INTRODUCTION:

Antibiotics are generally prescribed among hospitalized patients especially in intensive care unit and surgical departments as a prophylaxis or to control infection from superbugs¹.

In developing countries, excess and indiscriminate use of antibiotics in community and hospital settings can lead to adverse effects leading to prolongation of therapy, harbour antibiotic resistance bacteria, rise in health expenditures and decrease quality of life^2,3.Antimicrobial therapy in ICU patients requires special consideration as these patients are often in debilitated physical condition, exposed to multiple invasive procedures, weakened immune system thereby vulnerable to multidrug –resistant pathogens, requiring intense antibiotic therapy for long duration. Antibiotic resistance in the ICU has emerged as an important problem in this scenario. Studies revealed that antibiotic use is roughly ten times larger in ICU than in general wards⁴. At this point, there is a need of awareness about the rational antibiotic use with constant supervision along with stringent rules and regulations for monitoring infection control practices and their implementation which enable us to tackle down the multidrug resistance⁵. The pattern of antimicrobial use may be different from hospital to hospital, depending on the common strains of pathogens, the susceptibility pattern, cost and availability of AMAs. Research studies are required to gain suitable information concerning the use of antimicrobials (AMA) in ventilated patients which helps in improving the prescribing pattern of antimicrobial and also in executing infection control strategies in the therapy modification of such patients. There is barely limited data on antibiotic prescribing pattern in ventilated patients from India hence this study was carried out with an objective to know more about the antibiotic prescribing pattern and to analyze rationality among the prescriptions.

MATERIALS AND METHODS:

This retrospective study was conducted in the CCU of a tertiary care hospital in South India from June 2014 to December 2014. The prescribing pattern of antimicrobials for prophylaxis or treatment in patients aged between 10-90 years was included. All ventilated patients in CCU were included in this study. Ethical clearance from the institutional ethics committee was obtained before starting the study. The patient characteristics and treatment data were collected from patient’s record in the following approach:

· Age and sex of patient.

· Diagnosis/ reasons for hospitalization in CCU

· Duration of stay on ventilator

· Site of infection in ventilated patients

· Bacterial and fungal infections in ventilated patients

· Number and percentage of AMAs

· Change in AMAs, Dose and route of administration of AMAs , Combination therapy used and the Rationality

Rationality:

1.The treatment was considered as rational if the AMA use, its route of administration, dose, frequency and its duration of use were considered proper for the infection control.

2.The treatment was considered as irrational if the AMA was used without indication, if its prophylaxis under circumstances of unproven efficacy or by clearly inappropriate route, dose or duration for that indication.

The data was analyzed using Microsoft Excel and the results are compiled in number and percentage.

RESULTS:

The AMAs administration pattern to 70 consecutive ventilated patients admitted into CCU were analyzed. The age and gender distribution of patients are shown in Table 1 and Figure 1. Majority patients were males and the most common age groups were 70-80 yrs followed by 60-70 yrs in males and 50-60 yrs in females. The mean age was found to be 65 ±13.6yrs.

Fig. 1: Gender distribution of patients

Table 1: Age and gender distribution of patients

AGE

MALE No (%)

FEMALE No (%)

TOTAL No (%)

10-20

20-30

30-40

40-50

50-60

60-70

70-80

80-90

TOTAL

0(0)

3(6.1)

10(20.4)

12(24.4)

18(36.7)

6(12.2)

49(100)

1(1.4)

0(0)

4(10.0)

5(21.4)

2(20)

6(34.2)

2(11.4)

21(100)

1(1.4)

0(0)

7(10.0)

15(21.4)

14(20)

24(34.2)

811.4

70(100)

Reasons for hospitalization are shown in Table 2.

· Surgical interventions: Aortic valve replacement, RSOV device closure, EVAR repair etc.

· CVS and encephalopathy: MI, AF, cardiac arrest, ventricular fibrillation, metabolic acidosis, metabolic alkalosis.

· Respiratory tract complications: acute pulmonary edema, desaturation, respiratory distress, respiratory failure.

Table 2: Reason for hospitalization in Coronary Care Unit

REASONS

NO: OF PATIENTS (%)

Surgical interventions

CVS and encephalopathy

Respiratory tract complications and sepsis

Renal dysfunction

Stroke

Total

12(17.1)

21(30)

35(50)

1(1.4)

70(100)

Duration of stay on ventilator is shown in Table 3. Most frequent duration of stay on ventilator was 2-3 days followed by 4-5 days.

Table 3: Duration of stay on ventilator

DURATION OF STAY (DAYS)

MALE

No (%)

FEMALE

No (%)

TOTAL

No (%)

0-1

2-3

4-5

TOTAL

10(20.8)

17(35.4)

14(29.1)

8(16.6)

49(100)

2(9.5)

12(57.1)

4(19)

3(14.3)

21(100)

12(7.1)

29(41.4)

18(25.7)

11(16)

70(100)

The sites of infection in patients on ventilator are shown in Figure 2. Total no. of incidences of infection in 70 ventilated patients was found to be 44. The most commonly encountered infections were urinary tract infections followed by respiratory tract infections.

Fig.2: Site of infection in patients on ventilator

Bacterial infections in ventilated patients are shown in Table 4. Most commonly isolated organism was Klebsiella pneumoniae followed by Enterococcus faecalis.

Table 4: Bacterial infection in ventilated patients

Organism isolated	No. of incidence(n=43)
Aerobic, Glucose non-fermenting gram -negative rods
Acinetobacter baumannii	3
Burkholderia cepacia	2
Stenotrophomonas maltophila	1
Pseudomonas aeruginosa	4
Aerobic, Fastidious gram -negative rods
Escherichia coli	3
Klebsiella pneumonia	18
Serratia marcescens	1
Citrobacter freundii	3
Aerobic , Gram positive cocci
Enterococcus faecalis	5
Enterococcus faecium	3

Fungal infections in ventilated patients are shown in Table 5. Most commonly isolated fungus was Candida albicans followed by Candida tropicalis.

Table 5: Fungal infection in ventilated patients

Organism isolated	No. of incidence(n=15)
Candida albicans	6
Candida non-albicans	2
Candida tropicalis	4
Trichosporon species	1
Yeast	2

Antimicrobials used in patients on ventilator are shown in Table 6. Most commonly used group was beta–lactam antibiotics (59.7%) followed by fluoroquinolones (18.4%).

Table 6: Antimicrobials used in patients on ventilator

GENERIC NAME AND DOSE	MALE [No (%)]	FEMALE [No (%)]	TOTAL[No (%)]
BETA –LACTAMS
Piperacillin+ tazobactam 4.5-13.5gm Cefuroxime 1gm Cefazolin 1-3gm Meropenem 1-3gm Amoxicillin +clavulunate 2.4-3.6gm Imipenem 2gm Cefoperazone +sulbactam 1.5 -3gm Cefixime 2gm Amipicillin 4gm Cefoperazone 2-4gm Crystalline pencillin 60 lac units Ceftriaxone 2gm	22(44) 4(8.1) 3(6.1) 14(28.5) 2(4) 1(2) 9(18.3) 1(2) 1(2) 1(2) 1(2) 26(53)	6(11.3) 3(5.6) 2(3.8) 6(11.3) 2(3.8) 0(0) 2(3.8) 0(0) 0(0) 0(0) 0(0) 14(26.4)	28(13.9) 7(3.5) 5(2.4) 20(9.9) 4(2) 1(0.5) 11(5.5) 1(0.5) 1(0.5) 1(0.5) 1(0.5) 40(19.9)
MACROLIDE AND LINCOSAMIDES
Azithromycin 0.5gm Clindamycin 1.2-1.8gm	1(2) 2(4.0)	0(0) 0(0)	1(0.5) 2(0.9)
AMINOGLYCOSIDES AND GLYCOPEPTIDES
Teicoplanin 0.25gm Amikacin 0.3gm Vancomycin 1.5gm Gentamycin 1.6gm Tobramycin 0.3gm	1(2) 0(0) 1(2) 3(6.12) 1(2)	0(0) 1(1.8) 0(0) 0(0) 0(0)	1(0.5) 1(0.5) 1(0.5) 3(1.5) 1(0.5)
FLUOROQUINOLONES
Levofloxacin 0.25-1gm Ofloxacin 0.4gm Ciprofloxacin 1gm	23(46.9) 2(4.0) 1(2.0)	7(13.2) 2(3.8) 2(3.8)	30(1.5) 4(1.9) 3(1.5)
TETRACYCLINES
Doxycycline 0.2gm Tigecycline 0.1gm	3(6.12) 1(2.0)	1(1.8) 0(0)	4(1.9) 1(0.5)
OXAZOLIDINONE
Linezolid 1.2gm	3(6.12)	1(1.8)	4(1.9)
NITROIMIDAZOLES
Metronidazole 1.5gm	9(18.3)	1(1.8)	10(4.9)
ANTIFUNGAL ANTIBIOTICS
Fluconazole 150mg Amphotericin B 50mg Caspofungin 0.5gm	4(8.16) 1(2) 1(2)	2(3.8) 0(0) 0(0)	6(2.9) 1(0.5) 1(0.5)
ANTITUBERCULAR DRUGS
Rifampicin 1.2gm	1(2)	0(0)	1(0.5)
ANTIVIRAL
Acyclovir 0.8-1.2gm	0(0)	1(1.8)	1(0.5)
NITROFURANS
Nitrofurantoin 0.2gm	2(4.0)	0(0)	2(0.9)
POLYPEPTIDES
Colistin 2-6mu	3(6.12)	0(0)	3(1.5)

The change in antimicrobial therapy is shown in Table 7. An antimicrobial was changed in 36% of the patients.

Table 7: Change in antimicrobial therapy

ANTIMICROBIALS

MALE

FEMALE

TOTAL

No (%)

Change/substituted

No change

18(36.7)

31(63.3)

7(33.4)

14(66.7)

25(36)

45(64)

The route of administration of antimicrobial is shown in Table 8. Most commonly used route was intravenous followed by oral route.

Table 8: Route of administration of antimicrobials

ROUTE OF ADMINISTRATION

MALE No:49

FEMALE No:21

TOTAL No:70

INTRAVENOUS

ORAL

TOPICAL

(EYE /EAR DROPS)

NEBULIZATION

129

170

The pattern of antimicrobial therapy is shown in Table 9. In 54.3% of the patients combination therapy was used.

Table 9: Pattern of antimicrobial therapy

PATTERN

MALE:49 No (%)

FEMALE:21 No (%)

TOTAL:70 No (%)

MONOTHERAPY^$

COMBINATION THERAPY^*

NO THERAPY

16(32.6)

29(59.2)

4(8.2)

10(47.6)

9(43)

2(9.5)

26(37.1)

38(54.3)

6(8.6)

Table 10: Antimicrobial combinations prescribed

ANTIMICROBIAL AGENTS	No: OF PATIENTS
Cefazolin+levofloxacin	1
Ceftriaxone+levofloxacin	9
Meropenem+metronidazole+levofloxacin	2
(Piperacillin+tazobactam)+levofloxacin+linezolid	1
Meropenem+levofloxacin	1
(Amoxicillin+clavulanate) +ciprofloxacin	1
Meropenem+ levofloxacin+fluconazole	1
(Piperacillin+tazobactam)+levofloxacin+metronidazole	1
Ceftriaxone+metronidazole	1
Meropenem + Metronidazole	1
Cefuroxime +doxycycline	1
(Piperacillin+tazobactam ) +levofloxacin	6
Meropenem+doxycycline	1
Cefuroxime +levofloxacin	1
Cefazolin+linezolid	1
(Piperacillin+tazobactam) +ofloxacin	1
(Cefaperazone+sulbactam)+levofloxacin	2
Ceftriaxone+ciprofloxacin	1
(Cefaperazone+sulbactam)+nitrofurantoin	1
(Piperacillin+tazobactam ) +doxycycline	1
(Cefaperazone+sulbactam)+metronidazole	2
Ceftriaxone +crystalline pencillin +fluconazole	1
(Amoxicillin +clavulanate) +acyclovir+amikacin	1
(Piperacillin+tazobactam)+fluconazole	1
(Piperacillin+tazobactam)+fluconazole+metronidazole	1
Colistin+meropenem	2
Ceftriaxone+azithromycin	1
Cefuroxime +metronidazole	1
(Piperacillin+tazobactam)+clindamycin	2
Colistin+meropenem +fluconazole	1
Vancomycin+gentamicin+rifampicin	1
Amphotericin B+teicoplanin	1
Amphotericin B +teicoplanin +caspofungin	1
Amphotericin B+caspofungin +metronidazole+ (piperacillin +tazobactam)	1
Imipenem +doxycycline	1
Ampicillin +metronidazole	1
Meropenem +fluconazole	1
Meropenem +tigecycline +colistin	1
(piperacillin +tazobactam)+ceftriaxone +levofloxacin	1

Piperacillin+tazobactam, Cefoperazone +sulbactam, Amoxacillin +clavulunate were considered as single drug. ^* Concurrent use of two or more antimicrobial agents. The antimicrobial combinations prescribed are shown in Table 10. Most commonly prescribed combinations were Ceftriaxone + levofloxacin followed by (Piperacillin+ tazobactam) + levofloxacin.

Table 11: Outcome of antimicrobial therapy

OUTCOME	MALE:45	FEMALE:19	TOTAL:64
OUTCOME	No. (%)	No. (%)	No. (%)
Improved	20(44.4)	12(63.2)	32(50)
Expired	23(51)	7(37)	30(46.8)
Discharge against medical advice	2(4.4)	0(0)	2(3.2)

Outcome of antimicrobial therapy is shown in Table 11. 4 male and 2 female patients were not on any antibiotics in that 1 male and 1 female patient improved and other 3 male and 1 female patients expired. Acute myocardial injury and sepsis caused most of the CCU deaths. Maximum patients (50%) improved on antimicrobial therapy.

The evaluation of antimicrobial therapy is shown in Table 12. The number of rational prescription was found to be 63.

Table 12: Evaluation of antimicrobial therapy

EVALUATION	No. OF PATIENTS (%)
RATIONAL	63(90)
IRRATIONAL	7(10)

DISCUSSION:

Patients admitted in the CCU always experience from chronic and critical illness. In majority of the cases, patients will be on polypharmacy ranging from anti-ulcers, multivitamins and antimicrobials. The drug therapy should be rationale and awareness of prescribing patterns will aid in rational drug therapy. AMAs are the basis of treatment for life threatening infections. But the selection of AMAs is dependent on the physician’s personal choice. The lack of standardization in choice of AMAs leads to widespread abuse⁶. The demographic details of the ventilated patients admitted to CCU are shown in Table 1 and 2. The most common age group was 70-80yrs and the mean age was 65 ±13.6yrs, in contrast to study done by Anand et al in Mangalore where the mean age was 52 ±16.9 yrs⁷. The reasons for admission in the CCU are shown in Table 4. The usual sites of infection include respiratory tract, blood stream and urinary tract. In the present study, the most commonly encountered site of infections were urinary tract followed by respiratory tract in contrast to other studies were respiratory tract infections dominate^8,9. Infections caused by gram negative organism was common than gram positive organism similar to study done by Shrikala et al¹⁰. Total 33 antimicrobial preparations were used either single or in combination. In the present study, the commonly used AMAs were beta-lactam antibiotics, particularly ceftriaxone, levofloxacin followed by piperacillin + tazobactam (extended –spectrum penicillins +β-lactamase inhibitor) as single or combination therapy. This is in accordance with the related study by John et al in Bengaluru¹¹ where ceftriaxone was commonly prescribed. These drugs were favoured because of their wider antimicrobial spectrum covering the majority of the common pathogens and comparatively lesser toxicity. An altered pattern of antimicrobial use has been reported in other studies by Shankar et al, Erlandsson et al and Biswal et al ^9,12,13. Metronidazole was used as an adjuvant to other AMAs for effective coverage on anaerobic organisms, as also reported in other studies^9,14. The initial empirical antimicrobial therapy was continued in 64% of subjects, but changed in 36% of subjects by adding or substituting with other AMAs, based on the laboratory report or inadequate clinical response or both. This data is almost similar to the study by Srishyla et al ¹⁵ where there was more number of AMAs substituted based on culture and sensitivity. Infections were effectively prevented or controlled in 50% of the patients (n=32) who showed a favourable outcome with AMAs. The effectiveness of AMA therapy could not be assessed in 3.2% patients who got discharged against medical advice and also in 46.8% patients who died due to various complications. 4 male and 2 female patients were not on any antibiotics in that 1 male and 1 female patient improved and other 3 male and 1 female patients expired. The route of administration of AMAs is generally determined by the site and severity of infection; parenteral route being preferred in CCU as the patients are critically ill⁹. In our study, majority of antimicrobials were administered mostly IV comparable to study done by Patanaik SK et al¹⁶and some of the AMAs like metronidazole, levofloxacin, linezolid, ofloxacin were administered orally. AMAs which are used in topical application form are ciprofloxacin ear drops and tobramycin eye drops. AMAs were used for prophylaxis in 60% of subjects which included both medical and surgical prophylaxis which was almost similar to an earlier reported study¹⁷. Combination of AMAs was used in 54.3% of patients (n=38). Piperacillin or ceftriaxone based combinations were most frequently used, often with levofloxacin. Amikacin was included in case of gram negative infections and to increase the synergistic prolongation of the post antibiotic effect of beta lactams. Other combinations involved, addition of specific antimicrobials as needed like anti-viral, anti-malarial and anti-tubercular agents. However, the combined use of ceftriaxone, levofloxacin with piperacillin in 1 patient, and meropenem, tigecycline and colistin in 1patient and some other combinations like piperacillin, levofloxacin with linezolid in 1 patient and later combinations with piperacillin may not be measured rational as there is no renowned advantage with this combination. In other studies, the most regularly used combinations were ceftriaxone with metronidazole and penicillins with amino glycosides such as gentamicin⁹. In the present study, the antimicrobial agents were used empirically in most of the cases (64%) and the definitive therapy was possible in 36% of patients, relatively high compared to other similar studies^18,19. The overall mortality rate in the study subjects was 46.8%, acute myocardial injury and sepsis caused most of the CCU deaths which was comparable with other studies by Siddiqui S et al²⁰and Ratcliffe JA et al²¹.

CONCLUSION:

Most commonly prescribed AMAs were third generation cephalosporins (Ceftriaxone) along with levofloxacin followed by extended spectrum penicillins (Piperacillin+tazobactam) along with levofloxacin. Antibiotic resistance is a risk factor which leads to increased morbidity, mortality and treatment cost. In order to achieve good outcome right use of antibiotic at right time and right dose is required. It is necessary to implement antibiotic policy based on general antibiotic prescribing pattern and antibiogram, which controls irrational use of antibiotic.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. Krivoy N, El-Ahal WA, Bar-Lavie Y, Haddad S. Antiobiotic prescription and cost patterns in a general intensive care unit. Pharmacy Practice. 2007; 5(2): 67-73.

2. Isturiz RE, Carbon C. Antibiotic use in developing countries. Infect Control Hosp Epidemiol. 2000; 21: 394-7.

3. Lakshmi R, Lavanya Chandran R, Christymol Baby, Swathi Krishna K.A study on antibiotic prescribing pattern in obstructive lungDisease inpatients. Asian journal of pharmaceutical and clinical research. 2016;9(1): 342-4.

4. Roder BL, Nielsen SL, Magnussen P, Engquist A, Frimodt-Moller N. Antibiotic usage in an intensive care unit in a Danish University hospital. J Antimicrob Chemother. 1993; 32: 633-42.

5. Kollef MH. Optimizing antibiotic therapy in the intensive care unit setting. Critical care. 2001; 5(4): 189-95.

6. Avorn J, Solomon DH. Cultural and economic factors that (Mis) shape antibiotic use: The non-pharmacological basis of therapeutics. Ann Intern Med. 2000; 133: 128-35.

7. Anand N, Nagendra Nayak IM, Advaitha MV, Thaikattil NJ, Kantanavar KA, Anand S. Antimicrobial agents’ utilization and cost pattern in an Intensive Care Unit of a Teaching Hospital in South India. Indian J Crit Care Med. 2016; 20: 274-9.

8. d Mala R, Kanaki AR, BV P, Raikar SR. Pattern of antimicrobial use in patients on ventilator in a tertiary care hospital. World Journal of Pharmacy and Pharmaceutical Sciences. 2013; 2(5): 3270-82.

9. Shankar PR, Partha P, Dubey AK, Mishra P, Deshpande VY. Intensive care unit drug utilization in a teaching hospital in Nepal. Kathmandu Univ Med J (KUMJ). 2005; 3: 130-7.

10. Shrikala B, Kranthi K, Nafisa. A Prospective study on evaluation of antibiotic prescription practices in an intensive care unit of a tertiary care hospital. Journal of Clinical and Diagnostic Research. 2010; 4: 3387-91.

11. John LJ, Devi P, John J, Guido S. Drug utilization study of antimicrobial agents in medical intensive care unit of a tertiary care hospital. Asian J Pharm Clin Res. 2011; 4: 81-4.

12. Erlandsson M, Burman LG, Cars O, Gill H, Lennart E, Nilson et al. Prescription of antibiotic agents in Swedish ICU is empiric and precise; Scandinavian J of infect diseases. 2007; 39(1): 63-9.

13. Biswal S, Mishra P, Malhotra S, Puri GD, Pandhi P. Drug utilization pattern in the intensive care unit of a tertiary care hospital. J Clin Pharmacol. 2006; 46: 945-51.

14. Alvarez- Lerma F, Palmoar M, Grau S. Management of antimicrobial use in the intensive care unit, Drugs. 2001; 61(6): 763-75.

15. Srishyla MV, Naga Rani MA, Venkataraman BV. Drug utilization of antimicrobials in the patient setting of a tertiary hospital. Indian Journal of Pharmacology. 1994; 26: 282-87.

16. Patanaik SK, Pattanayak C, Prasad A, Chauhan AS. Drug utilization pattern in an intensive care unit setting in Eastern India. Int J Basic Clin Pharmacol. 2015; 4(6): 1136-41.

17. Malacarne P, Rossi C, Bertolini G. Antibiotic usage in intensive care units: a pharmacoepidemiological multicentre study. J Antimicrob Chemother. 2004; 54(1): 221-4.

18. Bergmans DC, Bonten MJ, Gaillard CA, van Tiel FH, Van der Geest S, de Leeuw PW, Stobberingh EE. Indications for antibiotic use in ICU patients: a one- year prospective surveillance. 1997; 39(4): 527-35.

19. Usluer G, Ozgunes I, Leblebicioglu H. A multicenter point –prevalence study: antimicrobial prescription frequencies in hospitalized patients in Turkey. Ann Clin Microbiol Antimicrob. 2005; 4: 16.

20. Siddiqui S. Mortality profile across our intensive care units: A 5-year database report from a Singapore restructured hospital. Indian J Crit Care Med. 2015; 19: 726-7.

21. Ratcliffe JA, Wilson E, Islam S, Platsman Z, Leou K, Williams G et al. Mortality in the coronary care unit. Coron Artery Dis. 2014; 25(1): 60-5.

Received on 29.07.2016 Modified on 18.08.2016

Research J. Pharm. and Tech. 2017; 10(1): 05-10.

DOI: 10.5958/0974-360X.2017.00002.6