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 Table of Contents  
Year : 2020  |  Volume : 6  |  Issue : 3  |  Page : 224-228

Hurdles to managing a case of methicillin-susceptible Staphylococcus aureus: A clinical nightmare

Department of Internal Medicine, Aster Medcity, Kochi, Kerala, India

Date of Submission13-May-2019
Date of Acceptance18-Jan-2020
Date of Web Publication26-Sep-2020

Correspondence Address:
Dr. Geetha Philips
Department of Internal Medicine, Aster Medcity, Cherannallor, South Chittoor, Kochi - 682 027, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJAM.IJAM_24_19

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Staphylococcus aureus (SA), the most virulent of the many staphylococcal species, has been rightly described to be a cause of aggressive infections. Its versatility in evading host immune mechanisms and its ability to invade any human tissue make it a major cause for morbidity and mortality worldwide. With the current focus being on methicillin-resistant SA, the hurdles to the management of methicillin-susceptible SA (MSSA) are often underestimated. Here, we present a case of MSSA that was a skin colonizer, which gained entry inside the host following a fall. Although timely and adequate treatment for bacteremia was given, he progressed to sepsis with multiorgan dysfunction syndrome (MODS) and succumbed to the infection. A 79-year-old male, with a history of a recent fall which was treated, presented 2 weeks later, with complaints of fever and altered sensorium. The initial culture from the knee was negative. He was currently admitted for altered sensorium, which turned out to be MSSA bacteremia. He progressed to sepsis with MODS-septic arthritis, lobar pneumonia, and possible infective endocarditis (IE). He was on daptomycin and cefazolin. However, the patient did not respond to the treatment, progressed to septic shock, and unfortunately succumbed to infection. In our scenario, heavy skin colonization, followed by the breach in the skin following fall, possibly was the cause for septic arthritis weeks later. The lack of clinical response to daptomycin and the rapid clinical decline raised the suspicion of another source of SA invasion. Keeping in mind the aggressiveness of SA, a diagnosis of possible IE was also considered, and treatment was initiated. The management guidelines for treating MSSA are clearly defined by the Infectious Diseases Society of America and the National Health Service. We report this case to reflect on possible causes for nonresponse to treatment and to remind physicians of the devastating infectiveness of MSSA.
The following core competencies are addressed in this article: Medical knowledge, Patient care, Practice-based learning and improvement.

Keywords: Methicillin-susceptible Staphylococcus aureus, methicillin-susceptible, treatment failure methicillin-susceptible Staphylococcus aureus

How to cite this article:
Bhattacharjee S, Philips G. Hurdles to managing a case of methicillin-susceptible Staphylococcus aureus: A clinical nightmare. Int J Acad Med 2020;6:224-8

How to cite this URL:
Bhattacharjee S, Philips G. Hurdles to managing a case of methicillin-susceptible Staphylococcus aureus: A clinical nightmare. Int J Acad Med [serial online] 2020 [cited 2022 Dec 10];6:224-8. Available from: https://www.ijam-web.org/text.asp?2020/6/3/224/296141

  Introduction Top

Staphylococcus aureus (SA), the most virulent of the many staphylococcal species, has demonstrated its versatility by remaining a major cause of morbidity and mortality worldwide despite the availability of numerous effective antistaphylococcal antibiotics. SA is a pluripotent pathogen, causing disease through both toxin- and nontoxin-mediated mechanisms.[1] It is implicated as the most common cause of skin and soft-tissue infections (SSTIs), nosocomial infections, and healthcare-associated infective endocarditis (IE).[2] Although substantial evidence suggests that clinical manifestations of SA are influenced by the genetic characteristics of the infecting strain,[3],[4] the association between SA genes and severity of illness is incompletely understood.[5] However, with the advancement of molecular techniques, a study by Nienaber et al. showed SA in a clonal complex thirty is associated with a higher degree of hematogenous complications, IE in particular.[5] With the rising concern about community-associated methicillin-resistant SA (MRSA) in both developed and developing countries, the hurdles to the management of methicillin-susceptible SA (MSSA) are often underestimated. The management guidelines for treating MSSA are clearly defined by the Centre for Disease Control and Prevention and Infectious Disease Society of America (IDSA), but the diverse armamentarium of virulence-associated genes of SA is one of the possible causes leading to nonresponse to treatment.[6]

Before the antibiotic era, the mortality of bloodstream infections caused by SA was >80%.[7] After the discovery of penicillin, the mortality of SA infections reduced dramatically.[4] However, this was short-lived as penicillinase-producer SA strains emerged. These penicillin-resistant strains spread into hospitals and years later into the community.[8] Antibiotic drugs that were effective against penicillinase-producer strains such as methicillin became the drugs of choice for treating SSTI and other SA-related infections. However, soon after the introduction of methicillin, SA strains with a modified transpeptidase that had low affinity for beta-lactam antibiotics were described.[2] Thus, began the race for treating the dreaded MRSA infections.


SA is a Gram-positive, nonmotile coccus which belongs to the family of Micrococcaceae. It forms grape-like clusters on Gram's staining. It is known for its capacity to induce abscess formation at sites of both local and metastatic infections. The bacteria elicit an inflammatory response characterized by an initial intense infiltration of polymorphonuclear (PMNs) and a subsequent infiltration of macrophages and fibroblasts. To cause invasive disease, it uses the following methods – (1) Contamination and colonization of host tissue surfaces, (2) breach of cutaneous or mucosal barriers, (3) establishment of a localized infection, (4) invasion, (5) evasion of the host response, and (6) metastatic spread.


A family of structurally related SA surface proteins referred to as microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) plays an important role in mediating adherence. By adhering to exposed matrix molecules (e.g., fibrinogen and fibronectin), MSCRAMMs such as clumping factor and collagen-binding protein enables the bacteria to colonize different tissue surfaces.

Evasion of host immune response

SA contains an antiphagocytic polysaccharide microcapsule which as the name suggests prevents effective phagocytosis by macrophages. Another unique feature is the presence of Protein A, an MSCRAMM, which acts as an Fc receptor, binding the Fc portion of immunoglobulin G subclasses 1, 2, and 4 and preventing opsonophagocytosis by PMNs. The armamentarium of host immune evasion methods is represented in [Figure 1].
Figure 1: (Image taken from: Michael E. Powers, Juliane Bubeck Wardenburg, Igniting the Fire: SA Virulence Factors in the Pathogenesis of Sepsis, Published: February 13, 2014, https://doi.org/10.1371/journal. ppat. 1003871). (a) Leukocytes are targeted and injured by bi-component leukocidins, phenol-soluble modulins, and α-toxin. (b) Inhibition of host complement pathways occurs through chemotaxis inhibitory protein of staphylococci binding to the C5a receptor. (c) staphylococcal complement inhibitor-mediated blockade of C3 convertase activity. (d) Staphylococcal protein A binds to host antibodies, preventing opsonophagocytosis, and contributing to apoptotic death of B cells. (e) Coagulase A and von Willebrand factor-binding protein initiate fibrin clot formation, facilitating the formation of staphylococcal aggregates. (f) Platelet traps surround staphylococci that adhere to macrophage-like Kupffer cells in the liver sinusoid. (g) Fibronectin- binding proteins A and B (FnBPA/B) bind to integrins, enabling the tethering of SA to endothelial cells. (h) Expression of SA a -toxin (Hla) causes direct injury to the endothelium, disrupting the integrity of the endothelial barrier

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  Case Report Top

We present the case of a 79-year old male, with background history of coronary artery disease (CAD) and systemic hypertension. He presented to our center with complaints of generalized weakness which was insidious in onset and gradually progressive over a week. He also complained of dysuria of 3 days duration. There was no history of fever/hematuria. His relatives noticed a decline in sensorium – he was disoriented and had increased sleep for 3 days. There was no history suggestive of localizing neurological deficits, bowel involvement. On further questioning, he revealed a history of a fall 2 weeks back, resulting in left-sided knee pain which was evaluated and treated. Arthroscopic examination revealed a sterile culture. However, the pain persisted. His initial clinical examination revealed a dehydrated appearance, pallor, and a septic picture consisting of tachypnea, borderline blood pressure (100/70 mmHg), and mild disorientation. He was admitted to the intensive care unit (ICU) according to the quick sequential organ failure assessment score and was started on piperacillin-tazobactam to cover Gram-positive and most Gram-negative organisms. Cardiology and orthopedics teams were involved in view of the history of CAD and recent falls. His initial investigations revealed elevated total counts, raised C-reactive protein, low sodium, and urine routine showed the presence of abundant leukocytes. Electrocardiogram (ECG) revealed T inversions in V1–V3, and Troponin I was positive. Over the next 2 days, he improved symptomatically with medications. However, his knee pain worsened and looked red and was warm to touch. Orthopedics team planned for an arthroscopic debridement. Unfortunately, the same day, he complained of chest pain and ECG revealed non ST elevation myocardial infarction (NSTEMI) in lateral leads with rising Troponin I. ECHO revealed ischemic heart disease, regional wall motion abnormality, and ejection fraction (EF) of 46%. Blood culture revealed MSSA. Suspecting possibility of septic arthritis, the infectious diseases team was involved and he was initiated on daptomycin in accordance to latest IDSA treatment guidelines. After explaining risk versus benefits to the relatives, arthroscopic debridement was done, and pus was sent for culture. He improved with daptomycin monotherapy, but fever persisted. By day 9, repeat blood cultures were negative. He was shifted out of the medical ICU to the ward. However, by day 11, the patient desaturated in the ward was dyspneic, chest auscultation revealed bilateral basal crepitations. Chest X-ray revealed pulmonary edema. He was initiated on BiPAP. Blood culture was sent again and it came back positive for MSSA. Pus culture from the knee also grew MSSA. ECHO revealed the worsening of EF at 36%. With the rationale that there must be a focus of infection from where, SA is being intermittently released into the bloodstream, the possibility of IE was considered, in addition to septic arthritis. He was initiated on cefazolin according to the latest guidelines. Unfortunately, he did not respond to antibiotics and succumbed to sepsis and worsening heart failure.

  Discussion Top

SA is both a commensal and an opportunistic pathogen. Approximately 30% of healthy persons are colonized with SA, with a smaller percentage (~10%) persistently colonized. The rate of colonization is elevated among insulin-dependent diabetics, HIV-infected patients, patients undergoing hemodialysis, injection drug users, and individuals with skin damage.[1] MSSA causes 45% of SA bloodstream infections (BSI) and is the most important cause of BSI-associated death. The standard of care therapy for MSSA is Injectable penicillin for penicillin-sensitive organisms, nafcillin, or a first-generation cephalosporin–cefazolin for MSSA. Vancomycin is less effective for the treatment of SA bacteremia than beta-lactam agents and should not be administered as primary therapy for MSSA strains unless the use of a beta-lactam agent is precluded by drug intolerance. However, vancomycin and daptomycin are indicated for the treatment of septic arthritis. Nafcillin, cefazolin, and vancomycin are indicated for proven native valve endocarditis with MSSA.[9],[10]

In our scenario, the initial sterile culture from knee rules out the possibility of previously existing septic arthritis. Heavy skin colonization, followed by the breach in the skin following fall possibly was the cause for septic arthritis weeks later. The history of structural heart disease and the ongoing acute coronary event further hindered the ability of his body to cope with the sepsis. The lack of clinical response to daptomycin and the rapid clinical decline raised the suspicion of another source of SA invasion. Unfortunately, a transoesophageal ECHO could not be performed to confirm IE in view of clinical status. However, according to the modified Duke's criteria, our patient fit into the diagnosis of “possible IE.” The combination of cefazolin and daptomycin was the expected path to clinical recovery, especially with the knowledge that the isolated strain was sensitive to daptomycin and cefazolin.

The successful treatment of SA infections is an International quality indicator for any health-care facility.[11] National Health Service Scotland in 2017 describes the quality indicators for successful management of SA bacteremia.[12] Yet, the lack of response to the right treatment is a learning opportunity.

About 20% of MSSA isolates have a substantial inoculum effect with cefazolin, suggesting that cefazolin treatment may be associated with clinical failure for serious MSSA infections.[13] A study by Singh KV et al. shows ceftaroline to be an adequate alternative, comparable to nafcillin.[14] More relevant to our case scenario, a recent case report by Sakoulas et al. demonstrated acquired daptomycin (lipopeptide) resistance in an immune-competent adult patient with native valve endocarditis due to MSSA.[15] Daptomycin resistance developed following exposure to levofloxacin and vancomycin before daptomycin treatment. The observation that vancomycin exposure may induce resistance mechanisms in staphylococcal species is consistent with another recent report in which vancomycin exposure was accompanied by decreased expression of agr, resulting in resistance to platelet microbicidal proteins.[16]

What makes things even more scary is a study published by the University of Massachusetts which shows an MSSA culture-positive bacteremia progressing to MRSA during the course of treatment.[17]

  Conclusion Top

The rising emergence of resistance mechanisms to available drugs by SA is a major concern. Until newer drugs are available to combat these mechanisms, clinicians should remain alert and adhere to recommended guidelines and multidrug-regimens rather than monotherapy wherever feasible. Comorbidities such as structural heart disease and immunocompromised states such as diabetes mellitus further worsen outcomes in the management of MSSA sepsis.

In the famous words of Chinese Philosopher Sun Tzu, if you know both yourself and your enemy, you can win a hundred battles without a single loss.

Declaration of patient consent

The authors certify that they have obtained appropriate patient consent forms. The patient has given their consent for the publication of their images and other clinical information to be reported in the journal. The patient understands that their name and initials will not be published, and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

Ethical conduct of research

The authors declare that this scientific work complies with reporting quality, formatting, and reproducibility guidelines set forth by the EQUATOR Network. The authors also attest that this clinical investigation did not require Institutional Review Board/Ethics Committee Review. For this work, formal consent of the patient was obtained.

  References Top

Kasper DL, Fauci AS, Hauser SL, Longo DL, Jameson JL, Loscalzo J. Harrison's Principles of Internal Medicine. 19th ed. New York: McGraw Hill Education; 2015.  Back to cited text no. 1
Alvarez-Uria G, Reddy R. Prevalence and antibiotic susceptibility of community-associated methicillin-resistant Staphylococcus aureus in a rural area of India: Is MRSA replacing methicillin-susceptible Staphylococcus aureus in the community? ISRN Dermatol 2012;2012:248951.  Back to cited text no. 2
Campbell SJ, Deshmukh HS, Nelson CL, Bae IG, Stryjewski ME, Federspiel JJ, et al. Genotypic characteristics of Staphylococcus aureus isolates from a multinational trial of complicated skin and skin structure infections. J Clin Microbiol 2008;46:678-84.  Back to cited text no. 3
Peacock SJ, Moore CE, Justice A, Kantzanou M, Story L, Mackie K, et al. Virulent combinations of adhesin and toxin genes in natural populations of Staphylococcus aureus. Infect Immun 2002;70:4987-96.  Back to cited text no. 4
Nienaber JJ, Sharma Kuinkel BK, Clarke-Pearson M, Lamlertthon S, Park L, Rude TH, et al. Methicillin-susceptible Staphylococcus aureus endocarditis isolates are associated with clonal comple×30 genotype and a distinct repertoire of enterotoxins and adhesins. J Infect Dis 2011;204:704-13.  Back to cited text no. 5
Foster TJ. Immune evasion by staphylococci. Nat Rev Microbiol 2005;3:948-58.  Back to cited text no. 6
Skinner D, Keefer CS. Significance of bacteremia caused by Staphylococcus aureus: A study of one hundred and twenty-two cases and a review of the literature concerned with experimental infection in animals. Archiv Int Med 1941;68:851-75.  Back to cited text no. 7
Plorde JJ, Sherris JC. Staphylococcal resistance to antibiotics: Origin, measurement, and epidemiology. Ann N Y Acad Sci 1974;236:413-34.  Back to cited text no. 8
Fowler VG, Sexton DJ. Clinical Approach to Staphylococcus aureus Bacteremia in Adults. Waltham, MA: UpToDate, Wolters Kluwer; 2013.  Back to cited text no. 9
Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical practice guidelines by the infectious diseases society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:e18-55.  Back to cited text no. 10
Dendle C, Martin RD, Cameron DR, Grabsch EA, Mayall BC, Grayson ML, et al. Staphylococcus aureus bacteraemia as a quality indicator for hospital infection control. Med J Aust 2009;191:389-92.  Back to cited text no. 11
Scottish Antimicrobial Prescribing Group. Staphylococcus aureus bacteraemia clinical management quality indicators. NHS Scotland: Scottish Medicines Consortium; 2008.  Back to cited text no. 12
Lee S, Choe PG, Song KH, Park SW, Kim HB, Kim NJ, et al. Is cefazolin inferior to nafcillin for treatment of methicillin-susceptible Staphylococcus aureus bacteremia? Antimicrob Agents Chemother 2011;55:5122-6.  Back to cited text no. 13
Nannini EC, Singh KV, Arias CA, Murray BE.In vivo effects of cefazolin, daptomycin, and nafcillin in experimental endocarditis with a methicillin-susceptible Staphylococcus aureus strain showing an inoculum effect against cefazolin. Antimicrob Agents Chemother 2013;57:4276-81.  Back to cited text no. 14
Sakoulas G, Rose W, Rybak MJ, Pillai S, Alder J, Moellering RC Jr., et al. Evaluation of endocarditis caused by methicillin-susceptible Staphylococcus aureus developing nonsusceptibility to daptomycin. J Clin Microbiol 2008;46:220-4.  Back to cited text no. 15
Moise PA, Smyth DS, El-Fawal N, Robinson DA, Holden PN, Forrest A, et al. Microbiological effects of prior vancomycin use in patients with methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother 2008;61:85-90.  Back to cited text no. 16
Proulx MK, Palace SG, Gandra S, Torres B, Weir S, Stiles T, et al. Reversion from methicillin susceptibility to methicillin resistance in Staphylococcus aureus during treatment of bacteremia. J Infect Dis 2016;213:1041-8.  Back to cited text no. 17


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