Substitution of the Empirical Antibiotic Regimen Eliminated an Outbreak of Tobramycin Resistant Staphylococcus aureus of spa  type t084 in a Swedish Neonatal Intensive Care Unit – We recommend an Early Warning System for Antibiotic Resistance

doi:10.21203/rs.3.rs-4693322/v1

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Substitution of the Empirical Antibiotic Regimen Eliminated an Outbreak of Tobramycin Resistant Staphylococcus aureus of spa type t084 in a Swedish Neonatal Intensive Care Unit – We recommend an Early Warning System for Antibiotic Resistance

https://doi.org/10.21203/rs.3.rs-4693322/v1

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During spring 2010, four cases of bacteraemia caused by a tobramycin resistant Staphylococcus aureus (TRSA) of spa type t084 were identified in the neonatal intensive care unit at Ryhov County Hospital, Jönköping, Sweden. Retrospective investigation and screening revealed an outbreak of TRSA t084 that may have started in late 2009. This study describes the outbreak and the measures taken to eradicate it. Screening of infants, staff members, environmental samplings, antibiotic susceptibility testing and spa typing was done. Moreover, pasteurization and bacteriology screening of donated human milk, multimodal hygiene interventions, antibiotic substitution (tobramycin for amikacin) were done. TRSA septicaemia was statistically significantly more common before compared to after the antibiotic substitution in infants with TRSA in clinical samples. This may indicate an insufficient empirical antibiotic regimen. The S. aureus prevalence among the infants was reduced (p = 0.002) after the multimodal hygiene interventions, but had no effect on the proportion of TRSA. No TRSA was found after July 2019 to the end of follow-up in December 2021. Only S. aureus spa type t084 resulted in secondary spread, indicating that this strain may have virulence traits that improve colonization and spread. Hygiene interventions reduced the prevalence of S. aureus. After the antibiotic substitution, no more cases of TRSA septicaemia were observed. The outbreak strain was eliminated after five years. Antibiotic resistance surveillance systems may reveal the presence of resistant strains and facilitate early identification of an outbreak. Furthermore, it provides guidance for an effective empiric antibiotic regimen.

Staphylococcus aureus

screening

colonization

infections

aminoglycoside resistance

NICU

antibiotic rotating regimen

early warning system

Yearly, three million newborns suffer from bloodstream infections (1). Preterm infants without a fully developed immune system are more susceptible to invasive Staphylococcus aureus infections than full-term infants are (2), and proper antibiotic treatment is crucial (3). Knowledge of the antibiotic resistance pattern of S. aureus in the local ward is crucial, and surveillance programs on antibiotic resistance are important (4).

Antibiotic resistance is a global threat, and is estimated to cause 1.27 million deaths annually (5) of which 140 000 are neonates (1).

The spread of antibiotic-resistant strains in a ward is facilitated by antibiotic pressure (6). To eliminate resistant strains, the use of rotating antibiotic regimens based on knowledge of the local resistance pattern, is possible (7).

S. aureus is a human commensal, and 20–30% of newborns are colonized. The most important colonization site is suggested to be the anterior nares (8). The mortality rate for S. aureus at NICUs is 1% (9).

S. aureus causes outbreaks in neonatal intensive care units (NICUs) (10) and health care associated infections in neonates admitted to NICUs lead to longer hospital stays (9). Staff members and parents are important transmission reservoirs (8) and cross transmission between staff members and infants seems to be an important route (11, 12). In addition, inanimate surfaces can be contaminated with S. aureus (13). The importance of multimodal hygiene interventions to prevent bacterial transmission has been documented (11, 14, 15).

In 2010, four cases of bacteraemia caused by a tobramycin-resistant S. aureus (TRSA) of spa type t084 were identified in the NICU at Ryhov County Hospital, Jönköping, Sweden. Screening revealed an outbreak of TRSA of spa type t084 among the infants, during a period when tobramycin was used as the empirical antibiotic.

In this study, we describe a decade-long endemic outbreak of TRSA spa type t084 in a Swedish NICU and the measures taken.

Clinical setting

Approximately 400 newborns (median gestation week 29 + 4, [range 23 + 3–42 + 2]) are admitted yearly to the NICU at Ryhov County Hospital, Jönköping, Sweden, with a median length of stay of 43 days. In 2010, the NICU had 13 beds, divided into two double rooms, one four-bed room and five rooms for rooming in. After a reconstruction in 2012–2013, it has 16 beds with one more double room and one more room for rooming in.

The TRSA outbreak and interventions

In 2010, four cases of S. aureus bacteraemia (three patients with septicaemia and one with a peripheral venous catheter infection) caused by TRSA of spa type t084, were identified in the NICU at Ryhov County Hospital, Jönköping, Sweden. A retrospective search of laboratory reports for TRSA, among neonatal clinical samples (isolates not stored) from 2004 through 2009 and stored environmental samples from 2008 and 2009 was made. Point prevalence screening of all infants (four times) admitted to the NICU, staff members (once) and environmental samplings (four times) were done between 2010 and 2011. The multimodal hygiene interventions, in 2010 and 2014, were done in collaboration with the infection prevention and control department, the microbiology laboratory and the NICU. It included lectures on hygiene guidelines, workshops and infection control audits, to improve adherence to standard precautions and hygiene guidelines. Donor milk screening and pasteurization were initiated in 2011. In 2014 (May 12th ), tobramycin was substituted for amikacin, in combination with penicillin G as an empiric antibiotic regimen. Figure 1 shows the timeline of the outbreak and the interventions.

Infections with TRSA in infants before and after antibiotic substitution

All clinical cultures (collected based on a suspected infection) from infants admitted to the NICU between May 11, 2012 and 2019, with growth of TRSA, which was available in the laboratory information system, were identified. An examination of the medical records of these infants was done.

Sampling from infants and staff members

Screening samples were collected from infants every two weeks and at admission from other NICUs beginning in 2012. In 2015, weekly screening was initiated (Fig. 1). Samples were collected from the anterior nares, umbilicus, perineum and any catheters or skin lesions using swabs (Copan Italia, Brescia, Italy). Sampling from the perineum was excluded from screening in 2016. Screening samples from staff members were collected from the anterior nares and throat. Swabs were inoculated on BBL CHROMagar Staph aureus agar (CSA) media (BD Diagnostics, Sparks, Md.), with a tobramycin disk and incubated for 20 to 24 hours. S. aureus was confirmed by MALDI-TOF MS (Bruker GmbH, Bremen, Germany).

Environmental sampling

Staff from the infection control department collected environmental samples, from clinical equipment and frequently touched surfaces in the ward and in the staff member areas. Environmental sampling from surfaces was done with swabs (Copan Italia, Brescia, Italy) or in-house contact blood agar plates (1 000 g of dehydrated Difco Columbia blood agar base (279240, Thermo Fischer Scientific, Waltham, Ma), 22 700 mL deionized water and between 1 350 and 1 650 mL of human blood). The mixture was dispensed in plates (5 cm in diameter), in a convex form.

For air sampling 1000 L of air was collected using a surface air sampler (air IDEAL, bioMeriéux AB, Marcy l'Etoile, France).

All plates were incubated aerobically for 48 hours in 37°C.

Antibiotic susceptibility testing

Antibiotic susceptibility testing (AST) was done by disk diffusion on IsoSensitest Agar (Oxoid, Ltd., UK), with antibiotic disks (Oxoid) according to the EUCAST Disk Diffusion Test Methodology (http://www.eucast.org). The following antibiotic disks were used before antibiotic substitution: cefoxitin (30 µg), erythromycin (15 µg), fusidic acid (10 µg), clindamycin (2 µg), and tobramycin (10 µg). Amikacin (30 µg), gentamicin (10 µg), linezolid (10 µg), netilmicin (30 µg), rifampicin (5 µg) and trimethoprim-sulfamethoxazole (25 µg) were added after substitution. The methicillin resistance of isolates resistant to cefoxitin was verified by PCR detection of mecA (16).

spa typing

spa typing was done as previously described (17). The sequencing was done by GATC Biotech (Konstanz, Germany) and each isolate was assigned as a spa type by RidomStaphType software (v1.5.21, Ridom GmbH, Würzburg, Germany).

Statistical analyses

Statistica 13.3.1 and Microsoft Excel 2010 were used. A two-sided chi-square test and Fischer’s exact test with one degree of freedom were used for the evaluation of proportions. A p value of ≤ 0.05 was considered significant.

Ethics

The Regional Ethical Review Board in Linköping, Sweden (2017/187 − 31) approved the study.

The TRSA outbreak

Figure 1 illustrates the details of the outbreak and the interventions. The prevalence of S. aureus and TRSA during the outbreak in infants admitted to the NICU, staff members and environmental samples is shown in Table 1. The prevalence of S. aureus among infants decreased from 79% in 2010 to 52% (p = 0.002) following the multimodal hygiene intervention in 2010. Thereafter, no further reduction in S. aureus prevalence was observed (Table 1). The proportion of TRSA in infants was not reduced by the multimodal hygiene interventions (Table 1). After the antibiotic substitution in 2014, the TRSA proportion gradually decreased (Table 1) and no TRSA was detected from July 2019 to the end of the study period, i.e., December 2021 (Fig. 2).

Table 1

Point prevalence of *S. aureus* and tobramycin-resistant *S. aureus* (TRSA) in screening samples from 2010 through 2019 and the *spa* types of TRSA in the NICU.
	S. aureus no. (% of samples)	TRSA no. (% of S. aureus)	TRSA t084/TRSA all spa types (% t084)
2010
Infants (3 occasions) (n = 38)	30 (79*)	14 (47**)	14/14 (100)
Staff members (n = 68)	25 (37)	2 (8)	2/2 (100)
Environment (n = 23)	2 (9)	1 (50)	1/1 (100)
2011
Infants (n = 18)	13 (72)	7 (54)	7/7 (100)
Environment, (n = 59)	4 (13)	8 (57)	8/8 (100)
2012–2013
Air sampling (n = 80)	11 (14)	3 (27)	3/3 (100)
2012-05-11 to 2014-05-11 (continuous screening, before the antibiotic substitution)
Infants (n = 396)	207 (52*)	80 (39)	78/80 (96)
2014-05-12 to 2019-12-31 (continuous screening, after the antibiotic substitution)
Infants (n = 1597)	851 (53)	94 (11**)	87/94 (93)
2014
Environment (n = 11)	0 (0)	0 (0)	0 (0)
2019
Environment (n = 46)	1 (2)	0 (0)	0 (0)
*p = 0.002
^**p = 4x10^− 9

The point-prevalence of S. aureus among the staff members in 2010 was 37% (25 out of 68), and two of these staff members were colonized with TRSA t084.

Infections with TRSA in infants before and after antibiotic substitution

From May 11, 2012 through 2019, 2 746 infants were admitted to the NICU (Table 2). Before and after antibiotic treatment on May 12, 2014, the proportion of patients with suspected infections was the same. However, the proportion of TRSA in clinical samples gradually decreased. No infants presented with TRSA septicaemia after antibiotic substitution (Table 2).

Table 2

Tobramycin resistant *S. aureus* (TRSA) infections among infants in the neonatal intensive care unit (NICU) before and after antibiotic substitution.
Number of infants	2012-05-11 to 2014-05-11	2014-05-12 to 2019-12-31	p
admitted to the NICU	611	2135
with a sample based on clinical indication	119	401	0.75*
with TRSA in clinical samples	11	13	0.006**
with a TRSA septicaemia	4	0	0.02***
* comparing infants with a clinical sample to admitted infants comparing infants with TRSA in clinical samples to infants with a clinical sample * comparing infants with a TRSA septicaemia to infants with TRSA in clinical samples

Retrospective search (data not shown)

Clinical samples

From 2004 through 2009 ten positive blood cultures for S. aureus were found. None of these were TRSA or spa type t084. In clinical nonblood cultures from September, October and November 2009, three TRSA of spa type t084 were detected.

Environmental samples

Seven S. aureus strains were found in the environmental samples (n = 21) collected in 2005 during a MRSA outbreak. MRSA was found in one sample and tobramycin-susceptible S. aureus (TSSA) was found in six, of which two were spa type t084. A follow-up screening in 2006 (n = 17) revealed no S. aureus. Between January 2008 and February 2009, S. aureus was found in 21 out of 118 samples during seven sampling occasions, none of which were TRSA. In December 2009 S. aureus was found in 5 out of 22 samples. Of the S. aureus strains, three were TRSA t084.

Environmental sampling during the outbreak

The results from the environmental samplings from 2010 to 2019 are shown in Table 1. Before antibiotic substitution 162 environmental and air samples were collected and TRSA was found in 12 of these samples. After antibiotic substitution TRSA was not detected in any of the 57 environmental samples collected (p = 0.03).

Antibiotic susceptibility

All S. aureus isolates tested for amikacin, gentamicin and netilmicin resistance were sensitive before and after antibiotic substitution, independent of tobramycin resistance, except for one isolate in an environmental sample from 2010, which was resistant to tobramycin, amikacin, gentamicin and netilmicin (not found in any infant). During the study period ten infants were colonized with MRSA.

spa types of the TRSA

TRSA was isolated from 21 infants during two screening occasions in 2010 and 2011, and all the isolates were spa type t084 (Table 1). In continuous screening, TRSA was isolated from 80 and 94 infants before and after the substitution, respectively (Table 1). Before the substitution, 78 isolates were spa type t084 and the remaining two were spa types t021 and t7094. After the substitution, 87 isolates were of spa type t084, two each were of spa type t346 and t091 and one each was of spa type t2530, t19104 and t5196. All TRSA isolated from the environment and staff members were spa type t084 (Table 1).

TRSA of spa type t084 resulted in secondary cases in May 2013 (18 cases), October 2016 (6 cases) and June 2018 (19 cases). No TRSA of the other spa types resulted in secondary cases (Fig. 2).

Outbreaks with resistant S. aureus in NICUs may be fatal and prolong the average length of hospital stay (18). Blood cultures revealed four infants with TRSA of spa type t084 in the NICU, at Ryhov County Hospital, Jönköping, Sweden, during the spring of 2010, indicating an outbreak. TSSA of this spa type has been prevalent in previous studies during the same time period from the same area (19–21). To evaluate outbreaks, samples from infants (22), screening of staff members and sampling from the environment can be used to identify the source of the outbreaks (9). The extent of the outbreak reported here was indeed revealed by screening infants and staff members and by environmental sampling. This finding is in line with a recent CDC recommendation to do active surveillance testing for S. aureus colonization in NICU patients in an outbreak setting (23).

Retrospective investigation of clinical samples revealed three TRSA isolates of spa type t084 in 2009, prior to the detection of the outbreak. In environmental samples collected during an outbreak of extended spectrum beta-lactamase (ESBL) producing Citrobacter freundii in late 2009 at the NICU, three TRSA t084 isolates were present in the environmental samples but were not identified until the retrospective investigation in 2010. This indicates that environmental screening is important for rapidly identifying circulating resistant strains. Our conclusion is that the outbreak strain was introduced, in 2009, and its spread was facilitated by the antibiotic pressure exerted by tobramycin through its use as an empirical antibiotic regimen.

Hygiene interventions significantly reduced the prevalence of S. aureus, but 53% of the infants were still colonized after the interventions. This may reflect a high proportion of formula-fed infants in the NICU, as formula-feeding results in a greater colonization rate (24) than breast feeding (19).

As no concomitant aminoglycoside resistance was detected, a change in the empiric aminoglycoside antibiotic regimen was possible (25). The outbreak strain was eradicated after the antibiotic substitution. This indicates that antibiotic pressure had a major impact on the pattern of antibiotic resistance (26). It is possible that the previously persistent TSSA of spa type t084 developed tobramycin resistance. Knowledge of the antibiotic resistance pattern is therefore crucial in choosing an empirical antibiotic regimen (5). Antibiotic resistance surveillance systems are important on a global, national and local basis and an early warning system might facilitate the selection of antibiotic regimens (27). An antibiotic rotation regimen should be considered during endemic outbreaks caused by resistant strains in NICUs (28).

The proportion of TRSA in clinical samples decreased and no cases of septicaemia were detected in TRSA-infected infants after the antibiotic substitution. This indicates that antibiotic substitution had an impact on the prevalence and severity of TRSA infections.

The actual route of transmission was not studied in detail in this study and there are few reports on this issue (29). A previous study indicated that 60% of full-term infants are colonized with the same S. aureus as their parents (19). It has been suggested that the impact on ward cleaning should be emphasized (30). A limitation of this study is that no samples were obtained from parents, and few samples were obtained from staff members.

The outbreak strain was not detected in the NICU for one year between July 2017 and June 2018. However, it was reintroduced in 2018, possibly from another hospital, and was thereafter detected through June 2019. No TRSA was detected between July 2019 and December 2021. In addition, S. aureus of spa type t084 may have virulence traits that improve colonization and transmission. Further analysis is required to investigate the genetic background for the transmissibility of this TRSA t084 strain.

We found that hygiene interventions reduced the prevalence of S. aureus in infants in the NICU, but were not sufficient to eliminate the outbreak of TRSA. After antibiotic substitution, no additional cases of septicaemia due to TRSA were observed and the strain was gradually eliminated from the ward. Antibiotic resistance surveillance systems are important for identifying outbreaks and facilitating the selection of empiric antibiotic regimens.

Conflict of interest statements

The authors confirm that they have no conflicts of interest.

Funding statements

The study was funded by Futurum, the Academy for Health and Care Region Jönköping County.

Author Contribution

AJ, SM, SL had full access to the clinical microbiology data and take responsibility for the integrity of the data.AJ, SM, JB and FI had full access to the clinical data and take responsibility for the integrity of the data. AM, AJ and SM design the study. SW and MB were responsible for the hygiene intervention.AM, AJ, SM, SL, MB, JB and FI were responsible for the analysis and interpretation of data. AJ, SL and SM were responsible for tables and figures. AJ, SL, AM, SM were responsible for drafting of the manuscript. AM, AJ, SM, SL, MB, JB and FI were responsible for critical review of the manuscript for important intellectual content.AJ and SL were responsible for statistical analysis.

Acknowledgement

The authors would like to thank the infants and their families for participating in this study. We also thank the nurses and medical staff of the NICU for their full co-operation. We would also like to thank the laboratory personnel for technical assistance.

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No competing interests reported.

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Substitution of the Empirical Antibiotic Regimen Eliminated an Outbreak of Tobramycin Resistant Staphylococcus aureus of spa type t084 in a Swedish Neonatal Intensive Care Unit – We recommend an Early Warning System for Antibiotic Resistance

Status:

Version 1

Abstract

Figures

Introduction

Methods

Clinical setting

The TRSA outbreak and interventions

Infections with TRSA in infants before and after antibiotic substitution

Sampling from infants and staff members

Environmental sampling

Antibiotic susceptibility testing

Statistical analyses

Ethics

Results

The TRSA outbreak

Infections with TRSA in infants before and after antibiotic substitution

Retrospective search (data not shown)

Clinical samples

Environmental samples

Environmental sampling during the outbreak

Antibiotic susceptibility

Discussion

Conclusions

Declarations

Conflict of interest statements

Funding statements

Author Contribution

Acknowledgement

References

Additional Declarations

Supplementary Files

Status:

Version 1