Systemic inflammatory response syndrome (SIRS) and a left bundle branch block (LBBB) due to nitrofurantoin

Abstract

We present a case of a 74-year-old woman, who was on nitrofurantoin treatment for urinary tract infection (UTI), with fever and chills 7 hours after taking nitrofurantoin. She was hospitalised and evaluated for worsening UTI and sepsis. Initially, it appeared to be secondary to post-UTI sepsis because of possible resistant infection or conditions like pulmonary embolism or acute hepatitis. The patient also developed systemic inflammatory response syndrome, left bundle branch block (LBBB), thrombocytopaenia and transaminitis. Considering the side effects of nitrofurantoin, it was stopped. The patient showed improvement and recovered completely with symptomatic and supportive treatment. During follow-up visits with her primary care physician, thrombocytopaenia, transaminitisandLBBB were found to have been resolved.

Background

Nitrofurantoin is the first-line antimicrobial agent for uncomplicated urinary tract infections (UTIs) and is active against a variety of bacteria including extended-spectrum beta-lactamase (ESBL) producing Escherichia coli and Klebsiella. ESBL and other resistances among bacteria are increasing, which makes nitrofurantoin an attractive option. The adverse effect profile of nitrofurantoin is usually considered to be better than other UTI antimicrobials like trimethoprim/sulfamethoxazole and quinolones. Systemic inflammatory response syndrome (SIRS) is a rare adverse effect of nitrofurantoin. SIRS is a widespread inflammatory response, which could include fever, tachycardia, tachypnoea, and it may or may not be associated with the infection. Sepsis is a serious epidemiological and therapeutic problem. UTI is a common cause of sepsis in hospitalised patients. SIRS is often associated with sepsis, although it could be associated with drug reaction. In this setting of UTI, the inflammatory signs like tachypnoea, tachycardia and fever could be difficult to discern, whether they are due to SIRS with or without sepsis.

Case presentation

We present a case of a 74-year-old woman with a medical history of hypertension and urinary bladder prolapse. The urogynaecologist examined her on 26th of February for dysuric symptoms, and urine culture was isolated on 27th of February. The result of the urine culture was positive for E. coli. She was started on nitrofurantoin 100 mg orally two times a day on 3rd of March. Nitrofurantoin was given based on the cumulative antibiogram results as an empirical therapy for uncomplicated UTI. Seven hours later, she developed shaking chills along with fever up to 102.7°F. Her dysuric symptoms were mild, without any evidence of ascending infection or pyelonephritis on examination. She was given ceftriaxone and was kept in the hospital from 3rd of March to 5th of March. She did not have any more chills or fever and was discharged on 5 th of March in the afternoon. She took a dose of nitrofurantoin on 5 th of March in the afternoon at home and started having chills within 6 hours. She came back to the emergency room. Her temperature was 102.9°F and she was tachypnoeic and tachycardic, but stayed normotensive. By then, she did not have any more dysuric symptoms. She was started on vancomycin and piperacillin/tazobactam and was observed in the cardiac telemetry unit as her heart rate was up to 151 beats/min. She was also found to have a left bundle branch block (LBBB) on the ECG with normal ejection fraction. On 6 th of March, while in the hospital, she was given a dose of nitrofurantoin. Six hours later, she had a sudden shortness of breath, nausea, desaturations, chills with a pulse of 110, respiratory rate of 30 breaths/min and blood pressure of 160/70 mm Hg. She improved with Solu-Medrol and supportive care and was discharged the next day. The patient was advised not to take nitrofurantoin again.

It was felt to be nitrofurantoin-associated SIRS with desaturation, fever, chills tachycardia and tachypnoea along with a left bundle block, thrombocytopaenia and transaminitis. To the best of our knowledge, this is the first case reported with nitrofurantoin SIRS and a left bundle block along with thrombocytopaenia and transaminitis.

The application of Naranjo scale (table 1) showed a score of 9, suggesting a definitive adverse drug reaction.¹ The use of the WHO—The Uppsala Monitoring Center system for standardised case causality assessment showed a causality of ‘certain’ (table 2).²

Table 1.

Naranjo algorithm

	Yes	No	Do not know or not done	Our patient
(1) Are there previous conclusive reports on this reaction?	+1	0	0	+1
(2) Did the adverse events appear after the suspected drug was given?	+2	-1	0	+2
(3) Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?	+1	0	0	+1
(4) Did the adverse reaction appear when the drug was re-administrated?	+2	-1	0	+2
(5) Are there alternative causes that could have caused the reaction?	-1	+2	0	+2
(6) Did the reaction reappear when placebo was given?	-1	+1	0	0
(7) Was the drug detected in any body fluid in toxic concentrations?	+1	0	0	0
(8) Was the reaction more severe when the dose was increased, or less severe when the dose was increased?	+1	0	0	0
(9) Did the patient have a similar reaction to the same or similar drug in any previous exposure?	+1	0	0	0
(10) Was the adverse event confirmed by any objective evidence?	+1	0	0	+1
Total				9

>9: definitive adverse drug reaction; 5–8: probable adverse drug reaction; 1–4: possible adverse drug reaction; 0: doubtful adverse drug reaction.

Table 2.

WHO-UMC causality categories

Causality term	Assessment criteria	Yes/no
Certain	Event or laboratory test abnormality, with plausible time relationship to drug intake.	Yes
	Cannot be explained by disease or other drugs.	Yes
	Response to withdrawal plausible (pharmacologically, pathologically).	Yes
	Event definitive pharmacologically or phenomenologically (ie, an objective and specific medical disorder or a recognised pharmacological phenomenon).	Yes
	Re-challenge satisfactory, if necessary.	Yes
	Final outcome	Certain

WHO-UMC, WHO—The Uppsala Monitoring Center.

Investigations

On 27th of February, urine culture was done and showed Enterococcus sp (motility, negative), and on 3 rd of March, the culture showed from 10 000 up to100 000 contaminated with vaginal flora (table 3).³

Table 3.

Antibiotic susceptibility report of Enterococcus species

	Enterococcus sp (motility, negative)
Mic charge Mic (μg/mL) (Minimal inhibitory concentration)	Y
Gentamycin synergy	SYN- (Synergy)S (Susceptibilty)	S
Levofloxacin	0.5	S
Linezolid	2	S
Nitrofurantoin	≤16	S
Penicillin-G	4	S
Streptomycin synergy	SYN-S (Synergy)	S
Vancomycin	1	S

On 3rd of March, blood cultures were done and showed Gram-positive cocci in clusters, Staphylococcus sp coagulase negative, Staphylococcus epidermidis.

The blood culture results were considered as suspected contamination. Repeat blood cultures were negative.

C reactive protein and procalcitonin were not tested.

On 3rd of March, CT of abdomen/pelvis without contrast was done to evaluate kidneys and showed no evidence of renal or ureteric calculi. There was mild prominence of the small bowel loops in the left upper abdomen and mid-abdomen.

On 3rd of March, troponin levels were done and amounted 0.03 ng/mL. On 5th of March they were 0.04 ng/mL, 0.08 ng/mL and 0.10 ng/mL. Cardiologist evaluated mildly elevated troponin levels and did not believe that they were elevated secondary to myocardial infarction (MI) or any ischaemic event.

ECG was done on 3 rd of March and showed sinus tachycardia and LBBB (figure 1).

Figure 1.

ECG showing sinus tachycardia and left bundle branch block.

On 3rd of March, liver function tests (LFTs) were normal.

On 4th of March, LFTs showed alanine transaminase (ALT) of 44 U/L (7–52 U/L), aspartate transaminase (AST) of 60 U/L (13–39 U/L); on 7th of March ALT of 65 U/L, AST of 58 U/L; and on 8th of March ALT of 216 U/L and AST of 160 U/L.

On 5th of March, when she had an episode of fever, chills and tachycardia along with oxygen desaturations, chest CT angiography was done to rule out pulmonary embolism and showed no evidence of pulmonary embolism. Mildly enlarged bilateral hilar nodes with a small paratracheal, aortopulmonary window and subcarinal lymph nodes needed further evaluation.

On 5th of March, complete acute metabolic panel was done and it showed non-reactive hepatitis A antibody IgM, hepatitis B core IgM, hepatitis B surface antigen and hepatitis C antibody. On 8th of March, complete echocardiogram (ECHO) was done to evaluate LBBB and showed normal left ventricular size. Systolic function was normal. Ejection fraction was estimated to be 65%. There were no regional wall motion abnormalities. Wall thickness was normal. Doppler ECHO showed an increased relative contribution of atrial contraction to ventricular filling. On 9th of March, ultrasonography (US) of abdomen was done to evaluate transaminitis and showed no intrahepatic biliary ductal dilatation. The patient showed the absence of surgically removed gallbladder, and there was no evidence of portal vein thrombosis.

Differential diagnosis

• Sepsis

• LBBB due to MI

• Acute hepatitis

• Pulmonary embolism

• Anxiety attack

Treatment

The patient was treated symptomatically for SIRS. She was evaluated for hepatitis, MI and was followed up. She was discharged home in stable condition on 9th of March. Her transaminitis and LBBB eventually resolved.

Outcome and follow-up

LFTs that were done on 3rd of March were normal. On 4th of March, LFTs showed an ALT of 44 U/L, AST of 60 U/L; on 7th of March, ALT of 65 U/L, AST of 58 U/L; on 8th of March, ALT of 216 U/L and AST of 160 U/L. One of the adverse effects of nitrofurantoin is liver dysfunction. Patient’s LFTs resolved after the cessation of nitrofurantoin.

The patient’s repeated laboratory tests done 3 weeks later showed resolution of thrombocytopaenia and transaminitis. LFTs done on 25th of March (alkaline phosphatase of 103 U/L, ALT of 42 U/L, AST of 34 U/L, platelet count (PLT) of 245,000 /uL) were compared with those done on 8th of March (alkaline phosphatase of 177 U/L, ALT 216 U/L, AST 160 U/L, PLT 125,000 /uL).

ECG done 1 year later showed resolution of LBBB (figure 2).

Figure 2.

ECG showing resolution of sinus tachycardia and left bundle branch block.

Discussion

UTIs account for about 10%–20% of all community-acquired infections. According to statistics, bacteriuria occurs at least once in a human lifetime. Approximately 10% of the female population and about 1%–2% of the male population are affected. Low incidences of symptoms of UTI in females are probably two times more often.⁴ UTIs could be a serious clinical problem due to complications such as sepsis, pyelonephritis, renal abscess, renal failure and pregnancy-related complications. UTIs can be recurrent, especially in drug-resistant cases, like ESBL-producing organisms.

Nitrofurantoin is active against the majority of Gram-positive and Gram-negative bacteria. Pathogens, however, like Pseudomonas spp and a significant number of Proteus strains are not susceptible.⁵ Although derivatives of nitrofurantoin do not reach therapeutic levels in the blood and tissues, they can be successfully used in UTIs, as over 80% of the dose of antibiotic is excreted in unchanged form in the urine, which provides antimicrobial activity.

Nitrofurantoin is used mainly in subacute and chronic UTIs.⁶ Its disadvantage is, as with other antibiotics, its side effects. Nitrofurantoin has certain adverse effects, which include: gastrointestinal symptoms, allergic reactions (especially the skin), polyneuritis, chills, fever and bundle branch block.⁴ SIRS is often associated with sepsis, although it could be associated with drug reaction. In this setting of UTI, the inflammatory signs like tachypnoea, tachycardia and fever could be difficult to discern, whether they are from SIRS with or without sepsis. During treatment, nitrofurantoin derivatives may change urine or saliva to a brown colour.⁷ Nitrofurantoin has been shown to be effective against some ESBL-positive strains and has renewed the interest of physicians struggling to find oral antibiotic options for those hard-to-treat patients.

Nitrofurantoin derivatives decompose in the weakly acidic and alkaline urine; this inhibits the reabsorption, accelerates secretion and stops the penetration of tissue. The acidic environments of urine favours the conversion of nitrofurantoin derivatives in all of the molecules, which are readily soluble in lipids and penetrate into the tissue, resulting in enhancing their reabsorption and accumulation in the tissues and increase the risk of toxic effects.⁸ Therefore, due to the severity of reabsorption and increased risk of toxic effects, it is not recommended to take nitrofurantoin derivatives with ascorbic acid and other drugs, which can acidify urine at the same time.

Nitrofurantoin is not recommended for patients with creatine clearance rate of <60 mL/min.

The local antibiotics susceptibility pattern should be considered before choosing an antibiotic for infections like UTI. In general, hospitals do keep a record of antibiotic susceptibilities in the form of antibiograms.

Table 4 shows a recent antibiogram from Pocono Medical Center for urine cultures in outpatient setting. This reflects the prevalent bacterial susceptibility to nitrofurantoin. The Enterococcal susceptibility is 98%, E. coli 97% and Klebsiella 80%, making nitrofurantoin an excellent choice for UTI (table 4).⁹

Table 4.

Antibiogram report

	Enterobacter cloacae spp cloacae (5)		Enterococcus faecalis (69)		E. faecium (7)		Enterococcus spp(65)		Escherichia coli (868)		Klebsiella ocytoca (15)
	S	Total	S	Total	S	Total	S	Total	S	Total	S	Total
Gentamicin	80%	5							89%	868	100%	15
Gentamicin high level (synergy)			63%	68	100%	7	76%	63
Imipenem	100%	5							100%	867	100%	15
Inducible clindamycin resistance
Levofloxacin	80%	5	59%	69	29%	7	69%	65	79%	867	93%	15
Linezolid			99%	69	100%	7	91%	65
Moxifloxacin
Nitrofurantoin	20%	5	100%	69	14%	7	98%	65	97%	868	80%	15
Oxacillin MIC
Piperacillin/tazobactam	80%	5							97%	864	100%	15
Quinupristin/dalfopristin			0%	68	100%	7	19%	64
Rifampicin
Streptomycin high level (synergy)			68%	68	86%	7	71%	63	90%	868
Tetracycline			25%	69	14%	7	23%	65	75%	867
Tigecycline			100%	68	100%	7	100%	60
Tobramycin	100%	5									100%	15
Trimethoprim/sulfamethoxazole	80%	5									100%	15
Vancomycin			97%	69	57%	7	98%	65

S, susceptibility.

Learning points.

• Urinary tract infections are common reasons for outpatient and inpatient visits.

• Nitrofurantoin is a preferred antibiotic for uncomplicated cystitis in females as per 2010 Infectious Diseases Society of America (IDSA) guidance,¹⁰ and the treatment is 5 days rather than 3 days as in trimethoprim/sulfamethoxazole or quinolones.

• Nitrofurantoin can cause acute pulmonary hypersensitivity and chronic lung disease/fibrosis.

• Lesser-known adverse effects of nitrofurantoin are systemic inflammatory response syndrome and left bundle branch block as presented in this case.