DIABETES/METABOLISM RESEARCH AND REVIEWS REVIEW ARTICLE

Diabetes Metab Res Rev 2007; 23: 3–13.

Published online 8 September 2006 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/dmrr.682

Common infections in diabetes: pathogenesis,

management and relationship to glycaemic control

Anton Y. Peleg1† Summary

Thilak Weerarathna2
Specific defects in innate and adaptive immune function have been identified
James S. McCarthy1,3
in diabetic patients in a range of in vitro studies. However, the relevance
Timothy M. E. Davis2 * of these findings to the integrated response to infection in vivo remains
1 unclear, especially in patients with good glycaemic control. Vaccine efficacy
Department of Infectious Diseases,
seems adequate in most diabetic patients, but those with type 1 diabetes
Royal Brisbane and Women’s
Hospital, Herston, Brisbane, Australia and high glycosylated haemoglobin levels are most likely to exhibit hypo-
2
responsiveness. While particular infections are closely associated with
University of Western Australia,
diabetes, this is usually in the context of extreme metabolic disturbances such
School of Medicine and
as ketoacidosis. The link between glycaemic control and the risk of common
Pharmacology, Fremantle Hospital,
Fremantle, Australia community-acquired infections is less well established but could be clarified
3
if infection data from large community-based observational or intervention
The Queensland Institute of Medical
studies were available. The relationship between hospital-acquired infections
Research and Australian Centre for
and diabetes is well recognized, particularly among post-operative cardiac
International and Tropical Health
and Nutrition, The University of and critically ill surgical patients in whom intensive insulin therapy improves
Queensland, Brisbane, Australia clinical outcome independent of glycaemia. Nevertheless, further research is
needed to improve our understanding of the role of diabetes and glycaemic
*Correspondence to: control in the pathogenesis and management of community- and hospital-
Timothy M. E. Davis, School of acquired infections. Copyright  2006 John Wiley & Sons, Ltd.
Medicine and Pharmacology,
Fremantle Hospital, PO Box 480, Keywords diabetes; infection; immunity; glycaemic control
Fremantle, Western Australia
6959, Australia. E-mail:
[email protected] Introduction
† Current address: Division of Before the discovery of insulin and antibiotics, infections contributed
Infection Diseases, Beth Israel
substantially to diabetes-associated morbidity and death. It has been estimated
Deaconess Medical Center and
that infections killed 1 in 5 diabetic patients in the 1920s compared to <1
Harvard Medical School, Boston,
MA 02215, USA. in 20 in the late 1960s [1]. Despite recent advances in the management of
both diabetes and infectious diseases, diabetic patients remain at increased
risk of infection [2]. Although intensive blood glucose control significantly
reduces vascular complications in both type 1 and type 2 diabetes [3,4], the
relationship between glycaemia and infections is less well established. Other
factors, including attenuated immune responsiveness and diabetic tissue
damage, may play important roles. The present review assesses the current
understanding of the relationship between diabetes, immune function and
the management of common community- and hospital-acquired infections.

Search strategy and selection criteria

We searched PubMed, Excerpta Medica Database (EMBASE) and Med-
line using ‘diabetes’ in combination with keywords including ‘infec-
Received: 8 June 2006 tion’, ‘sepsis’ and ‘immunity’. The reference lists in the articles gen-
Accepted: 1 August 2006 erated were used to identify other publications of interest. The pri-
mary criterion for inclusion in the present review was clinical relevance.

Copyright  2006 John Wiley & Sons, Ltd.

4 A. Y. Peleg et al.

Immune function ambient glucose concentrations >12 mmol/L [7]. The

reduced superoxide production may reflect an increase
Components of host defense that may be impaired in in polyol pathway activity as a consequence of raised
diabetes have been studied in detail [5,6], especially intracellular glucose [23,24]. As an electron donor,
the innate immune system and the polymorphonuclear NADPH is a necessary part of the polyol pathway and its
neutrophil (PMN). Defects in adaptive immunity are consequently increased utilisation may be at the expense
less well characterized, but are likely to be important of reduced levels of superoxide production.
cofactors given the diversity of organisms, including fungi In an attempt to improve PMN function in diabetic
and Mycobacterium spp., to which diabetic patients show patients, several investigators have studied the role
increased susceptibility. of immune-modulating agents. Firstly, improving PMN
superoxide production has been studied using aldose
reductase inhibitors [22–25], agents that inhibit the
Innate immunity polyol pathway. However, the role of such therapy in the
The steps involved in pathogen elimination by PMN prevention or treatment of infection in diabetes remains to
are (1) PMN adhesion to vascular endothelium, initially be established. Secondly, and probably of greater clinical
via the cell surface adhesion molecule L-selectin and relevance, granulocyte-colony stimulating factor (G-CSF)
then integrins, (2) transmigration through the vessel wall has been used as adjuvant therapy in diabetic patients with
down a chemotactic gradient, and (3) phagocytosis and foot infections. G-CSF induces terminal differentiation and
microbial killing. Although an increase in PMN adhesion release of PMN from the bone marrow and improves PMN
to vascular endothelium has been documented in patients function, particularly superoxide production [26–28]. In
with diabetes [7], the significance of this change in one trial [26], diabetic patients with lower limb infections
mediating a predisposition to infection is unclear. Such who received G-CSF showed earlier microbial eradication
increased adhesion does not relate HbA1c levels and from wound swabs, quicker resolution of cellulitis, and
does not persist after PMN stimulation [7], but could shorter duration of intravenous antibiotic administration
predispose to vascular complications given the potential and hospitalisation. Unfortunately, these findings were
for endothelial injury. not confirmed in a similar, subsequent study [28]. Given
Transmigration of PMN, as measured through endothe- the cost and paucity of data, G-CSF cannot yet be
lial cell monolayers, is impaired in patients with diabetes recommended as an adjunctive therapy for infections in
in parallel with an increase in the concentration of diabetic patients.
advanced glycosylation end products [8]. Several studies
have also shown that PMN chemotaxis may be reduced
in diabetic patients irrespective of glycaemia [9–12] but Adaptive immunity
the data are difficult to interpret because of variations Detailed study of cell-mediated immunity (CMI), pre-
in experimental methodology. In one well-standardized dominately T-lymphocyte function, has identified specific
study [7], chemotaxis was reduced in PMN from diabetic defects in poorly controlled type 1 patients [29,30]. How-
versus control subjects, especially in the presence of glu- ever, in a recent in vitro study involving type 1 patients,
cose concentrations >12 mmol/L and when PMN were all with a HbA1c <8.0% [31], there were impaired prolif-
isolated from patients with vascular complications [7]. erative CD4+ cell responses to primary protein antigens,
Similar results have been reported for monocytes from perhaps due to altered expression of cellular adhesion
diabetic patients [13]. In a more recent study, hyperin- molecules and/or reduced cytokine release independent
sulinaemia in the presence of euglycaemia significantly of glycaemia [32]. By contrast, another study involving
improved PMN chemotaxis, raising important questions patients with relatively good metabolic control showed a
about the direct role of insulin in the immunity of diabetes robust secondary immune response to standard antigens,
[14]. suggesting normal T memory cell and CD4+ lymphocyte
Studies of phagocytic function are also confounded function [33]. Thus, although tight blood glucose control
by variations in experimental technique. Initial evidence may help to normalize CMI in diabetic patients, other
for reduced phagocytosis of opsonized Staphylococcus factors may be important.
aureus [6,15] and pneumococcus [5] by PMNs from With regard to humoral immunity, it is possible
diabetic subjects has not been confirmed by more that glycosylation may impair the biological function of
recent investigations using the opsonized latex bead antibodies, whether generated by natural exposure or
ingestion test [7] or other bacteria and fungi [16,17]. vaccination. IgG glycosylation occurs in patients with
As with chemotaxis, PMN phagocytosis has recently been diabetes in proportion to HbA1c [34]. In one study,
shown to improve in the presence of hyperinsulinaemic the antigen-binding fragment of IgG was glycosylated
euglycaemia [14], adding support to the suggestion that in preference to the effector fragment [34]. The clinical
insulin is an important influence on PMN function. relevance of these observations is unclear since the
The most convincing evidence of PMN dysfunction in antibody response and protection after vaccination
diabetic patients relates to microbial killing [7,18–21]. against the common infections, influenza, pneumococcal
Superoxide production is reduced in parallel with infection and hepatitis B show adequate responses in
increasing glycaemic exposure [20–22], especially at patients with diabetes [35–44]. Thus, we support the

Copyright  2006 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2007; 23: 3–13.
DOI: 10.1002/dmrr
Common Infections in Diabetes 5

recommendation that adult diabetic patients receive the Mucocutaneous candidiasis (usually due to C. albicans)
influenza vaccine before every epidemic season and the is associated with diabetes and other hyperglycaemic
polysaccharide pneumococcal vaccine on one occasion states such as hyperalimentation [68,69]. This association
followed by a booster at 5 years [45–49]. may reflect increased microbial virulence since, in the
presence of hyperglycaemia, Candida spp. express a
protein that enables more avid adherence to surface
Common community-acquired epithelial cells [69]. In clinical studies, however, findings
infections have been inconsistent. In a recent review of 21 studies
[70], oral carriage rates in diabetic subjects ranged from
Contemporary management of common infections in
18 to 80%. In the 15 studies that employed controls,
diabetes is summarized in Table 1, with an emphasis
only half showed a statistically significant increase in
on diagnosis and antimicrobial therapy. In the following
the carriage of C. albicans in diabetes, and there was
sections, features of these infections in diabetic patients
a variable relationship between salivary glucose and
are discussed.
oral carriage [68]. Between-study differences are likely
to reflect methods of selection of diabetic subjects and
Skin, nail, mucous membrane and soft tissue infections controls, sampling techniques, and perhaps also group
Skin infections are common in diabetes. In a large differences in putative aetiological factors such as denture
study of unselected diabetic outpatients, skin infections wearing and xerostomia [70].
(mainly fungal) were present in 20% of the sample and Diabetic foot infections often lead to hospitalisation,
were the commonest dermatological complaint [55]. In and serious consequences such as osteomyelitis and
another study analysing the epidemiology of inpatient amputation can supervene. This is due, at least in
care resulting from peripheral neuropathy, peripheral part, to their painless nature in patients with peripheral
vascular disease and skin infections in a UK population sensory neuropathy [71] and the fact that most non-
of >400 000, diabetic patients had a 6–7 times greater severe diabetic foot infections do not produce systemic
risk of hospitalisation owing to skin and soft tissue manifestations such as fever or leucocytosis [72]. A
infections and related conditions compared to age- culture of swabs collected from ulcers and other foot
matched controls [56]. A recent Dutch primary care study lesions in diabetic patients often yields several pathogens
that captured medically attended episodes of skin and that can be difficult to distinguish from colonising
mucous membrane infections showed odds ratios that organisms, especially in chronic or previously treated
were >30% greater for patients with either type 1 or 2 wounds [73]. Evidence suggests that the culture results
diabetes than for controls after adjustment for potential do not reliably identify the pathogens present unless the
confounders [57]. involved bone is cultured [74]. The role of antibiotics for
Certain bacterial and fungal pathogens are found the treatment of foot ulcers in diabetic patients without
commonly on the skin and mucous membranes of clinical signs of infection remains unclear [75]. However,
diabetic patients, notably S. aureus and Candidia albicans. surgery, especially consideration of revascularisation
Evidence suggests that diabetic patients have an increased [76], remains a high priority in the management of the
prevalence of staphylococcal carriage [58], although this infected diabetic foot as part of multidisciplinary care
is not a consistent finding [59]. Poor glycaemic control [77]. The roles of adjunctive therapies, such as growth
appears to be a major predisposing factor [58,60–62]. factors and hyperbaric oxygen, are yet to be established
In type 1 diabetic children, nasal carriage of S. aureus is [78].
higher (>70% in some studies) than in both age-matched
controls and older type 2 patients [58,59], and similar
to that in young intravenous drug users [63]. There is Respiratory tract infections
an association between colonisation with S. aureus and In a large UK survey, respiratory tract infections (both
local and systemic infections, which are responsible for upper and lower) were responsible for a significantly
significant morbidity and mortality in diabetes [62,64]. In higher number of general practitioner consultations
the case of common skin infections, S. aureus is the most among diabetic patients compared with matched control
common pathogen isolated in cases of cellulitis and 10% subjects [79]. However, in one prospective study,
of patients with this condition will also have diabetes that the percentage of diabetic patients hospitalized with
is either known or unmasked by the infection [65]. community-acquired pneumonia (CAP) was <5% [80],
The prevalence of onychomycosis is increased several a figure similar to the prevalence of diabetes in many
fold in patients with diabetes, especially males [66]. communities. The spectrum of organisms responsible for
Treatment may be complicated by the presence of vascular CAP in diabetic patients appears to differ from that in
disease, Candida infection and potentially significant non-diabetic individuals, with an over-representation of S.
interactions between antifungal drugs and concomitant aureus and Gram-negative bacteria such as K. pneumoniae
blood glucose-lowering and cardiovascular therapies. [81]. The higher prevalence of staphylococcal skin and
Because of its high efficacy and good tolerability, nasal carriage, increased pharyngeal carriage of Gram-
terbinafine is the treatment of choice for this condition in negative bacteria and gastropathy-associated aspiration
diabetes [67]. are likely predisposing factors [81]. In a meta-analysis of

Copyright  2006 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2007; 23: 3–13.
DOI: 10.1002/dmrr
 6

Table 1. Treatment of common infections in diabetes

Empirical antimicrobial treatmenta

Diagnostic tests Organisms First line Alternative Other treatments

Copyright  2006 John Wiley & Sons, Ltd.

Skin and soft tissueb
Cellulitis [50] Clinical diagnosis +/− S. aureus, S. pyogenes, less Nafcillin/flu/dicloxacillin/1–2 g/IV Cephazolin 1 g IV 8 hourly or
wound swab for culture common gram-negative aerobes 4–6 hourly clindamycin 600 mg IV 8 hourly
and anaerobes or 300–450 mg PO 8 hourly or
vancomycin 1g IV 12 hourly
Diabetic foot infection [51] Culture of tissue specimen S. aureus, S. pyogenes, Mild–moderate Cephalexin 500 mg PO 6 hourly Surgical review, assess
from base of debrided ulcer, gram-negative aerobes including Usually an oral regimen to cover plus metronidazole 400 mg PO requirement for
‘probe to bone’ testc , Pseudomonas aerigunosa, gram +ve and common 8–12 hourly, broad-spectrum revascularisation, wound
operative biopsy for culture, anaerobes. Often polymicrobial. gram-negative organisms. e.g. fluoroquinolone, or ciprofloxacin debridement, avoidance of
plain radiograph Amoxicillin-clavulanate 500 mg PO 12 hourly plus pressure-induced ischaemia with
875/125 mg PO 12 hourly OR clindamycin 600 mg IV 8 hourly orthotic devices.
ampicillin/sulbactam 3 g IV 6 or 300–450 mg PO 8 hourly.
hourly
Severe Ciprofloxacin 750 mg orally 12
Ticarcillin-clavulanate 3.0–0.1 g hourly plus clindamycin 600 mg
IV 6 hourly or IV 8 hourly or lincomycin 600 mg
Piperacillin-tazobactam 3.375 g IV 8 hourly
IV 8 hourly or Add vancomycin 1g IV 12 hourly
Mero/imipenem-cilastatin if MRSA isolated
500 mg–g 8/6 hourly
Necrotizing fasciitis [50] Clinical appearance/surgical S. pyogenes or Clostridium sp. or Meropenem 1 g IV 8 hourly plus Ampicillin-sulbactam 1.5–3 g Surgical removal of devitalized
findings/imaging (plain polymicrobial clindamycin 600 mg IV 8 hourly 6–8 hourly or tissue is the basis of treatment.
radiography/CT/MRI)/gram or lincomycin 600 mg IV 8 hourly piperacillin-tazobactam 3.375 g
stain and culture of operative 6–8 hourly, plus ciprofloxacin
specimens 400 mg IV 12 h plus clindamycin
600–900 mg IV 8 hourly
Community-acquired Chest radiography, sputum Streptococcus pneumoniae, Mild
pneumonia [52] gram stain and cultures, Mycoplasma pneumoniae, An advanced macrolided or A respiratory fluoroquinolonee
blood cultures, urinary Chlamydia pneumoniae, amoxycillin 1 g PO 8 hourly plus
antigen testing, serology Legionella spp., Haemophilus doxycycline 200 mg PO for first A respiratory fluoroquinolonee
influenzae, S. aureus, Klebsiella dose and then 100 mg PO daily
pneumoniae, Mycobacterium
tuberculosis Moderate
An advanced macrolided
Plus a β -lactam (benzylpenicillin
1.2 g IV 6 hourly or ampicillin
1 g IV 6 hourly or
cefotaxime/ceftriaxone 1 g IV
daily or ampicillin-sulbactam)
A. Y. Peleg et al.

Diabetes Metab Res Rev 2007; 23: 3–13.

DOI: 10.1002/dmrr
 Severeb An antipseudomonal β -lactam Requirement for
Ceftriaxone 1 g IV daily or plus either an advanced antipseudomonal cover will
cefotaxime 1 g IV 8 hourly plus macrolided or a respiratory depend on risk factorsf
either an advanced macrolided fluoroquinolonee Local prevalence rates of
or a respiratory fluoroquinolonee community-acquired MRSA
should guide empiric treatment
and may include vancomycin 1 g
IV 12 hourly or linezolid 600 mg
IV 12 hourly
Urinary tract
Asymptomatic bacteriuria Urine microscopy and culture Various, most frequently No treatment
Common Infections in Diabetes

[53] ≥105 cfu/mL Enterobacteriaceae

Cystitis [54] Urine microscopy and culture Enterobacteriaceae, 3 days oral antibiotic treatment Trimethoprim 300 mg or

Copyright  2006 John Wiley & Sons, Ltd.

Staphylococcus saprophyticus, guided by local antibiotic norfloxacin 400 mg orally 12
Enterococcus sp., rarely Candida sensitivity pattern hourly or ciprofloxacin 500 mg
spp. e.g. trimethoprim- orally 12 hourly
sulfamethoxazole orally daily
Pyelonephritis [54] Urine microscopy and 14 days oral/IV antibiotic Ceftriaxone 1 g IV daily or Emphysematous pyelonephritis is
culture/renal tract imaging treatment guided by local cefotaxime 1 g IV 8 hourly or a rare but serious complication
antibiotic sensitivity pattern. ticarcillin-clavulanate 3.0–0.1 g requiring early surgical
Ciprofloxacin 500/400 mg PO/IV IV 6 hourly or intervention.
12 hourly or ampicillin 2 g IV 6 piperacillin-tazobactam Post-treatment urine microscopy
hourly plus gentamicin (see local 4.0–0.5 g IV 8 hourly and culture recommended in all.
dosing and monitoring
guidelines) or
ampicillin/sulbactam 1.5 g IV 6
hourly
Other
Necrotizing otitis externa Clinical examination/ear P. aeruginosa Ciprofloxacin 400 mg IV 12 Imipenem-cilistatin/meropenem Otolaryngology review.
swab culture/magnetic hourly or ticarcillin-clavulanate 1 g IV 6/8 hourly
resonance imaging 3.0–0.1 g IV 6 hourly or
cefepime 2 g IV 12 hourly or
ceftazidime 2 g IV 8 hourly plus
gentamicin 4–6 mg/kg IV daily
Rhinocerebral mucormycosis Clinical Rhizopus (>90%), mucor and Amphotericin B 0.8–1.5 mg/kg Lipid-based amphotericin B for Control diabetic ketoacidosis if
examination/magnetic absidia species IV daily those with renal impairment or present. Surgical debridement
resonance imaging/biopsy of posaconazole 800 mg PO daily in required.
infected tissue 2–4 divided doses

a All treatment regimens are for average sized, non-pregnant patients with normal renal and liver function.
b If community-acquired MRSA is documented in the geographic area then empirical treatment for life-threatening infections should include vancomycin 1 g IV 12 hourly. An alternative treatment may be linezolid
600 mg IV 12 hourly or linezolid 600 mg IV 12 hourly. Treatment of other infections should be based on sensitivity data and may include clindamycin 300–450 mg orally 8 hourly or trimethoprim/sulfamethoxazole
160/800 mg orally 12 hourly.
c Ability to insert probe to bone suggests concomitant osteomyelitis.
d Azithromycin or clarithromycin.
e Moxifloxacin, levofloxacin, gemifloxacin.
f Structural lung disease, >10 mg prednisolone/day, broad-spectrum antibiotics for >7 days in the past month.
7

Diabetes Metab Res Rev 2007; 23: 3–13.

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8 A. Y. Peleg et al.

33 000 patients with CAP [82], a higher mortality was Asymptomatic bacteriuria (ASB), the presence of single
observed among diabetic patients, but diabetes was not bacterial species at >105 colony forming units/mL in
among the three most common co-morbidities predicting culture of at least two mid stream urine specimens from
death (smoking, pre-existing pulmonary disease and an individual without symptoms, is the most frequently
cardiac failure). Diabetes is one of the conditions observed category of UTI in diabetic patients. ASB has a
associated with recurrent pneumonia [83]. reported prevalence of up to 29% in diabetic women, a
Bacteraemic pneumococcal pneumonia occurs rela- figure that is approximately three times greater than that
tively commonly in diabetic individuals [84,85], but a in non-diabetic women [98]. In diabetic men, however,
recent population-based study found a death rate that the overall prevalence of ASB (1 to 11%) is similar
was similar to that in non-diabetic patients with this to that in non-diabetic men [99], consistent with the
condition [86]. However, the adverse impact of diabetes female preponderance of UTIs in the general population.
on morbidity and mortality during influenza epidemics A number of predisposing factors for ASB have been
has long been recognized [87]. In fact, the first patient reported. In most [99–102] but not all [103] studies,
to receive insulin died following an influenza-like illness there is no relationship between glycaemic control and
[88]. Diabetic patients have a sixfold higher relative risk ASB. Chronic complications such as nephropathy and
of hospitalisation than non-diabetic individuals during neuropathy have been associated with ASB in type 1 but
influenza epidemics [45]. This observation might reflect not type 2 diabetes [99,104], a pattern that holds for
an increased incidence of secondary staphylococcal pneu- longer diabetes duration [104]. ASB is more frequent
monia [45], but metabolic compromise and the high in patients with cardiac and peripheral vascular disease
prevalence of co-morbid conditions, such as cardiac fail- [105]. Localisation studies in diabetic patients using
ure, are also important [89]. techniques such as bladder wash-out have shown that
Pulmonary tuberculosis has a recognized association the upper urinary tract is involved in more than half
with diabetes. Studies carried out during the early of the patients [106]. Despite this, the decline in renal
part of the twentieth century revealed that diabetic function in diabetic patients with ASB followed for up to
patients with pulmonary tuberculosis had a mortality 2 years did not differ from a group with diabetes alone
approaching 50% [90]. Recent data from Asia and Africa [107]. Diabetic women with ASB are at greater risk of
demonstrate that pulmonary tuberculosis still poses a UTI [100] and subsequent hospitalisation with urosepsis
significant threat to diabetic subjects. A Japanese study [103]. However, there is no evidence that presumptive
that investigated patients hospitalized with tuberculosis antibiotic therapy for ASB is beneficial [101,108].
over a 6-year period found that 13.2% had diabetes, Acute pyelonephritis also occurs more commonly in
a percentage that increased steadily with time [91]. diabetic than non-diabetic individuals. Post mortem
In a smaller but similar Pakistani study, nearly half studies during the pre-antibiotic era found a fivefold
of the sample had abnormal glucose tolerance [92]. increase [97]. A Canadian study of inpatients with
A study of bacterial infections in hospitalized diabetic pyelonephritis [109] revealed that 63% of women and
patients in Papua New Guinea showed that the annual 21% of men had diabetes, indicating that diabetes is a
incidence of tuberculosis was 11 times higher than predisposing factor regardless of gender. Complications of
in the general population [93]. In addition to an acute pyelonephritis, both systemic and renal, also occur
increased risk of tuberculosis, diabetic patients are more often and with greater severity in diabetes. These
prone to unusual forms, including predominant lower include bilateral renal involvement, intrarenal abscesses,
lobe involvement, multilobar disease and a higher renal carbuncle and emphysematous pyelonephritis
incidence of pleural effusion [94]. Diabetic subjects [97,101]. Indeed, some authorities recommend routine
respond appropriately to anti-tuberculous treatment [95]. imaging of the renal tract in all diabetic patients with
An important treatment-related issue is the possibility pyelonephritis to rule out obstruction and emphysematous
that peripheral neuropathy may worsen because of and other changes [97,110]. Because of the potential
isoniasid therapy unless pyridoxine supplementation is for complications, UTIs should be carefully managed
given [96]. Interactions between anti-tuberculous and in diabetes. Attempts should be made to culture the
oral hypoglycaemic drugs can occur, including reduced organism both to guide antibiotic therapy and to confirm
efficacy of sulfonylurea treatment with rifampicin. cure after treatment, especially since there is evidence
that resistant organisms are found more frequently in
diabetic patients with community-acquired UTI [111].
Urinary tract infections
Several factors are thought to predispose diabetic subjects
to urinary tract infections (UTIs) [21,97]. Reduced Periodontal disease
sensitivity and altered distensibility of the urinary bladder Available evidence suggests that diabetes is associated
due to autonomic neuropathy can result in stagnation of with increased periodontal disease and tooth loss, but
urine and higher rates of instrumentation. Glycosuria data implicating diabetes as a risk factor for dental
can enhance bacterial growth and impair phagocytosis. caries are inconsistent [112]. Cross-sectional studies have
Vaginitis and renal microangiopathy are also associated revealed a high prevalence of periodontal disease in
with recurrent UTIs. both type 1 and type 2 diabetes [113,114]. Although

Copyright  2006 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2007; 23: 3–13.
DOI: 10.1002/dmrr
Common Infections in Diabetes 9

sample sizes have been small and the criteria used in the increased risk of wound infection among diabetic patients.
assessment of gingival involvement have been variable, a This increased risk was related to hyperglycaemia during
number of studies have found an association between poor the first 48 h after surgery but not HbA1c or pre-operative
glycaemic control and periodontal disease [114–117]. glycaemia. Patients with previously undiagnosed diabetes
Microangiopathy, abnormal collagen metabolism, raised had a similar infection rate to that in those with
salivary glucose concentrations and low salivary pH known diabetes [126]. The importance of post-operative
may also be contributing factors [113,114,117,118]. metabolic control is further highlighted by the observation
Poor glycaemic control can increase the incidence that a plasma glucose >12 mmol/L on the first post-
and accelerate the progression of periodontal disease operative day increased the rate of hospital-acquired
[114,116,117], while, in the presence of periodontal infection (excluding simple UTI) almost sixfold [129].
infection, glycaemic control can worsen [119]. Good oral Owing to the substantial morbidity, mortality and
hygiene remains an essential component of diabetes care socioeconomic impact associated with deep sternal wound
but the addition of a tetracycline may provide additional infection (DSWI) following cardiac surgery, several
benefit in type 1 patients with periodontal defects [120]. investigators have targeted modifiable risk factors such
as glycaemic control. In a large prospective study [133],
diabetic patients undergoing open-heart surgery were
Glycaemic control and community-acquired infections allocated non-randomly to conventional intermittent
Few clinical studies have looked at the relationship subcutaneous insulin or to an intensive continuous
between glycaemic control and the general risk of intravenous insulin (CII) infusion. CII achieved better
community-acquired infection and the data do not post-operative glycaemic control and was associated with
support a strong link. In the UK Prospective Diabetes a 2.5-fold lower rate of DSWI, results that were in accord
Study(UKPDS) involving type 2 patients [3], intensive with a previous retrospective review [132]. In a study
blood glucose control strategies prevented chronic of PMN function among diabetic patients randomized
vascular complications but infection-related data have yet to CII or standard insulin therapy after cardiac surgery
to be reported. In the Diabetes Control and Complications [134], there was greater phagocytic activity in PMN
Trial (DCCT) in type 1 patients [4], there was a 46% taken from the CII group immediately after operation.
lower rate of self-reported vaginitis requiring medical The investigators hypothesized that insulin-mediated
treatment in intensively treated versus conventionally hormonal or cytokine effects improved PMN function
managed patients, but there were no other between- [134].
group differences in rates of foot, urinary, respiratory There is increasing evidence that hyperglycaemia
or gastrointestinal infections [121]. In a community- may substantially increase the risk of hospital-acquired
based, 12-month prospective study of type 2 patients and infection in the severely ill, regardless of diabetes status
their non-diabetic partners [122], similar proportions of [135,136]. In the Leuven Study [136], critically ill
subjects in each group reported any infection but there patients in a surgical intensive care unit were randomized
was a significantly greater number of infections in the to either CII titrated to maintain normoglycaemia
diabetic group. There was no relationship between the or less intensive treatment (target blood glucose
incidence of infection and HbA1c [122]. By contrast, a 10–11 mmol/L). Mortality was significantly lower in the
retrospective study of diabetic outpatients demonstrated intensive compared to the less intensive insulin group
a significant correlation between infection and glycaemia (4.6% vs 8% respectively), with the greatest reduction
assessed from blood glucose levels [21]. in mortality in patients with multi-organ failure and a
The relationship between glycaemic control and proven septic focus. CII also reduced the incidence of
predisposition to specific community-acquired infections, septicemia by 46%, with a concomitantly reduced need
as reviewed above, is also generally weak. The strongest for prolonged antibiotic therapy. More recently, a similar
associations are for periodontal disease and S. aureus study in a medical ICU showed no improvement in overall
skin carriage, but respiratory infections, UTIs (including mortality or infection-related outcomes in patients given
ASB) and mucocutaneous carriage of C. albicans show no intensive insulin therapy, except for a lower death rate
consistent relationship. This includes a number of studies in patients whose ICU stay was ≥3 days [137]. Given
performed before the DCCT [4] and UKPDS [3] results these inconsistent results, the question of whether selected
were reported (in 1993 and 1998, respectively), when groups of critically ill patients will benefit from CII should
diabetic patients may not have had as good a glycaemic be addressed in further adequately powered multi-centre
control as in later years. prospective studies.

Hospital-acquired infections
Conclusion
Most of the data relating to hospital-acquired infections
in diabetes are from studies of post-operative wound Although various diabetes-specific in vitro defects in
infections, especially after cardiac surgery [123–132]. In innate and adaptive immunity have been found, their
one large prospective study [126], there was a 2.7-fold clinical relevance remains to be established, particularly

Copyright  2006 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2007; 23: 3–13.
DOI: 10.1002/dmrr
10 A. Y. Peleg et al.

in patients with at least moderate glycaemic control 11. Molenaar DM, Palumbo PJ, Wilson WR, Ritts RE Jr. Leukocyte
chemotaxis in diabetic patients and their nondiabetic first-
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