoir. However, it has also numerous other presentations both inside and outside the genitourinary tract (14). In recent years, despite the worldwide increase in genital gonococcal infections, complicated cases such as DGI have rarely been reported (6, 9, 14). The clinical manifestations of DGI include skin disorders, arthritis, endocarditis (rarely occurring in 1 or 2% of cases), or other localized infections (1, 7-9, 13, 14). The pathogenesis of DGI has been associated with both microbial and host factors. The patient's complement deficiency is considered one of the most important causes favoring the course of disease (12). In this report, we investigated a case of DGI in an immunocompetent patient with suspected bacterial endocarditis. The N. gonorrhoeae isolate was completely characterized for its microbiological features.
Considering the history of the patient, infection very likely occurred in Southeast Asia; the isolated strain showed multiple-antibiotic resistance, and this is particularly significant, since N. gonorrhoeae isolates with these properties have not been frequently described in cases of DGI. Moreover, the American type plasmid, responsible for tetracycline resistance, although frequent in Africa, has rarely been described in Thailand.
Two main comments arise from the case described. First, despite a widespread increase in the rates of reproductive tract infections, this case is evidence of a low attention to sexually transmitted infections, since a sexually transmitted pathogen was not initially suspected despite the history of travel and sexual exposure in a country with a high prevalence of sexually transmitted infections. Travel to such areas must be regarded as a risk factor for acquiring gonorrhea.
Second, since the last series of DGI described (7-9), many changes have occurred in the laboratory diagnosis of gonococcal infection. Now, molecular epidemiology can efficiently clarify transmission dynamics and geographic patterns; it may also be helpful in exploring bacterial virulence factors and drug resistance. The infection had probably been contracted in an area where drug resistance is a well-recognized issue. However, besides sharing common features with the majority of gonococci responsible for DGI, identified as penicillinase-producing N. gonorrhoeae (10, 11), and the presence of the most commonly identified plasmid in tetracycline-resistant N. gonorrhoeae strains (16), the imported strain is characterized by the presence of an IA/IB serotype. Hybrid N. gonorrhoeae strains expressing both IA and IB porin proteins are quite uncommon among clinical isolates (4, 5). However, the most characterized hybrid strains are those described previously by Gill et al. (5). Those authors hypothesized two possible reasons for the rare occurrence of a hybrid form of porin: first, there might be a reduced fitness of such strains since they could be more easily recognized and killed by bactericidal antibodies in patients with a previous gonococcal infection; second, a hybrid form of this porin could be responsible for its altered function on the surface of the gonococcus. A possible selective antibiotic pressure, for instance, penicillin and tetracycline, could also contribute to the appearance and survival of such hybrid gonococcal strains (5). To date, this is the first case of DGI due to a multidrug-resistant strain reported in Italy. The spread of gonococci with multiple-antibiotic resistance could partially explain the occurrence of DGI without any particularly altered host factor. The characterization of molecular changes associated with gonococcal resistance in DGI is essential to provide rapid advice for clinical management of cases. In fact, multidrug-resistant DGI can be fatal if not recognized and treated correctly. Moreover, the sporadic occurrence of DGI highlights the need for a reconsideration of diagnostic and epidemiologic criteria to include the search for N. gonorrhoeae in clinical samples in order to avoid misidentification and thus a delay in appropriate treatment.
ACKNOWLEDGMENTS
We are grateful to Rosangela Milano and Barbara Fianchino for technical assistance. We also thank Tonino Sofia and Marta Boffito for editing the manuscript and Paola Mastrantonio for helpful comments.
This work was supported by Ministero della Salute grant Quinto Programma Nazionale di Ricerca sull'AIDS (20F/F-Art529).
FOOTNOTES
Corresponding author. Mailing address: Department of Infectious, Parasitic, and Immune-Mediated Diseases, Istituto Superiore di Sanita, Viale Regina Elena 299, Rome, Italy. Phone: 390649902126. Fax: 390649387112. E-mail: paolaste@iss.it.
REFERENCES
Abe, H., T. Nishimura, Y. Norose, T. Aoto, H. Ohzuka, and H. Ohkuni. 2003. Frequency of alterations in the GyrA subunit of DNA gyrase and the ParC subunit of topoisomerase IV in 19 clinical isolates of Neisseria gonorrhoeae in Tokyo in 2002. J. Infect. Chemother. 9:310-313.
Arreaza, L., C. Salcedo, B. Alcala, S. Berron, E. Martin, and J. A. Vazquez. 2003. Antibiotic resistance of Neisseria gonorrhoeae in Spain: trends over the last two decades. J. Antimicrob. Chemother. 51:153-156.
CLSI. 2005. Performance standards for antimicrobial susceptibility testing. 15th informational supplement, vol. 5. CLSI, Wayne, Pa.
Cooke, S. J., K. Jolley, C. A. Ison, H. Young, and J. E. Heckels. 1998. Naturally occurring isolates of Neisseria gonorrhoeae, which display anomalous serovar properties, express PIA/PIB hybrid porins, deletions in PIB or novel PIA molecules. FEMS Microbiol. Lett. 162:75-82.
Gill, M. J., J. Jayamohan, M. P. Lessing, and C. A. Ison. 1994. Naturally occurring PIA/PIB hybrids of Neisseria gonorrhoeae. FEMS Microbiol. Lett. 119:161-166.
Holmes, K. K., P. J. Weisner, and A. H. Pedersen. 1971. The gonococcal arthritis-dermatitis syndrome. Ann. Intern. Med. 75:470-471.
Mehrany, K., J. M. Kist, W. J. O'Connor, and D. J. DiCaudo. 2003. Disseminated gonococcemia. Int. J. Dermatol. 42:208-209.
Mirmiran, R., J. L. Hembree III, W. P. Reed, and D. Jessup. 2000. Disseminated gonococcal infection: a case of beta-lactamase-producing Neisseria gonorrhoeae. J. Am. Podiatr. Med. Assoc. 90:273-275.
O'Brien, J. P., D. L. Goldenberg, and P. A. Rice. 1983. Disseminated gonococcal infection: a prospective analysis of 49 patients and a review of pathophysiology and immune mechanisms. Medicine (Baltimore) 62:395-406.
Pagotto, F., A. T. Aman, L. K. Ng, K. H. Yeung, M. Brett, and J. A. Dillon. 2000. Sequence analysis of the family of penicillinase-producing plasmids of Neisseria gonorrhoeae. Plasmid 43:24-34.
Palmer, H. M., J. P. Leeming, and A. Turner. 2000. A multiplex polymerase chain reaction to differentiate beta-lactamase plasmids of Neisseria gonorrhoeae. J. Antimicrob. Chemother. 45:777-782.
Petersen, B. H., T. J. Lee, R. Snyderman, and G. F. Brooks. 1979. Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency. Ann. Intern. Med. 90:917-920.
Shetty, A., D. Ribeiro, A. Evans, and S. Linnane. 2004. Gonococcal endocarditis: a rare complication of a common disease. J. Clin. Pathol. 57:780-781.
Spencer, S. E., and M. C. Bash. 2006. Extragenital manifestations of Neisseria gonorrhoeae. Curr. Infect. Dis. Rep. 8:132-138.
Tanaka, M., H. Nakayama, M. Haraoka, T. Saika, I. Kobayashi, and S. Naito. 2000. Susceptibilities of Neisseria gonorrhoeae isolates containing amino acid substitutions in GyrA, with or without substitutions in ParC, to newer fluoroquinolones and other antibiotics. Antimicrob. Agents Chemother. 44:192-195.
Turner, A., K. R. Gough, and J. P. Leeming. 1999. Molecular epidemiology of tetM genes in Neisseria gonorrhoeae. Sex. Transm. Infect. 75:60-66.(Ivano Dal Conte, Stefania Starnino, Giov)