Patterns of Antibiotic Use in The One Hour Bundle Treatment of Sepsis

BACKGROUND

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis and septic shock are major health problems, affecting millions of people worldwide each year and are the leading cause of death, accounting for one in three and one in six respectively. Early identification and appropriate management in the early hours after the development of sepsis, will improve good outcomes.1

Since 2016, sepsis criteria have been assessed through the Sequential Organ Failure Assessment (SOFA) score, while for emergency room patients using quick SOFA (qSOFA) which consists of three variables, namely: changes in consciousness (GCS <15), tachypnea (respiratory rate > 22 x/minute) and hypotension (systolic pressure ≤100 mmHg). 4 In the latest guidelines from the Society of Critical Care Medicine (SCCM) in 2021, it is no longer recommended to use the qSOFA score as the sole tool for screening against sepsis, but rather to use Systemic Inflammatory Response Syndrome (SIRS), and National Early Warning Score (NEWS), or Modified Early Warning Score (MEWS).1

Data from Germ Patterns and Their Sensitivity to Antibiotics at Adam Malik Haji Center General Hospital (RSUP HAM) Medan for the January-December 2020 period showed >80% sensitivity to the antibiotics Meropenem, Amikacin, Tigecyclin (for Gram negative bacteria), and Minocycline, Doxycycline , Linezolid, Tigecyclin (for Gram-positive bacteria) in several treatment rooms, namely intensive care rooms, surgical inpatients, medical inpatients, pediatric inpatients. IV of 2018 concerning Guidelines for the Use of Antibiotics, such as administering Amikacin, Meropenem, Gentamicin,and the combination of Sefoperazone and Sulbactam can be given after being approved by the Antibiotic Resistance Control Program Team (PPRA) in inpatient rooms and the Intensive Care Unit (ICU).

METHOD

This study used a descriptive method to determine the empirical use of antibiotics as a one-hour bundle treatment with an observational design. Where each subject was only observed once and the measurement of subject variables was carried out at the time of the examination. This study was also conducted to determine the description of antibiotic resistance and to evaluate the suitability of broad-spectrum antibiotics in septic patients.

The study population was new patients who were diagnosed with sepsis or septic shock during the sampling period at the IGD Haji Adam Malik General Hospital, Medan, with a total of 42 samples. The sample of this study were sepsis patients who were given the one hour bundle of sepsis at the Haji Adam Malik General Hospital in Medan.

The data obtained will be processed with the help of the Statistical Package for Social Science (SPSS) program. This descriptive analysis was used to determine the characteristics of the sample, namely age, sex, culture results, and antibiotic sensitivity test results.

RESULTS

After conducting a descriptive study on 42 sepsis patients who received a one-hour sepsis bundle that met the inclusion and exclusion criteria at Haji Adam Malik General Hospital Medan from November 2022 to December 2022, the results of the study sample characteristics were obtained as follows.

Table 1 Characteristics of the Research Sample

Characteristics	N(%)
Gender n(%) Man Woman	25 (59.5) 17 (40.5)
Age n(%) 18 – 35 Years 36 – 45 Years 46 – 55 Years 56 – 65 Years > 65 years	3 (7,2) 3 (7,2) 8 (19) 19 (45.2) 9(21,4)

Based on gender, 25 patients (59.5%) were male and 17 patients (40.5%) were female. For age, the majority of patients were 19 people (45.2%) aged 56-65 years, followed by 9 patients (21.4%) aged > 65 years, 8 patients (19%) aged 46-55 years, and each 3 patients (7.2%) were aged 18-35 years and 36-45 years respectively.

Table 2 Antibiotics used in the One – Hour Bundle

Types of Antibiotics	N(%)
Ceftriaxone 1 gr	20 (47.6)
Ampicillin Sulbactam 1.5 gr	10(23,8)
Ciprofloxacin 200 mg	2(4,8)
Levofloxacin 750mg	6 (14,3)
Meropenem 1gr	4 (9.5)
Total	42 (100)

The most common use of antibiotics in the one hour bundle sepsis strategy was Ceftriaxone 1 gram in 20 patients (47.6%), Ampicillin-Sulbactam 1.5 grams in 10 patients (23.8%), Levofloxacin 750 mg in 6 people (14, 3 %), Meropenem 1 gram in 4 patients (9.5%), and Ciprofloxacin 200 mg in patients (4.8%).

Table 3 The timeliness of giving antibiotics according to the one hour bundle

No	Diagnosis Time	Time of Administration of Antibiotics	Time Difference
1	15:13	15:45	00:32:00
2	15:55	16:10	00:15:00
3	4:45 p.m	17:05	00:20:00
4	09:30	09:55	00:25:00
5	09:56	10:36	00:40:00
6	07:45	08:13	00:28:00
7	06:15	06:37	00:22:00
8	10:10	10:42	00:32:00
9	10:15	10:46	00:31:00
10	14:15	14:41	00:26:00
11	4:47 p.m	17:11	00:24:00
12	13:24	13:54	00:30:00
13	12:32	12:52	00:20:00
14	06:40	07:10	00:30:00
15	12:00	12:36	00:36:00
16	13:05	13:42	00:37:00
17	13:22	13:41	00:19:00
18	14:44	15:11	00:27:00
19	16:22	16:54	00:32:00
20	16:11	16:42	00:31:00
21	12:55	13:25	00:30:00
22	07:26	07:59	00:33:00
23	12:43	13:12	00:29:00
24	11:34	11:54	00:20:00
25	09:54	10:17	00:23:00
26	18:02	18:47	00:45:00
27	15:23	15:53	00:30:00
28	12:12	12:42	00:30:00
29	06:22	06:22	00:00:00
30	12:00	12:35	00:35:00
31	12:22	12:48	00:26:00
32	14:14	14:53	00:39:00
33	14:54	15:43	00:49:00
34	09:23	09:54	00:31:00
35	09:30	09:59	00:29:00
36	13:02	13:43	00:41:00
37	15:45	16:27	00:42:00
38	12:22	12:42	00:20:00
39	2:45 p.m	15:25	00:40:00
40	18:06	18:56	00:50:00
41	17:00	17:43	00:43:00
42	18:22	18:47	00:25:00

After documenting the time of diagnosis and the time of administration of antibiotics, it was found that the time difference between the two did not reach 1 hour, with the shortest span being 15 minutes and the longest being 49 minutes.

The following data have been collected for the suitability of the empiric antibiotics given with the results of culture and sensitivity tests and the underlying pathological condition.

Table 4 Conformity of empirical antibiotics given with culture results and sensitivity tests.

Given antibiotics	Blood Culture	Resistant Antibiotics	suitability
Ceftriaxone 1 gr	Acinobacter Baumani, Klebsiella Pneumoniae	Gentamycin, Tetracycline, Aztreonam, Chloramphenicol	Not Resistance
Ampicillin Sulbactam 1.5 gr	Klebsiella pneumoniae	Ampicillin	Not Resistance
Ceftriaxone 1 gr	Candida Albicans, Negative MTB, Acinobacter Baumani	Amocixilin, Ampicillin, Ampicillin/Sulbactam	Not resistant
Ampicillin Sulbactam 1.5 gr	Corynebacterium striatum	Ampicillin/Sulbactam	resistance
Ampicillin Sulbactam 1.5 gr	Acinobacter Baumani, Klebsiella Pneumoniae	Ampicillin/Sulbactam	resistance
Ceftriaxone 1 gr	Escherichia coli	Cefazolin	Not Resistance
Ampicillin Sulbactam 1.5 gr/6 Hours	Pseudomonas aeruginosa	Ampicillin/Sulbactam
Ceftriaxone 1 gr	Acinobacter Baumani, Klebsiella Pneumoniae	Tetracycline	Not Resistance
Ceftriaxone 1 gr	Enterococcus faecium	Tetracycline	Not Resistance

Ceftriaxone 1 gr	Acinobacter Baumani, Klebsiella Pneumoniae	Cefazolin, Tigecycline	Not Resistance
Ceftriaxone 1 gr	Pseudomonas aeruginosa	Chloramphenicol, Levofloxacin, Ciprofloxacin, Amoxilin/clavulanate, Ampicillin, Ampicillin/sulbactam, Aztreonam, Cefazolin, Cefepime, Cefotaxime	Not Resistance
Levofloxacin 750 mg	Acinobacter Baumani, Klebsiella Pneumoniae	Tetracycline	Not Resistance
Ceftriaxone 1 gr	Acinobacter Baumani, Klebsiella Pneumoniae	Chlorampenicol	Not Resistance
Ceftriaxone 1 gr	Acinobacter Baumani, Klebsiella Pneumoniae	Chlorampenicol	Not Resistance
Ampicillin Sulbactam 1.5 gr	Staphylococcus aureus	Gentamicin, Chlorampenicol, Chlorampenicol, Amocixilin/Clevoanate,	Not Resistance
Ceftriaxone 1 gr	Escherichia coli	Ampicillin, Ampicillin/Sulbactam, Cefazolin, Ceftazidime	Not Resistance
Ciprofloxacin	Pseudomonas aeruginosa	Piperacillin/Tazobactam, Cefazolin, Aztreonam, Ciprofloxacin, Tigecycline	resistance
Ciprofloxacin	Pseudomonas aeruginosa, Acinobacter baumani, Candida Ciferii	Piperacillin/Tazobactam, Cefazolin, Ceftazidime, Cefixime, Astreonam. Gentamicin, Tygeciline	Not Resistance
Levofloxacin 750mg	Enterococcus faecium	Gentamicin, Chlorampenicol, Chlorampenicol, Amocixilin/Clevoanate,	Not Resistance
Ceftriaxone 1 gr	Escherichia coli	Ampicillin/Sulbactam, Piperacillin/Tazobactam, Cefazolin, Ceftazidime, Ceftriaxone, Cefepime, Aztreonam, Meropenem, Amikacin, Gentamicin, Ciprofloxacin	resistance
Ceftriaxone 1gr, Azithromycin 500mg	Enterococcus faecium	Ampicillin, Ampicillin/Sulbactam, Cefazolin, Ceftazidime, Ceftriaxone, Aztreonam, Ciprofloxacin, Trimethoprim/Sulfamethoxazole	resistance
Ceftriaxone 1 gr	Escherichia coli	Ampicillin, Ampicillin/Sulbactam, Cefazolin, Ceftazidime, Ceftriaxone, Aztreonam, Ciprofloxacin, Trimethoprim/Sulfamethoxazole	resistance
Levofloxacin 750mg	Acinetobacter baumannii	Ampicillin/Sulbactam, Piperacillin/Tazobactam, Cefazolin, Ceftazidime, Ceftriaxone	Not Resistance
Ceftriaxone 1 gr	Stenotrophomonas maltophilia	Cefazolin, Tigecycline	Not Resistance
Levofloxacin 750 mg	Enterococcus faecalis	Ampicillin/Sulbactam	Not Resistance
Ceftriaxone 1 gr	Acinetobacter baumannii	Ampicillin/Sulbactam, Piperacillin/Tazobactam, Cefazolin, Ceftazidime, Ceftriaxone	resistance
Ceftriaxone 1 gr	Candida albicans	Cefazolin, Tigecycline	Not Resistance
Ampicillin Sulbactam 1.5gr	Corynebacterium striatum	Tetracycline, Ciprofloxacin, Clindamicin, Levofloxacin	Not Resistance
Levofloxacin 750mg	Acinetobacter baumannii	Gentamycin, Tetracycline, Aztreonam, Chloramphenicol	Not Resistance
Ceftriaxone 1 gr	Enterococcus faecium	Benzylpenicillin, Ampicillin, Gentamicin, Ciprofloxacin	Not Resistance
Meropenem 1 gr	Acinetobacter baumannii	Ampicillin/Sulbactam, Piperacillin/Tazobactam, Cefazolin, Ceftazidime, Ceftriaxone	Not Resistance
Ampicillin Sulbactam 1.5gr	Pseudomonas aeruginosA	Cefazolin	Not Resistance
Ceftriaxone 1 gr	Stenotrophomonas maltophilia	Tigecycline	Not Resistance
Levofloxacin 750mg	Acinetobacter baumannii	Ampicillin, Ampicillin/Sulbactam, Cefazolin, Ceftazidime, Ceftriaxone, Aztreonam, Ciprofloxacin, Trimethoprim/Sulfamethoxazole	Not Resistance
Ceftriaxone 1 gr	Acinetobacter baumannii	Cefazolin	Not Resistance
Meropenem 1 gr	Acinetobacter baumannii	Ampicillin/Sulbactam, Piperacillin/Tazobactam, Cefazolin, Ceftazidime, Ceftriaxone	Not Resistance
Ceftriaxone 1 gr	Escherichia coli	Ampicillin	Not Resistance
Meropenem 1gr	Acinetobacter baumannii	Piperacillin/Tazobactam, Cefazolin, Ceftazidime, Ceftriaxone	Not Resistance
Meropenem 1 gr	Enterococcus faecium	Benzylpenicillin, Ampicillin, Gentamicin, Streptomycin, Ciprofloxacin	Not Resistance
Levofloxacin 750mg	Staphylococcus aureus	Benzylpenicillin, Oxacillin, Gentamicin, Ciprofloxacin, Levofloxacin, Moxifloxacin, Erythromycin, Clindamycin, Amoxicillin, Cefadroxil, Cefradine	Not Resistance
Ampicillin Sulbactam 1.5 gr	Acinetobacter baumannii	Cefazolin	Not Resistance
Ceftriaxone 1 gr	Candida albicans	Piperacillin/Tazobactam, Cefazolin, Ceftazidime, Ceftriaxone	resistance

After documenting data on antibiotic resistance in sepsis patients at H. Adam Malik General Hospital Medan, the results showed that the most resistance was to Cefazolin, Ampicillin and Ceftazidime with a total of 21, 19 and 12 patients, respectively. In addition, 10 patients were found to be resistant to Ceftriaxone, 9 patients to be resistant to Gentamicin and Piperacillin-Tazobactam, respectively; 8 patients were resistant to Aztreonam and Ciprofloxacin, respectively; 5 patients were resistant to Tigecycline and Tetracycline, respectively; 3 patients were resistant to Amoxicillin, Chloramphenicol, Levofloxacin, Benzylpenicillin and Trimethoprim-Sulfamethoxazole, respectively; 2 patients were resistant to Clavulanate and Cefepime, respectively and 1 patient was resistant to Cefotaxime and Streptomycin, respectively.

Table 5 Description of antibiotic resistance in HAM Hospital

Types of Antibiotics	Number of Patients
Gentamycin	9 samples
Ceftriaxone	10 samples
Ampicillin	19 samples
Amoxicillin	3 samples
Cefazolin	21 samples
Tigecycline	5 samples
Chloramphenicol	3 samples
Levofloxacin	3 samples
Aztreonam	8 samples
Tetracycline	5 samples
Cefepime	2 samples
Cefotaxime	1 sample
Clavulanate	2 samples
Ceftazidime	12 samples
Piperacillin/Tazobactam	9 samples
Benzylpenicillin	3 samples
Trimethoprim/sulfamethoxazole	3 samples
Ciprofloxacin	8 samples
Streptomycin	1 patient

DISCUSSION

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis and septic shock are major health problems, affecting millions of people worldwide each year and are the leading cause of death, accounting for one in three and one in six respectively. Early identification and appropriate management in the early hours after the development of sepsis, will improve good outcomes.¹

Improved recognition of sepsis, consistent with the overall one-hour bundle, and with three main components: fluid resuscitation, blood cultures, and administration of antibiotics. The risk of death before implementing the protocol was four times greater, and the absolute risk reduction was 9%.

Data from Germ Patterns and Their Sensitivity to Antibiotics at Haji Adam Malik General Hospital Medan for the January-December 2020 period showed >80% sensitivity to the antibiotics Meropenem, Amikacin, Tigecyclin (for Gram negative bacteria), and Minocycline, Doxycycline , Linezolid, Tigecyclin (for Gram-positive bacteria) in several treatment rooms, namely intensive care rooms, surgical inpatients, medical inpatients, pediatric inpatients. IV of 2018 concerning Guidelines for the Use of Antibiotics, such as administering Amikacin, Meropenem, Gentamicin,and the combination of Sefoperazone and Sulbactam can be given after being approved by the Antibiotic Resistance Control Program Team (PPRA) in inpatient rooms and the Intensive Care Unit (ICU).

From the data collected, it is shown about the pattern of empirical antibiotic use given to patients who experience sepsis at H. Adam Malik General Hospital. RSUP H. Adam Malik has made a Guidebook for the Use of Antibiotics (PPAB) Edition IV of 2018 to regulate the use of antibiotics in H. Adam Malik General Hospital.

The following lists drugs that can be given for giving antibiotics to patients with sepsis:

Table 6 Antibiotics for sepsis patients

Diagnosis	line	Choice of Antibiotics
Pneumonia	First	Amikasin
	Second	Meropenem; Cefoperazone + Sulbactam
	Third	Gentamicin; Cefoperazone + Sulbactam
Urinary tract infection	First	Amikasin
	Second	Meropenem
	Third	Fosfomycin, Imipenem
Skin and Soft Tissue Infection (SSTI)	First	Amikasin
	Second	Gentamicin; Cefoperazone + Sulbactam
	Third	Meropenem
Intra-abdominal infection	First	Amikacin; Meropenem
	Second	Gentamicin; Amikasin (room)
	Third	Cefoperazone + Sulbactam

From the guide almost all first line of choice for giving antibiotics in Sepsis is Amikacin. In this study, no patients were given Amikacin. The empiric antibiotics given were: Ceftriaxone 1 gram in 20 patients (47.6%), then Ampicillin-Sulbactam 1.5 grams in 10 patients (23.8%), Levofloxacin 750 mg in 6 patients (14.3%), Meropenem1 gram to 4 patients (9.5%), and Ciprofloxacin 200 mg in 2 patients (4.8%).

Among the components of the one hour bundle, only blood culture taking and administration of antibiotics may have contributed to the reduction in in-hospital mortality. These time-dependent factors are equally important as they are dichotomized within 1 hour after diagnosis or as hourly continuous variables. Early administration of antibiotics within 1 hour is sometimes difficult to achieve in the critical care setting.⁶¹ Based on the Surviving Sepsis Campaign (SSC) guidelines it is recommended that once severe sepsis or septic shock is recognized, broad-spectrum IV antibiotics should be given as early as possible and always within 1 hour ( for patients identified on a general medical examination on the ward) or 3 hours (for patients identified in the emergency department).⁶²

Kumar et al reported that delay in administration of antibiotics was common: 79% of patients did not receive antibiotics until hypotension developed, and of those patients, only 14.5% received them within the first hour of hypotension. Only 32.5% received antibiotics within 3 hours and only 51.4% within 6 hours. Kumar et al demonstrated that each additional hour without antibiotics increased the risk of death in septic shock patients by 7.6% during the first 6 hours. 62 However, Bloss et al demonstrated that delay in administration of antimicrobial therapy was more than 1 hour after the onset of organ dysfunction (OR (95). % CI): 0.96 (0.69 to 1.33)) not associated with an increase in 28-day mortality.³

Researchers examined 42 samples with the results of 33 samples that had a suitability of the empirical antibiotics given. This shows how important it is to carry out blood culture examinations and sensitivity tests to antibiotic drugs to provide better therapeutic results. Blood culture tests are also important to do in order to see what type of organism is infecting the patient so that it will be able to select antibiotics or even antifungals for these patients. Many bacteria are naturally resistant to one or even most antibiotics. The development of acquired resistance occurs through horizontal gene transfer (HGT), external genetic acquisition of a neighboring resistant organism, or gene mutation. HGT allows the transmission of antibiotic resistant genes (ARGs),

The SSC guidelines recommend performing blood cultures and giving intravenous broad-spectrum antimicrobials within 1 hour of the onset of severe sepsis or septic shock; guidelines also recommend performing source control surgically within 12 hours. In the study of Bloss et al, blood cultures were performed prior to administration of antimicrobial therapy in 649 (64.2%) patients, and 48.8% of these cultures were positive. In 269 patients (41.4% of patients whose blood cultures were taken), only one set of blood cultures was obtained. In 317 positive blood cultures, 187 (62.1%) showed Gram positive bacteria, 127 (42.2%) showed Gram negative bacteria, and 20 (6.6%) showed fungi; 32 (10.6%) of the positive blood cultures showed more than one pathogen. Among 317 patients with positive blood cultures, 63, 3% received antimicrobials before organ dysfunction occurred and 103 (33.7%) received antimicrobials after organ dysfunction occurred. Mortality at 28 days in both groups was 35.9% and 31.5% (P = 0.440), respectively.³

Rapid molecular diagnostics (RMD) can speed up the evaluation of patients with sepsis and septic shock to ensure that effective initial antibiotic therapy is administered and avoid unnecessary use of broad-spectrum agents. Studies of bacteremic pneumonia indicate that Enterobacteriaceae are most likely to receive initiation of inappropriate antibiotic therapy (ie, initial regimen with no demonstrable in vitro activity against the causative pathogen), whereas Pseudomonas aeruginosa infection is associated with the greatest mortality. The greater mortality from Pseudomonas aeruginosa infection may be related to the intrinsic virulence of the pathogen.

Attempts to avoid giving broad-spectrum antibiotics have had mixed success. For example, a recent randomized controlled study in patients with systemic Escherichia coli or Klebsiella pneumoniae infection and ceftriaxone resistance found that definitive treatment with piperacillin-tazobactam compared with meropenem showed no reduction in mortality at 30 days. Patients receiving pipercillin-tazobactam had a statistically higher mortality rate than patients treated with meropenem.

This study has a major limitation, namely not following up on outcomes such as morbidity and mortality rates from one hour bundle sepsis applied to patients. This is an observational study of the one-hour bundle of sepsis treatment, especially broad-spectrum empiric antibiotics and the results of their resistance cultures.

CONCLUSION

The antibiotics given in the study were not in accordance with sepsis regulations at Haji Adam Malik General Hospital Medan. The time for administering antibiotics was less than 1 hour in the one hour bundle strategy. Most of the antibiotics given are in accordance with the antibiotic sensitivity test results, but there are still some patients who still experience resistance to the antibiotics given so it is important to always or immediately carry out culture tests and sensitivity tests on patients so that the antibiotics given can be more optimal. The description of antibiotic resistance in Haji Adam Malik General Hospital Medan has the most resistance results to Cefazolin, Ampicillin and Ceftazidime with a total of 21, 19 and 12 patients, so that it can be considered to select other types of drugs for empiric drug administration in patients.

BIBLIOGRAPHY

1. Evans L et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Intensive Care Med (2021) 47:1181-1247.
2. Rodrigues-Santos G; Magalhaes-Barbosa MC; Raymundo CE; Lima-Setta F; Cunha AJL; Prata-Barbosa A. Improvement of 1st-hour bundle compliance and sepsis mortality in pediatrics after the implementation of the surviving sepsis campaign guidelines. Jornal de Pediatria 2021;97(4):459-467
3. Bloos F; Thomas-Ruddel D; Ruddel H; Engel C; Schwarzkopi D; Marshall JC; et al. Impact of compliance with infection management guidelines on outcome in patients with severe sepsis: a prospective observational multi-center study. Critical Care 2014, 18:R42
4. Zhou, M.H.; Zhang, L.; Song, MJ; Sun, WJ MicroRNA-218 prevents lung injury in sepsis by inhibiting RUNX2. euro. Rev. med. Pharm. sci. 2018(22):8438–8446.
5. Kollel MH; Burnham J.P. Thresholds for Sepsis and Septic Shock Antibiotics. cid 2019:69.