Emergence of fluoroquinolone-resistant Streptococcus pneumoniae in a South African child in a tuberculosis treatment facility

Pneumococcal resistance to fluoroquinolones is an emerging threat in adults associated with hospital treatment of pneumonia and exacerbations of chronic bronchitis. We report for the first time the emergence of fluoroquinolone resistance in a pneumococcus isolated from a child, temporally associated with the treatment of another hospitalized child who was given fluoroquinolones for the management of multiple drug-resistant tuberculosis. Fluoroquinolone resistance in the pneumococcus has been described, largely associated with hospital treatment of exacerbations of chronic bronchitis and pneumonia among adults. 1–3 It has not been described in childhood infections. We describe the emergence of resistant Streptococcus pneumoniae in a child, associated with a new risk factor, namely hospital treatment of tuberculosis (TB). Concern has been expressed that use of fluoroquinolones in children might lead to the rapid emergence of resistance in the pediatric population. 4 Fluoroquinolones are currently under investigation for more widespread use to reduce the duration of TB therapy. Methods and case report. An HIV-infected 5-month-old female child was treated empirically with antituberculous therapy in April 2001 after admission to a district hospital with a history of cough, dyspnea and diarrhea. The patient did not attend follow-up outpatient appointments and was readmitted 1 month later with similar complaints to an academic hospital in Durban, South Africa. At that time a gastric washing specimen showed acid-fast bacilli on Ziehl-Neelsen stain and grew a susceptible strain of Mycobacterium tuberculosis. She was given a regimen containing isoniazid, rifampin and pyrazinamide and was treated for Pneumocystis pneumonia. She spent 10 days in a secondary hospital to complete Pneumocystis pneumonia therapy, and then she was transferred to a chronic TB facility. Cerebrospinal fluid findings were suggestive of TB meningitis, and ethionamide was added to therapy at the beginning of June. She remained hospitalized for 2 months and had numerous episodes of pyrexia and diarrhea for which she received courses of amoxicillin/clavulanate, cephalosporins and aminoglycosides. On August 17 her clinical condition deteriorated acutely with features of pneumonia and septicemia. Empiric therapy with intravenous cefotaxime was initiated. Blood cultures yielded Streptococcus pneumoniae, intermediately resistant to penicillin. She improved slightly during the next few days but deteriorated on August 27 and died. At no time during her 21/2-month hospital stay did she receive fluoroquinolones. Her death was thought to be attributable to another episode of septicemia. The referral hospital has ∼600 beds, of which more than one-half are allocated to patients receiving therapy for tuberculosis. Other patients include specialized surgical and limited gynecologic patients. There were 4 pediatric TB wards, with 25 to 35 cots or beds in each. The patient was confined to her bed in a 25-cot ward. During her hospitalization a 3-year-old boy in this ward was receiving ofloxacin as part of a regimen for empiric therapy for multiple drug-resistant (MDR) TB. One other child in another ward was receiving ciprofloxacin for suspected MDR TB. Because routine susceptibility testing of pneumococci for fluoroquinolone resistance was not performed, the resistant strain was detected only many months later as part of the national surveillance program for invasive pneumococcal infections. Therefore no surveillance cultures could be taken from these children or from adult patients or health care workers. Reasons for use of fluoroquinolones in this hospital, aside from therapy of MDR, included syndromic therapy for sexually transmitted infections in adults. The strain isolated from this patient was of serotype 14. It was intermediately resistant to penicillin (agar dilution MIC, 0.5 μg/ml), resistant to rifampin (MIC > 256 μg/ml) and trimethoprim-sulfamethoxazole (MIC 32 μg/ml) and susceptible on disk diffusion to erythromycin, clindamycin, chloramphenicol and tetracycline. The MICs of ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin were 32, 32, 16, 8 and 4 μg/ml, respectively. PCR and DNA sequencing of the quinolone resistance determining region identified mutations in the parC (S79F, K137N) , gyrA (S81F) and parE (I460V) genes. Multilocus sequence typing (http://www.mlst.net/new/index.htm) showed that this isolate was not closely related to any strains present in the database, because of a novel allele sequence at the aroE locus. This isolate was also genetically distinct by pulsed field gel electrophoresis from three other fluoroquinolone-resistant clinical isolates recognized to date in South Africa (unpublished data). Discussion. Fluoroquinolone-resistant Streptococcus pneumoniae strains have been identified worldwide with prevalence figures increasing in Canada and Hong Kong, 1, 2 but still below 1% in the US. 3 Risk factors for colonization or infection with fluoroquinolone-resistant pneumococci in adults include presence of chronic obstructive airways disease, nosocomial infection, residence in a nursing home and previous therapy with fluoroquinolones. 1–3 Fluoroquinolone treatment for tuberculosis has not previously been associated with the emergence of fluoroquinolone resistance in the pneumococcus. The epidemiology of fluoroquinolone resistance in South Africa in part mirrors that described elsewhere in the world. There are very low levels of fluoroquinolone resistance in pneumococcal strains at the present time. The pneumococcus isolated from this child is the only fluoroquinolone-resistant isolate (ciprofloxacin MIC ≥ 4 μg/ml) among >6000 blood and cerebrospinal fluid isolates submitted to our surveillance unit in the past 3 years (August 1999 to October 2002). There have been 3 strains of fluoroquinolone-resistant pneumococci isolated from respiratory specimens in elderly hospitalized patients with chronic lung disease (data not shown). The emergence of a fluoroquinolone-resistant pneumococcus in a pediatric patient is of concern. Children are more frequently colonized than adults and are often the reservoir of multidrug-resistant pneumococci. 4 Multilocus sequence typing showed that this isolate was not related to any international multiresistant clones, although the emergence of fluoroquinolone resistance in these clones increases the likelihood of the spread of resistance in both children and adults. The triple mutations associated with resistance in this isolate suggest that the strain may have circulated in the hospital for some time and that overcrowding in an underresourced hospital, use of fluoroquinolones for therapy of MDR TB and prolonged hospital stay of an HIV-infected patient may all have contributed to the spread of this isolate. Concern that overuse of this class of drug might lead to the development of resistance has been expressed in the context of unnecessary use of fluoroquinolones for viral upper respiratory tract infections. 4 Emergence of resistance in mycobacteria after fluoroquinolone therapy for lower respiratory tract infections in patients at risk for TB has also been discussed, as well as the failure to identify underlying TB in patients empirically treated with fluoroquinolones because of the transient clinical responses to fluoroquinolone treatment in these patients. 5 Of particular concern for the emergence of resistance in the pneumococcus are current clinical trials designed to shorten TB therapy by the early empiric introduction of fluoroquinolone therapy. The potential benefits of this approach may be tempered by the impact on resistance in the pneumococcus. The very limited use of fluoroquinolones in children to treat MDR TB appears to be associated with the emergence of fluoroquinolone resistance in the pneumococcus isolated from this case. We cannot exclude transmission from an adult independent of fluoroquinolone use for TB therapy. The likelihood of widespread adult carriage of fluoroquinolone-resistant pneumococci at this hospital is very low, given our observation that no fluoroquinolone-resistant strains have been isolated to date in national surveillance (including this hospital) of >6000 invasive pneumococcal strains. Fluoroquinolone resistance among pneumococci isolated from children is unlikely to be detected in routine clinical laboratories where testing of this class of agent may not be considered for pediatric isolates. The detection of this case illustrates the importance of a national surveillance program for monitoring the emergence of antimicrobial resistance in this pathogen. ACKNOWLEDGMENTS. We are grateful to Aventis Pharmaceuticals for their support in the testing of the fluoroquinolone susceptibility of pneumococci. The sponsors of this study had no role in the study design, data collection, data analysis, data interpretation or writing of the report. We are grateful to the clinical staff for sharing their data, to Avril Wasas and Linda de Gouveia for technical assistance and to Louise Marcus, Quintiles Niehaus Pathologists, Pretoria, South Africa, for providing the comparator fluoroquinolone-resistant pneumococcal isolates from adults in South Africa.

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