Using gentamicin in the management of sepsis

Sepsis is defined as the inflammatory response toward an infection (1). It is either simple or severe sepsis depending on the organ dysfunction involved as a result of the infection and other factors (2). In terms of the pathophysiology of severe sepsis, a cascade of inflammation and activation of the coagulation system associated with impaired fibrinolysis causes changes in microvascular circulation associated with organ dysfunction, severe sepsis, multiple organ dysfunction syndrome, and death (3).

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In terms of definitions of other sepsis-associated symptoms, it was generally agreed at the International Sepsis Definitions Conference which was convened in 2001 and the following definitions of sepsis syndromes were published in order to clarify the terminology used to describe the spectrum of disease that results from severe infection. “Sepsis is the presence of infection in association with meeting the Systemic inflammatory response syndrome (SIRS) criteria (Box 1 (2)). The clinical significance of meeting SIRS criteria in the absence of organ dysfunction or shock is still unclear. Severe sepsis is defined as evidence of end-organ dysfunction such as altered mental status, episode of hypotension, elevated creatinine, or evidence of disseminated intravascular coagulopathy. Septic shock is defined as persistent hypotension despite adequate fluid resuscitation or tissue hypoperfusion manifested by a lactate greater than 4 mg/dL. Bacteremia is defined as the presence of viable bacteria within the liquid component of blood” (1). Acute pyelonephritis is defined as an acute infection of one or both kidneys; usually, the lower urinary tract is also involved (4).

Antibiotic regimen of choice for Sepsis that is associated with urinary tract infection is Co-amoxiclav 1.2g 8 hourly intravenously together with Gentamicin IV dose of 5mg/kg once daily (5). Although that is controversial whether to use the ideal body weight (IBW) or to obtain blood samples indicating Gentamicin level to get the optimal dosing regimen for Gentamicin in obese patient due to risk of accumulation with Aminoglycoside and the fear of oto- and nephrotoxicity (6). Other supportive measures depend on the patient’s status; table 1 (1) contains helpful measures that indicate markers of organ dysfunction.

Case Summary

Our patient, C.M., is a 56 years old female who was admitted to the Accident and Emergency department (A&E) due to an increased urinary frequency and a high temperature of 40.5°C. Other complaints were back pain and shortness of breath (SOB). Also, the patient had reported a fall the night before admission. Moreover, the patient had vomited the night before and in the morning of admission.

C.M. is a previous smoker who had stopped smoking several years ago and she lives with a partner. She is clinically obese weighing 100kg and her height is 152.4cm. Giving this, her ideal body weight (IBW) comes to 49kg. The only known allergy for this patient is microspores tapes.

The patient’s past medical history (PMH) included asthma, non-insulin dependent diabetes mellitus (NIDDM) and fibromyalgia. She was on one puff daily of each Symbicort Turbohaler 200/6 µg and Ventolin Accuhaler for the management of her stage 3 asthma. Metformin 1g daily was prescribed for her diabetes control; however, its formulation was not mentioned (whether it is a sustained release tablet or a normal release one!). For her fibromyalgia, she was taking 300mg of Quinine sulphate daily together with 150mg of Amitriptyline daily (which is a very high dose; low dose of tricyclic antidepressant (T CA) is recommended i.e. 20-30mg of Amitriptyline). For her pain, the patient was on Co-codamol tablet as required (strength, dose and frequency were not mentioned). Having that she is a diabetic patient over 40 years old, a dose of Simvastatin 40mg daily was prescribed as a primary cardiovascular disease (CVD) protection measure. In addition, Omeprazole 20mg daily was one of her regular medications with unclear indication.

Investigations

On admission, an Electrocardiography (ECG) was performed and indicated sinus tachycardia; which could be related to the high temperature, pain or sepsis. The patient’s vital signs were abnormal having a respiratory rate (RR) of 22 breaths per minute (normal is ~ 12bpm), a heart rate (HR) of 117 beat per minute (normal is ~ 70bpm) and a blood pressure (BP) of 142/65 mmHg (target for diabetic patients is < 130/80 mmHg).

Her laboratory investigations were almost normal except for some parameters. The Sodium level was a bit low which could be a result of the frequent urination or an Amitriptyline hyponatremic effect. Glucose and C-reactive protein (CRP) levels were high which might indicate the presence of infection. Thrombocytopenia may be caused by Quinine or Simvastatin administration!

Impression and related Management Plan

The patient was diagnosed as a pyelonephritis and sepsis case; so empirical antibiotic regimen was initiated with 1g Amoxicillin intravenously six hourly and 500mg ciprofloxacin orally once daily. Also, 1g Paracetamol intravenously six hourly and one liter Normal Saline intravenously over 24hours was started.

Urinalysis on the first day indicated the presence of leucocytes, nitrites, glucose, ketones and blood which means a presence of infection. On the second day, blood culture showed a growth of E. coli which is sensitive to Gentamicin, therefore, 400mg Gentamicin intravenously every 24 hour was prescribed and ciprofloxacin was discontinued. Gentamicin plasma level was requested 6-14 hours after administration of the first dose. In addition to the patient’s regular medications, 50 mg of Cyclizine eight hourly and 20mg of Citalopram once daily were added, paracetamol IV was switched to orally in the second day and 30mg of oral codeine as required was prescribed ; but the patient’s Salbutamol Inhaler had been stopped for unclear reason.

Discussion

Revising the management plan for this patient and in comparison to the local guidelines for the management of pyelonephritis and sepsis patients, we would notice that 1.2g intravenous Co-Amoxiclav is the first-line choice of Penicillins, not Amoxicillin, together with Gentamicin. However, if the ideal body weight is required to obtain the appropriate dosing of Gentamicin for obese patients, so in this case, 245mg of Gentamicin supposed to be prescribed instead of 400mg which is the maximum daily dose (Although that some infectious diseases specialist would recommend going to the maximum dose to make sure that we get the maximum benefit; but we must consider patient status and severity of infection!). Also, it is essential to check the optimal timing for monitoring each drug plasma level, in our case, Gentamicin therapeutic drug monitoring (TDM) has not deviated from the local guidelines recommendation for the once daily dosing of Gentamicin i.e 6-14 hours after giving first dose.

Having a patient with increased urination and vomiting, we must consider fluid replacement. Replacing with one liter Normal Saline (NS) might have not met the patient’s requirement! So it is recommended to check patient’s need to ensure appropriate replacement i.e. at least 2.5-3 liter daily. We could have recommended giving 2 liter NS each over 8 hours plus the addition of 500ml 5% Dextrose to ensure calories intake if the patient cannot tolerate oral intake.

Considering the patient’s asthma control, we must confirm that Salbutamol inhaler was not mistakenly missed after admission. Since that SOB was one of the patient’s complaints, we must ensure that it was relieved, if not, consider 5mg of Salbutamol nebulizer four times daily to be added to the regimen and if nebulizer is not necessary, ask for Salbutamol inhaler to be charted as if required basis (6). Also, blood gases were not mentioned so it is probably safer to ask for the oxygen and carbon dioxide saturations to consider if oxygen therapy is needed! Confirm that the patient and nursing staff are aware of inhalers techniques.

The patient is on Amitriptyline 150mg orally daily which is considered an old practice for the treatment of fibromyalgia (high dose TCA) and the current recommendation states 20-30mg of Amitriptyline daily for 8 weeks (6) so it is better to re-consider dosing or to change regimen. Low dose Sertraline or high dose Venlafaxine therapy may be effective (6) so consider changing if no further benefit of the use of Amitriptyline. For the associated pain, Paracetamol with Tramadol has better efficacy than Co-codamol. Pregabalin (150-300mg every 12 hours) may improve pain especially if combined with Tramadol; it also improves sleep and morning stiffness (6). So, knowing the patient’s control with the current medication would be helpful to consider treatment change or modeling to get the most of pharmacologic treatment. Suggesting alternative ways to manage symptoms is also recommended, e.g. spa therapy, physiotherapy, stress management, acupuncture or diet (6).

NICE guidelines for the management of type II diabetes mellitus state that Metformin is the first line choice for obese patients. Choosing appropriate formulation that suits the patient’s lifestyle is essential to ensure patient’s compliance. Once daily dosing of sustained release formula could provide 24 hour control over glucose, but in this case the present of infection interfered with having accurate reading so it is logical to check the HbA1c to check the glycemic control over the last 8 weeks to consider any therapy modification. Also, pre- and post-prandial glucose level monitoring is required to avoid both hyper- and hypoglycemia using the current regimen.

Statins must be prescribed for all diabetic patients who are over 40 years old (6) and having any risk factor of Coronary Vascular Diseases (CVD). The patient was on Simvastatin 40mg daily but no Cholesterol level obtained (consider Ezetimibe if high Cholesterol). Monitoring liver function tests (LFTs) and any muscular side effect is important. Also, having a high BP on admission, checking that BP is normal after sepsis reveals is vital. If persistent high BP, consider adding ACE inhibitors, having the benefit of BP control and protecting the heart in patients susceptible to Vascular Diseases. Weight loss in this patient is advisable so consider dietitian and physiotherapist review to consider going on diet and exercise. Also, annual eye check is recommended to control retinopathy due to DM.

Cyclizine was prescribed on regular basis, so we better check if the patient is really on need of a regular anti-emetic, otherwise, consider changing it to as required basis. Regarding Paracetamol, it was prescribed on as needed basis but it was not put clear not to exceed the maximum daily dose, so it is recommended to clarify that to not give the patient more than 4g per day. It is safer to contact the patient’s GP to confirm the indication of Omeprazole and to consider discontinuation if no clear indication was obtained. Additionally, the patient was thrombocytopenic, which could be a side effect of administration either Quinine or Simvastatin, so monitoring the platelets count is highly recommended to prevent any complication, although DVT prophylaxis is not needed as long as the patient is mobile.

Conclusion

In conclusion, the overall patient management had no much deviation from the current guidelines recommendation except for some practice that need to be reviewed considering the current patient’s status. Therapeutic monitoring should be carried on because the patient is under risk of many complications or side effects. Lastly, patient’s awareness of her clinical condition and treatment requirement for each problem is helpful to prevent or reduce future health problems.

Appendix 1: PATIENT MEDICATION PROFILE

Patient details

Name

C.M.

Consultant

General Practitioner

Address

Gender

Female

Weight

100 kg

Height

152.4 cm

Community Pharmacist

Date of Birth (Age)

56 y.o.

Known Sensitivities

Micropores tapes

Social History

Previous smoker, lives with partner

Patient hospital stay

Presenting complaint in primary care / reason for admission

Admission date

2008

Increased urinary frequency

Back pain

Shortness of breath

Vomiting

Fall (the night before)

Fever (40.5°C)

Discharge Date Discharged to

Relevant medical history

Relevant drug history

Date

Problem Description

Date

Medication

Comments

Asthma

Symbicort 200/6 Turbohaler 1 puff daily

Ventolin Accuhaler 1 puff daily

Non-insulin dependent diabetes mellitus

Metformin 1g daily

Formulation?

Fibromyalgia

Co-codamol PRN

Strength?

Amitriptyline 150mg daily

Too high!

Quinine sulphate 300mg daily

Duration?

Simvastatin 40mg daily

1ry CVD prevention

Omeprazole 20mg daily

Indication?

Relevant non drug treatment

Prescribed Medication

Start

Stop

Clinical/Laboratory Tests

Result

1

Paracetamol 1g IV 6 hourly

Day 1

Day 2

ECG

Sinus tachycardia

2

0.9% sodium chloride 1000ml IV over 24 hours

Day 1

HR

117 bpm

3

Amoxicillin 1g IV 6 hourly

Day 1

BP

142/65

4

Ciprofloxacin 500mg PO OD

Day 1

Day 2

RR

22 bpm

5

Metformin 1g PO OD

Day 1

Urine analysis

Leucocytes, nitrites. Glucose, ketones, & blood +ve

6

Omeprazole 20mg PO OD

Day 1

Blood culture

E. coli

7

Quinine sulphate 300mg PO OD

Day 1

Na

134 (135-145)

8

Simvastatin 40mg PO OD

Day 1

CrCl

145.3 (78-120)

9

Amitriptyline 150mg PO OD

Day 1

Glucose

8.9 (3.9-5)

10

Symbicort 200/6 inhaler 1 puff daily

Day 1

CRP

180 (<10)

11

Codeine phosphate 30mg PO PRN

Day 1

Bilirubin

35 (3-16)

12

Citalopram 20mg PO OD

Day 1

PT

17 (12-15)

13

Cyclizine 50mg PO 8 hourly

Day 1

APTT

39 (20-30)

14

Gentamicin 400mg IV 24 hourly

Day 2

Platelets

70 (150-400)

15

Paracetamol 1g PO PRN

Day 2

Clinical management

Diagnosis

Pharmaceutical Need

Pyelonephritis

Evidence-based treatment

Sepsis

Treatment according to guidelines

Care Issue/Desired Output

Action

Output

Confirm drug history + reconcile drug history

Ask patient how and when she takes her medication and the indication for each medicine.

Compare with GP’s DHx + Phone GP for indications for amitrip., omep. and quinine, and when they were initiated.

All regular meds have been charted except prn salbutamol.

Patient is SOB; advise Dr to chart it prn.

Confirm antibiotic regimen for pyelonephritis/sepsis in addition to TDM

Check the local guidelines that amoxicillin is first-line for the indication (culture sens. to gent.).Calc. her ideal body weight and CrCl.Calc. gent. dose based on ideal body weight and compare to 400mg iv od (max dose).Check local guidelines whether 6-14 post dose gent. level is correct procedure. Chase level.

Monitor BP, Temp, Pulse, RR for signs of resolving sepsis whilst on current regimen.

Co-amox 1.2g iv tds is first-line with gent 5mg/kg (max 400mg, ideal body wt 49kg, CrCl 71ml/min).

Recommend switch to co-amox because she needs 7/7 iv + oral.

Recommend 245mg gent iv od

Obtain level before 2nd dose is given+TDM for gent is correct. Review need for gent in 48h

Fluid requirements possibly not being met by 1L N. saline in 24hours

Request a running fluid balance chart due to vomiting + increased urinary frequency. Ask patient if she can tolerate oral liq. or if feels thirsty.

Assess if iv is necessary (2.5L daily + replace losses)

Advise doctor to amend first bag to 8 hours and chart 1L N.saline over 8hours + 500ml glucose 5% over 8 hours if patient can’t tolerate oral liq.

Is her current SOB being treated appropriately?

If patient is still wheezy, ask for PaCO2 + PaO2.

Request salbutamol nebs 5mg qds + O2 60% to be charted.

If not currently SOB, ask for accuhaler to be charted prn.

Assess inhaler technique for both inhalers when breathing ok

Is her fibromyalgia regimen in-line with current evidence?

Check Brit. Soc. Rheum for current guidance on fibromyalgia.

Check that citalopram is the SSRI of choice in fibromyalgia since it has been started on admin.

Review quinine; if has been in use for 3 months with no benefit consider stopping it

High dose TCA is an old practice; current evidence states 25mg/day for 8 weeks.

Advise a review of Amitrip.

Low dose sertraline has better evidence for use in Fibro. Advise switch + show evidence to prescriber.

Tramadol with paracetamol has better efficacy than co-codamol. Suggest trial switch and monitor for dizziness due to recent unexplained fall.

Consider pregabalin.

Lifestyle advice: stress management, diet, physiotherapy/massage, etc.

Is her type II diabetes under control?

Check SIGN guidelines on diabetes for current management.

Request HbA1c test to determine control over last 2-3/12

Monitor glucose pre/post-prandial and random.

Ask patient how she takes the metformin and how regularly

Metformin is first-line in obese type II.

From lab results, assist endocrinologist in determining whether metformin dose should be increased + which preparation suits patient’s lifestyle.

Is her CVD primary prevention needs being met?

Check SIGN guidelines on CVD primary prevention.

Check BP + Cholesterol. Next U&Es ask for urine albumin + protein levels.

Ask patient about current diet and exercise plan (obese) + last eye test.

Simvastatin 40mg charted. Check cholesterol. If it is high, may need ezetimibe 10mg od. LFTs ok

BP 142/65, upon resolving sepsis recheck BP and initiate ACEi if appropriate.

Advise dietician review (obese) + physiotherapy review (or GP) for plan (30mins exercise 5/7).

Advise eye test once a year

Regular cyclizine may be unnecessary

Endorse chart for paracetamol’s maximum daily dose

Reassess patient’s need for a regular anti-emetic and re-chart cyclizine as prn instead of regular if required

Max 4g in 24 hours (e.g. 1g QDS)

Highlight patient’s thrombocytopenia

No need for DVT prophylaxis if patient is mobile.

Mention that quinine or simvastatin could be the cause of low platelets.

Suggest trial withdrawal of quinine if not planning on stopping anyway.

Monitor Platelets level if continued.

Indication for omeprazole

Determine indication from GP and patient.

Consider trial withdrawal if indication unknown.

Appendix 2: Box 1. Consensus Conference of the American College of Chest Physicians and Society of Critical Care Medicine definitions for the various manifestations of infection.

ʉۢ Systemic Inflammatory Response Syndrome (SIRS):

Manifest by two or more of the following conditions:

1. A temperature >38oC or <36oC

2. A heart rate >90 beats per minute

3. A respiratory rate >20 breaths per minute or a PaCO2 <32 mmHg

4. A white blood cell count >12,000/mm3 or <4000/mm3, or the presence of >10% immature forms.

• Infection:Microbial phenomenon characterised by an inflammatory response to the presence of microorganisms or the invasion of normally sterile host tissue by these organisms.

• Bacteraemia: The presence of viable bacteria in the blood.

• Sepsis (Simple): The systemic response to infection, manifested by two or more of the SIRS criteria pus an infection.

• Sepsis (Severe): Sepsis associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities that may include, but are not limited to lactic acidosis, oliguria or an acute alteration in mental status.

• Septic shock: Sepsis-induced hypotension despite adequate fluid resuscitation, along with the presence of perfusion abnormalities that may include, but are not limited to lactic acidosis, oliguria or an acute alteration in mental status. Patients who are receiving inotropic or vasopressor agents may not be hypotensive at the time that the perfusion abnormalities are measured. This is a subset of severe sepsis.

• Sepsis-induced hypotension: A systolic blood pressure <90 mmHg or a reduction of > 40 mmHg from baseline in the absence of other causes for hypotension.

Adapted from Bone RC et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest 1992; 101: 1644-1655.

Appendix 3: Table 1. Clinical and laboratory markers of organ dysfunction.

Organ System

Clinical

Laboratory

Cardiovascular

Tachycardia

Hypotension

Cardiac arrest

Arrhythmias

Haemodynamic support

Altered CVP, PCWP

Reduced cardiac output

Endocrine

Weight loss

Hyperglycaemia

Hypoalbuminaemia

Haematological

Bleeding

Thrombocytopenia

Increased D-dimers

Abnormal white cell count

Abnormal clotting profile

Gastrointestinal

Ileus

GI bleeding

Acute pancreatitis

Acalculous cholecystitis

Decreased intestinal pH

Elevated amylase

Hepatic

Jaundice

Hyperbilirubinaemia

Increased PT

Elevated LFTs

Hypoalbuminaemia

Neurological

Delirium

Confusion

Altered consciousness

Altered EEG

Renal

Oliguria

Anuria

Renal replacement therapy

Elevated creatinine

Elevated urea

Respiratory

Tachypnoea

Cyanosis

Mechanical ventilation

PaO2 <70 mmHg

SaO2 <90%

PaO2/FiO2 <300

Immune

Pyrexia

Nosocomial infection

Altered white cell count

Impaired white cell function

Adapted from Balk RA. Pathogenesis and management of multiple organ dysfunction or failure in severe sepsis and septic shock. Crit Care Clin 2000; 16: 337-352.