Bacteremic Pneumonia Caused by Extensively Drug-Resistant Streptococcus pneumoniae

Abstract

The emergence of antimicrobial resistance threatens the successful treatment of pneumococcal infections. Here we report a case of bacteremic pneumonia caused by an extremely drug-resistant strain of Streptococcus pneumoniae, nonsusceptible to at least one agent in all classes but vancomycin and linezolid, posing an important new public health threat in our region.

CASE REPORT

An 81-year-old man who had been in a long-term-care facility was admitted to the Emergency Department (ED) of Samsung Medical Center, Seoul, Republic of Korea, with a high fever and decreased consciousness of 1 day's duration, on 25 April 2012. He had undergone surgery for stomach cancer 3 years previously and took antituberculosis (anti-Tb) medication for Tb pleurisy, with cure a year prior to presentation. Three months before admission, he had a traffic accident that caused hemoperitoneum, and he was mechanically ventilated in the intensive care unit (ICU). He also received piperacillin-tazobactam and levofloxacin for ventilator-associated pneumonia during the course of ICU treatment with improvement and was transferred to a long-term-care facility 1 month before admission to the ED.

On admission, he was febrile (39.3°C), with a pulse rate of 130 beats/min, blood pressure of 93/59 mm Hg, and a respiratory rate of 34 breaths/min. Physical examination showed vesicular breath sounds with crackles in the right lower lung field. Laboratory tests showed 2,250 leukocytes/μl, hemoglobin at 10.9 g/dl, and platelets at 144,000/μl. Other laboratory values included serum blood urea nitrogen (BUN) at 53.2 mg/dl, creatinine at 1.88 mg/dl, glucose at 105 mg/dl, sodium at 144 mM/liter, and lactic acid at 5.4 mM/liter. Arterial blood gas analysis showed pH 7.438, CO₂ partial pressure (pCO₂) at 28.1 mm Hg, pO₂ at 54.0 mm Hg, and peripheral capillary saturation (SaO₂) at 88.0% referenced to room air. His chest radiograph demonstrated pneumonic consolidation in the right lower lung zone.

Vancomycin and meropenem were empirically administered based on a diagnosis of health care-associated pneumonia. On the day of admission, his condition rapidly deteriorated and he was transferred to the ICU. He received ventilator support after intubation due to respiratory failure. Gram stain of the respiratory specimens showed many Gram-positive cocci and Gram-negative bacilli, and a urinary antigen test for Streptococcus pneumoniae was positive. A blood culture grew S. pneumoniae, susceptible only to vancomycin and linezolid, while a sputum culture grew methicillin-resistant Staphylococcus aureus and extended-spectrum-β-lactamase-producing Klebsiella pneumoniae. The meropenem was discontinued, and he recovered after vancomycin treatment lasting for 2 weeks.

This pneumococcal isolate, SMC1205-93, was serotype 11A, as determined by the standard Quellung method (Statens Serum Institut, Copenhagen, Denmark). Antimicrobial susceptibility testing was performed by broth microdilution according to CLSI guidelines (2). This isolate was nonsusceptible to all tested antimicrobial agents but tigecycline, vancomycin, and linezolid (Table 1). To investigate the genotype of SMC1205-93, multilocus sequence typing (MLST) was performed as previously described (4), which revealed ST8279, a double-locus variant of ST156 closely related to Pneumococcal Molecular Epidemiology Network (PMEN) global clone Spain9V-3 (http://www.sph.emory.edu/PMEN/pmen_criteria.html). Most isolates of this lineage, including ST166, a single-locus variant of ST156, have been circulating in South Korea (16). Analysis of penicillin binding protein (PBP) genes (pbp1a, pbp2b, and pbp2x; GenBank accession no. JX560510 to JX560512) of this isolate showed sequences highly divergent from those of S. pneumoniae R6 (25.9%, 14.1%, and 15.1% for nucleotide sequences and 17.1%, 9.3%, and 11.1% for amino acid sequences, respectively). The pbp1a, pbp2b, and pbp2x sequences of the isolate were very similar to those of the prototype Spain9V-3^ST156 strain (86.5%, 99.4%, and 93.0% for nucleotide sequence and 92.9%, 98.9%, and 96.3% for amino acid sequences, respectively), which likely contributed to the high level of resistance to penicillin. The amino acid sequences of PBP1A, PBP2B, and PBP2X of this isolate were 85.1% to 94.5%, 93.6% to 99.2%, and 96.8% to 98.1% identical to those of other penicillin-resistant isolates, respectively.

TABLE 1.

Antimicrobial resistance of Streptococcus pneumoniae isolate SMC1205-93

Antimicrobial agent	MIC (μg/ml)	Resistancea
Penicillin	4	I
Amoxicillin	16	R
Amoxicillin-clavulanate	16/8	R
Ceftriaxone	16	R
Cefuroxime	>32	R
Erythromycin	>64	R
Clarithromycin	>32	R
Tetracycline	16	R
Tigecycline	≤0.03	S
Levofloxacin	16	R
Moxifloxacin	4	R
Gatifloxacin	8	R
Ciprofloxacin	32	R
Clindamycin	>32	R
Trimethoprim-sulfamethoxazole	32/608	R
Meropenem	16	R
Imipenem	4	R
Doripenemb	4	NS
Linezolid	0.5	S
Ceftobiprolec	4	I
Vancomycin	0.25	S

^aR, resistant; I, intermediate; S, susceptible; NS, nonsusceptible.

^bThe MIC breakpoint for resistance to doripenem was ≥2 μg/ml according to the EUCAST guidelines (http://www.eucast.org/clinical_breakpoints/).

^cThe MIC breakpoints for ceftobiprole were ≥8 μg/ml for resistance and ≤2 μg/ml for susceptibility (13).

Analysis of quinolone resistance-determining regions (QRDRs) (12) revealed several amino acid substitutions in the gyrA, parC, and parE genes: Ser81-Phe in gyrA, Ser79-Phe and Lys137-Asn in parC, and Ile460-Val in parE. In addition, PCR analysis to detect the erm(B) and mef(A) genes (10) showed that this isolate possessed only the erm(B) gene, contributing to the macrolide resistance.

Despite decreasing rates of invasive pneumococcal disease caused by vaccine serotypes, S. pneumoniae continues to present a global threat and is associated with substantial morbidity and mortality. The emergence and spread of drug-resistant S. pneumoniae have been major causes of concern related to pneumococcal infection in recent years (9). The emergence of antimicrobial resistance threatens the successful treatment of pneumococcal infections (14). Several case reports have described patients with pneumococcal bacteremia or pneumonia in whom empirical treatment with β-lactams, macrolides, or fluoroquinolones failed (3, 5, 15, 17).

Although fluoroquinolone resistance rates remain low in S. pneumoniae in most countries, higher resistance rates have occasionally been reported in some countries (6, 8). In addition to the emergence of resistance to newer drug classes such as the fluoroquinolones, the evolution of strains with resistance to higher concentrations of antimicrobial agents is a cause for concern (14). The treatment of patients with suspected pneumococcal infections usually consists of administration of a third-generation cephalosporin or fluoroquinolone. The spread of such highly resistant strains in the community could lead to an increase in treatment failure and to the increased use of vancomycin in pneumococcal infections, including invasive diseases, which would be a most disturbing outcome.

For Gram-negative bacteria, extensive drug resistance (XDR) is defined as nonsusceptibility to at least one agent in all but two or fewer antimicrobial categories (11). Similarly, we propose the term “XDR S. pneumoniae” to describe those strains that are nonsusceptible to at least one agent in all categories except vancomycin and linezolid (1). The emergence of XDR pneumococci with very-high-level penicillin resistance poses a further challenge to the medical community. Since the first multidrug-resistant (MDR) pneumococci emerged in a limited, nosocomial setting, MDR pneumococci have spread worldwide (18). Therefore, interventions and public health measures are required to prevent the uncontrolled spread of XDR among pneumococci.

The newly licensed pneumococcal conjugate vaccine may be effective at limiting the spread of strains with very high levels of resistance to penicillin. A previous study showed that the majority of very highly resistant strains occurred in vaccine-induced serotypes (14). However, our case was not caused by the heptavalent polysaccharide conjugate vaccine serotype (1). Vaccine escape of XDR pneumococci such as the one reported here poses significant therapeutic challenges. In addition, use of fluoroquinolones should be restricted in patients who are at increased risk of MDR pneumococcal infection, as prior use of fluoroquinolones was reported to be a significant risk factor for fluoroquinolone resistance among pneumococci (7, 9).

Here, we reported a case of bacteremic pneumonia caused by XDR S. pneumoniae nonsusceptible to at least one agent in all classes but vancomycin and linezolid. This strain poses an important new public health threat in our region. More information on the emergence and spread of this XDR strain would be necessary in order to prevent its spread.